Comparative analysis of primary hepatocellular carcinoma with single and multiple lesions by iTRAQ-based quantitative proteomics.

PubMed

Xing, Xiaohua; Huang, Yao; Wang, Sen; Chi, Minhui; Zeng, Yongyi; Chen, Lihong; Li, Ling; Zeng, Jinhua; Lin, Minjie; Han, Xiao; Liu, Xiaolong; Liu, Jingfeng

2015-10-14

In clinical practices, the therapeutic outcomes and prognosis of hepatocellular carcinoma (HCC) patients with different tumor numbers after surgery are very different; however, the underlying mechanisms of the tumorigenesis and development of HCC with different tumor numbers are still not well understood. Here, we systematically compared the overall proteome profiles between the primary HCC with single and multiple lesions using iTRAQ-based quantitative proteomics approach. We identified that 107 and 330 proteins were dysregulated in HCC tissue with multiple lesions (MC group) and HCC tissue with a single lesion (SC group), compared with their non-cancerous tissue (MN and SN groups) respectively. The dysregulated proteins in MC group are concentrated in UBC signaling pathway and NFκB signaling pathway, but the dysregulated proteins in SC group are more concentrated in ERK signaling pathway and the NFκB signaling pathway. These information revealed that there might be different molecular mechanisms of the tumorigenesis and development of the HCC with single and multiple lesions. Furthermore, HSD17B13 were only down-regulated in MC group while HK2 were only up-regulated in SC group among these dysregulated proteins. Therefore, the protein HSD17B13 and HK2 might be potential biomarkers for the primary HCC with single and multiple lesions. Copyright © 2015 Elsevier B.V. All rights reserved.

Current status of liver diseases in Korea: hepatocellular carcinoma.

PubMed

Song, Il Han; Kim, Kyung Sik

2009-12-01

Primary liver cancer, most of which is hepatocellular carcinoma (HCC), is the third common leading cancer in Korea. During the last two decades, the incidence rate of primary liver cancer has shown a modest decrease, but its mortality rate has slightly increased. The incidence of HCC, according to age, peaks in the late sixth decade in men and in the early seventh decade in women. Hepatitis B virus (HBV) is the most important risk factor, which represents approximately 70% of all HCC, and hepatitis C virus (HCV) and alcohol are the next in order of major risk factors for the development of HCC in Korea. HBV-associated HCC occurs 10 years earlier than HCV-associated HCC due to a more prolonged exposure to HBV, which is vertically transmitted almost from HBsAg-positive mother in HBV-endemic area. National Cancer Control Institute, which was reorganized in 2005, is now working for several national projects such as National Cancer Registration Program, National R&D Program for Cancer Control and National Cancer Screening Program. International collaboration for the clinico-epidemiologic research would be needed to provide the specific measures for managing HCC in diverse etiologic situations. Finally, the mechanisms of hepatitis virus-associated hepatocellular carcinogenesis might be clarified to provide insights into the advanced therapeutic and preventive approaches for HCC in Korea, where the majority of HCC originate from chronic HBV and HCV infections.

Vitamin D and K signaling pathways in hepatocellular carcinoma.

PubMed

Louka, Manal L; Fawzy, Ahmed M; Naiem, Abdelrahman M; Elseknedy, Mustafa F; Abdelhalim, Ahmed E; Abdelghany, Mohamed A

2017-09-20

Hepatocellular carcinoma (HCC) is a primary liver malignancy, and is now the six most common in between malignancies. Early diagnosis of HCC with prompt treatment increases the opportunity of patients to survive. With the advances in understanding the molecular biology of HCC, new therapeutic strategies to treat HCC have emerged. There is a growing consensus that vitamins are important for the control of various cancers. Biochemical evidence clearly indicates that HCC cells are responsive to the inhibitory effect of vitamin D, vitamin D analogues and vitamin K. In this review, we summarize the mechanisms used by vitamin D and K to influence the development of HCC and the latest development of vitamin analogues for potential HCC therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Quantitative proteomic analysis for high-throughput screening of differential glycoproteins in hepatocellular carcinoma serum

PubMed Central

Gao, Hua-Jun; Chen, Ya-Jing; Zuo, Duo; Xiao, Ming-Ming; Li, Ying; Guo, Hua; Zhang, Ning; Chen, Rui-Bing

2015-01-01

Objective Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Novel serum biomarkers are required to increase the sensitivity and specificity of serum screening for early HCC diagnosis. This study employed a quantitative proteomic strategy to analyze the differential expression of serum glycoproteins between HCC and normal control serum samples. Methods Lectin affinity chromatography (LAC) was used to enrich glycoproteins from the serum samples. Quantitative mass spectrometric analysis combined with stable isotope dimethyl labeling and 2D liquid chromatography (LC) separations were performed to examine the differential levels of the detected proteins between HCC and control serum samples. Western blot was used to analyze the differential expression levels of the three serum proteins. Results A total of 2,280 protein groups were identified in the serum samples from HCC patients by using the 2D LC-MS/MS method. Up to 36 proteins were up-regulated in the HCC serum, whereas 19 proteins were down-regulated. Three differential glycoproteins, namely, fibrinogen gamma chain (FGG), FOS-like antigen 2 (FOSL2), and α-1,6-mannosylglycoprotein 6-β-N-acetylglucosaminyltransferase B (MGAT5B) were validated by Western blot. All these three proteins were up-regulated in the HCC serum samples. Conclusion A quantitative glycoproteomic method was established and proven useful to determine potential novel biomarkers for HCC. PMID:26487969

Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC).

PubMed

Srivastava, Jyoti; Robertson, Chadia L; Gredler, Rachel; Siddiq, Ayesha; Rajasekaran, Devaraja; Akiel, Maaged A; Emdad, Luni; Mas, Valeria; Mukhopadhyay, Nitai D; Fisher, Paul B; Sarkar, Devanand

2015-06-19

Non-thyroidal illness syndrome (NTIS), characterized by low serum 3,5,3'-triiodothyronine (T3) with normal l-thyroxine (T4) levels, is associated with malignancy. Decreased activity of type I 5'-deiodinase (DIO1), which converts T4 to T3, contributes to NTIS. T3 binds to thyroid hormone receptor, which heterodimerizes with retinoid X receptor (RXR) and regulates transcription of target genes, such as DIO1. NF-κB activation by inflammatory cytokines inhibits DIO1 expression. The oncogene astrocyte elevated gene-1 (AEG-1) inhibits RXR-dependent transcription and activates NF-κB. Here, we interrogated the role of AEG-1 in NTIS in the context of hepatocellular carcinoma (HCC). T3-mediated gene regulation was analyzed in human HCC cells, with overexpression or knockdown of AEG-1, and primary hepatocytes from AEG-1 transgenic (Alb/AEG-1) and AEG-1 knock-out (AEG-1KO) mice. Serum T3 and T4 levels were checked in Alb/AEG-1 mice and human HCC patients. AEG-1 and DIO1 levels in human HCC samples were analyzed by immunohistochemistry. AEG-1 inhibited T3-mediated gene regulation in human HCC cells and mouse hepatocytes. AEG-1 overexpression repressed and AEG-1 knockdown induced DIO1 expression. An inverse correlation was observed between AEG-1 and DIO1 levels in human HCC patients. Low T3 with normal T4 was observed in the sera of HCC patients and Alb/AEG-1 mice. Inhibition of co-activator recruitment to RXR and activation of NF-κB were identified to play a role in AEG-1-mediated down-regulation of DIO1. AEG-1 thus might play a role in NTIS associated with HCC and other cancers. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fu, Meili, E-mail: fumeilidrlinyi@tom.com; Wan, Fuqiang; Li, Zhengling

The aim of the present study is to investigate the potential anti-hepatocellular carcinoma (HCC) cell activity by 4SC-202, a novel class I HDAC inhibitor (HDACi). The associated signaling mechanisms were also analyzed. We showed that 4SC-202 treatment induced potent cytotoxic and proliferation–inhibitory activities against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, adding 4SC-202 in HCC cells activated mitochondrial apoptosis pathway, which was evidenced by mitochondrial permeability transition pore (mPTP) opening, cytochrome C cytosol release and caspase-3/-9 activation. Inhibition of this apoptosis pathway, by caspase-3/-9 inhibitors, mPTP blockers, or by shRNA-mediated knockdown of cyclophilin-D (Cyp-D,more » a key component of mPTP), significantly attenuated 4SC-202-induced HCC cell death and apoptosis. Reversely, over-expression of Cyp-D enhanced 4SC-202's sensitivity in HCC cells. Further studies showed that 4SC-202 induced apoptosis signal-regulating kinase 1 (ASK1) activation, causing it translocation to mitochondria and physical association with Cyp-D. This mitochondrial ASK1-Cyp-D complexation appeared required for mediating 4SC-202-induced apoptosis activation. ASK1 stable knockdown by targeted-shRNAs largely inhibited 4SC-202-induced mPTP opening, cytochrome C release, and following HCC cell apoptotic death. Together, we suggest that 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to potently inhibit human HCC cells. - Highlights: • 4SC-202 exerts potent anti-proliferative and cytotoxic activity against established/primary HCC cells. • SC-202-induced anti-HCC cell activity relies on caspase-dependent apoptosis activation. • 4SC-202 activates Cyp-D-dependent mitochondrial apoptosis pathway in HCC cells. • 4SC-202 activates ASK1 in HCC cells, causing it translocation to mitochondria. • Mitochondrial ASK1-Cyp-D complexation mediates 4SC-202's activity in HCC cells.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiang, Jianxin; Yu, Chao; Chen, Meiyuan

Hepatocellular carcinoma (HCC) is the most common cancer in the world especially in East Asia and Africa. Advanced stage, metastasis and frequent relapse are responsible for the poor prognosis of HCC. However, the precise mechanisms underlying HCC remained unclear. So it is urgent to identify the pathological processes and relevant molecules of HCC. TRIM37 is an E3 ligase and has been observed deregulated expression in various tumors. Recent studies of TRIM37 have implicated that TRIM37 played critical roles in cell proliferation and other processes. In the present study, we demonstrated that TRIM37 expression was notably up-regulated in HCC samples andmore » was associated with advanced stage and tumor volume, which all indicating the poor outcomes. We also found that TRIM37 could serve as an independent prognostic factor of HCC. During the course of in vitro and in vivo work, we showed that TRIM37 promoted HCC cells migration and metastasis by inducing EMT. Furthermore, we revealed that the effect of TRIM37 mediated EMT in HCC cells was achieved by the activation of Wnt/β-catenin signaling. These finding may provide insight into the understanding of TRIM37 as a novel critical factor of HCC and a candidate target for HCC treatment. - Highlights: • Highly expression of TRIM37 is found in HCC samples compared with nontumorous samples. • TRIM37 expression is correlated with advanced HCC stages and could be an independent prognostic factor. • TRIM37 promotes cell proliferation and metastasis. • We report an E3 ligase TRIM37 affects Wnt/β-catenin signaling.« less

Homeobox B9 is overexpressed in hepatocellular carcinomas and promotes tumor cell proliferation both in vitro and in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Fangyi; Dong, Lei, E-mail: dlleidong@126.com; Xing, Rong

2014-02-07

Highlights: • HOXB9 is overexpressed in human HCC samples. • HOXB9 over expression had shorter survival time than down expression. • HOXB9 stimulated the proliferation of HCC cells. • Activation of TGF-β1 contributes to HOXB9-induced proliferation in HCC cells. - Abstract: HomeoboxB9 (HOXB9), a nontransforming transcription factor that is overexpressed in multiple tumor types, alters tumor cell fate and promotes tumor progression. However, the role of HOXB9 in hepatocellular carcinoma (HCC) development has not been well studied. In this paper, we found that HOXB9 is overexpressed in human HCC samples. We investigated HOXB9 expression and its prognostic value for HCC.more » HCC surgical tissue samples were taken from 89 HCC patients. HOXB9 overexpression was observed in 65.2% of the cases, and the survival analysis showed that the HOXB9 overexpression group had significantly shorter overall survival time than the HOXB9 downexpression group. The ectopic expression of HOXB9 stimulated the proliferation of HCC cells; whereas the knockdown of HOXB9 produced an opposite effect. HOXB9 also modulated the tumorigenicity of HCC cells in vivo. Moreover, we found that the activation of TGF-β1 contributes to HOXB9-induced proliferation activities. The results provide the first evidence that HOXB9 is a critical regulator of tumor growth factor in HCC.« less

Global gene expression associated with hepatocarcinogenesis in adult male mice induced by in utero arsenic exposure.

PubMed

Liu, Jie; Xie, Yaxiong; Ducharme, Danica M K; Shen, Jun; Diwan, Bhalchandra A; Merrick, B Alex; Grissom, Sherry F; Tucker, Charles J; Paules, Richard S; Tennant, Raymond; Waalkes, Michael P

2006-03-01

Our previous work has shown that exposure to inorganic arsenic in utero produces hepatocellular carcinoma (HCC) in adult male mice. To explore further the molecular mechanisms of transplacental arsenic hepatocarcinogenesis, we conducted a second arsenic transplacental carcinogenesis study and used a genomewide microarray to profile arsenic-induced aberrant gene expression more extensively. Briefly, pregnant C3H mice were given drinking water containing 85 ppm arsenic as sodium arsenite or unaltered water from days 8 to 18 of gestation. The incidence of HCC in adult male offspring was increased 4-fold and tumor multiplicity 3-fold after transplacental arsenic exposure. Samples of normal liver and liver tumors were taken at autopsy for genomic analysis. Arsenic exposure in utero resulted in significant alterations (p < 0.001) in the expression of 2,010 genes in arsenic-exposed liver samples and in the expression of 2,540 genes in arsenic-induced HCC. Ingenuity Pathway Analysis revealed that significant alterations in gene expression occurred in a number of biological networks, and Myc plays a critical role in one of the primary networks. Real-time reverse transcriptase-polymerase chain reaction and Western blot analysis of selected genes/proteins showed > 90% concordance. Arsenic-altered gene expression included activation of oncogenes and HCC biomarkers, and increased expression of cell proliferation-related genes, stress proteins, and insulin-like growth factors and genes involved in cell-cell communications. Liver feminization was evidenced by increased expression of estrogen-linked genes and altered expression of genes that encode gender-related metabolic enzymes. These novel findings are in agreement with the biology and histology of arsenic-induced HCC, thereby indicating that multiple genetic events are associated with transplacental arsenic hepatocarcinogenesis.

Identification of mTOR as a primary resistance factor of the IAP antagonist AT406 in hepatocellular carcinoma cells

PubMed Central

Wu, Shao-Feng; Zhao, Yi-Lin; Liu, Ping-Guo; Yin, Zhen-Yu

2017-01-01

Dysregulation of inhibitor of apoptosis (IAP) proteins (IAPs) in hepatocellular carcinoma (HCC) is often associated with poor prognosis. Here we showed that AT406, an IAP antagonist, was cytotoxic and pro-apoptotic to both established (HepG2, SMMC-7721 lines) and primary HCC cells. Activation of mTOR could be a key resistance factor of AT406 in HCC cells. mTOR inhibition (by OSI-027), kinase-dead mutation or knockdown remarkably enhanced AT406-induced lethality in HCC cells. Reversely, forced-activation of mTOR by adding SC79 or exogenous expressing a constitutively active S6K1 (T389E) attenuated AT406-induced cytotoxicity against HCC cells. We showed that AT406 induced degradation of IAPs (cIAP-1 and XIAP), but didn't affect another anti-apoptosis protein Mcl-1. Co-treatment of OSI-027 caused simultaneous Mcl-1 downregulation to overcome AT406's resistance. Significantly, shRNA knockdown of Mcl-1 remarkably facilitated AT406-induced apoptosis in HCC cells. In vivo, AT406 oral administration suppressed HepG2 tumor growth in nude mice. Its activity was potentiated with co-administration of OSI-027. We conclude that mTOR could be a key resistance factor of AT406 in HCC cells. PMID:28036295

Identification of mTOR as a primary resistance factor of the IAP antagonist AT406 in hepatocellular carcinoma cells.

PubMed

Zhen, Mao-Chuan; Wang, Fu-Qiang; Wu, Shao-Feng; Zhao, Yi-Lin; Liu, Ping-Guo; Yin, Zhen-Yu

2017-02-07

Dysregulation of inhibitor of apoptosis (IAP) proteins (IAPs) in hepatocellular carcinoma (HCC) is often associated with poor prognosis. Here we showed that AT406, an IAP antagonist, was cytotoxic and pro-apoptotic to both established (HepG2, SMMC-7721 lines) and primary HCC cells. Activation of mTOR could be a key resistance factor of AT406 in HCC cells. mTOR inhibition (by OSI-027), kinase-dead mutation or knockdown remarkably enhanced AT406-induced lethality in HCC cells. Reversely, forced-activation of mTOR by adding SC79 or exogenous expressing a constitutively active S6K1 (T389E) attenuated AT406-induced cytotoxicity against HCC cells. We showed that AT406 induced degradation of IAPs (cIAP-1 and XIAP), but didn't affect another anti-apoptosis protein Mcl-1. Co-treatment of OSI-027 caused simultaneous Mcl-1 downregulation to overcome AT406's resistance. Significantly, shRNA knockdown of Mcl-1 remarkably facilitated AT406-induced apoptosis in HCC cells. In vivo, AT406 oral administration suppressed HepG2 tumor growth in nude mice. Its activity was potentiated with co-administration of OSI-027. We conclude that mTOR could be a key resistance factor of AT406 in HCC cells.

Elevated red blood cell distribution width is associated with liver function tests in patients with primary hepatocellular carcinoma.

PubMed

Wei, Ting-Ting; Tang, Qing-Qin; Qin, Bao-Dong; Ma, Ning; Wang, Li-Li; Zhou, Lin; Zhong, Ren-Qian

2016-11-25

Red blood cell distribution width (RDW), a routinely tested parameter of the complete blood count (CBC), has been reported to be increased in various cancers and correlated with the patients' clinical characteristics. However, the significance of RDW in primary hepatocellular carcinoma (pHCC) is largely unknown. The aim of this study was to evaluate the associations between RDW and the clinical characteristics of pHCC patients. Medical records of 110 treatment-naive pHCC patients were retrospectively reviewed. Their clinical characteristics on admission, including RDW, liver function tests and tumor stage, were extracted, and their relationships were analyzed using Spearman correlation and Kruskal-Wallis test. Sixty-eight healthy individuals were set as controls. RDW was significantly increased in pHCC patients and correlated with the liver function tests. However, no correlation between RDW and tumor stage was found. RDW may be used to assess the liver function, but not the tumor stage in pHCC patients.

MicroRNAs and liver cancer associated with iron overload: Therapeutic targets unravelled

PubMed Central

Greene, Catherine M; Varley, Robert B; Lawless, Matthew W

2013-01-01

Primary liver cancer is a global disease that is on the increase. Hepatocellular carcinoma (HCC) accounts for most primary liver cancers and has a notably low survival rate, largely attributable to late diagnosis, resistance to treatment, tumour recurrence and metastasis. MicroRNAs (miRNAs/miRs) are regulatory RNAs that modulate protein synthesis. miRNAs are involved in several biological and pathological processes including the development and progression of HCC. Given the poor outcomes with current HCC treatments, miRNAs represent an important new target for therapeutic intervention. Several studies have demonstrated their role in HCC development and progression. While many risk factors underlie the development of HCC, one process commonly altered is iron homeostasis. Iron overload occurs in several liver diseases associated with the development of HCC including Hepatitis C infection and the importance of miRNAs in iron homeostasis and hepatic iron overload is well characterised. Aberrant miRNA expression in hepatic fibrosis and injury response have been reported, as have dysregulated miRNA expression patterns affecting cell cycle progression, evasion of apoptosis, invasion and metastasis. In 2009, miR-26a delivery was shown to prevent HCC progression, highlighting its therapeutic potential. Several studies have since investigated the clinical potential of other miRNAs with one drug, Miravirsen, currently in phase II clinical trials. miRNAs also have potential as biomarkers for the diagnosis of HCC and to evaluate treatment efficacy. Ongoing studies and clinical trials suggest miRNA-based treatments and diagnostic methods will have novel clinical applications for HCC in the coming years, yielding improved HCC survival rates and patient outcomes. PMID:23983424

[The Clinical Significance of Serum Alpha-fetoprotein in Diagnosing Hepatocellular Carcinoma in a Health Screening Population].

PubMed

Ko, Young Sun; Bae, Joo Hwan; Sinn, Dong Hyun; Gwak, Geum Youn; Kang, Wonseok; Paik, Yong Han; Choi, Moon Seok; Lee, Joon Hyeok; Koh, Kwang Cheol; Paik, Seung Woon

2017-04-25

Serum alpha-fetoprotein (AFP) measurement is commonly included in a health check-up program in Korea. However, its benefits remain uncertain. We analyzed whether AFP measurement should be included in a general health check-up program to screen for hepatocellular carcinoma (HCC). A total of 36,552 adults aged 18 years or older-who participated in a routine health examination including AFP determination between January 2009 and December 2009 at the Health Promotion Center, Samsung Medical Center, South Korea-were analyzed. High risk of HCC was defined as positivity for hepatitis B surface antigen, anti-hepatitis C virus antibody or having liver cirrhosis. AFP level >10 ng/mL was observed in 27 participants (0.1%) and primary liver cancer was diagnosed in 9 patients (6 HCC and 3 cholangiocarcinoma). Among 1,619 participants with high risk factors of HCC, AFP level >10 ng/mL was observed in 16 participants, of which, 4 diagnoses were made. Sensitivity, specificity, positive predictive value, and negative predictive value of AFP for HCC was 0.66, 0.99, 0.25 and 0.99, respectively, for high risk participants. Among 34,933 participants without risk factors for HCC, 11 patients (<0.1%) showed elevated AFP levels above 10 ng/mL, and no case was diagnosed with primary liver cancer during a median follow-up period of 36 months (range: 0-48 months). AFP elevation was rare in participants without risk factors for HCC, and was unable to screen for HCC in this population. We discourage routine AFP measurements for asymptomatic adults without risk factors of HCC.

Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database.

PubMed

Welzel, Tania M; Graubard, Barry I; Zeuzem, Stefan; El-Serag, Hashem B; Davila, Jessica A; McGlynn, Katherine A

2011-08-01

Incidence rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have increased in the United States. Metabolic syndrome is recognized as a risk factor for HCC and a postulated one for ICC. The magnitude of risk, however, has not been investigated on a population level in the United States. We therefore examined the association between metabolic syndrome and the development of these cancers. All persons diagnosed with HCC and ICC between 1993 and 2005 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. For comparison, a 5% sample of individuals residing in the same regions as the SEER registries of the cases was selected. The prevalence of metabolic syndrome as defined by the U.S. National Cholesterol Education Program Adult Treatment Panel III criteria, and other risk factors for HCC (hepatitis B virus, hepatitis C virus, alcoholic liver disease, liver cirrhosis, biliary cirrhosis, hemochromatosis, Wilson's disease) and ICC (biliary cirrhosis, cholangitis, cholelithiasis, choledochal cysts, hepatitis B virus, hepatitis C virus, alcoholic liver disease, cirrhosis, inflammatory bowel disease) were compared among persons who developed cancer and those who did not. Logistic regression was used to calculate odds ratios and 95% confidence intervals. The inclusion criteria were met by 3649 HCC cases, 743 ICC cases, and 195,953 comparison persons. Metabolic syndrome was significantly more common among persons who developed HCC (37.1%) and ICC (29.7%) than the comparison group (17.1%, P<0.0001). In adjusted multiple logistic regression analyses, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio=2.13; 95% confidence interval=1.96-2.31, P<0.0001) and ICC (odds ratio=1.56; 95% confidence interval=1.32-1.83, P<0.0001). Metabolic syndrome is a significant risk factor for development of HCC and ICC in the general U.S. population. Copyright © 2011 American Association for the Study of Liver Diseases.

Hepatitis B and Hepatitis C Infection Biomarkers and TP53 Mutations in Hepatocellular Carcinomas from Colombia

PubMed Central

Navas, Maria-Cristina; Suarez, Iris; Carreño, Andrea; Uribe, Diego; Rios, Wilson Alfredo; Cortes-Mancera, Fabian; Martel, Ghyslaine; Vieco, Beatriz; Lozano, Diana; Jimenez, Carlos; Gouas, Doriane; Osorio, German; Hoyos, Sergio; Restrepo, Juan Carlos; Correa, Gonzalo; Jaramillo, Sergio; Lopez, Rocio; Bravo, Luis Eduardo; Arbelaez, Maria Patricia; Scoazec, Jean-Yves; Abedi-Ardekani, Behnoush; Santella, Regina M.; Chemin, Isabelle; Hainaut, Pierre

2011-01-01

Hepatocellular Carcinoma (HCC) is a leading cause of cancer-related death worldwide. Globally, the most important HCC risk factors are Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV), chronic alcoholism, and dietary exposure to aflatoxins. We have described the epidemiological pattern of 202 HCC samples obtained from Colombian patients. Additionally we investigated HBV/HCV infections and TP53 mutations in 49 of these HCC cases. HBV biomarkers were detected in 58.1% of the cases; HBV genotypes F and D were characterized in three of the samples. The HCV biomarker was detected in 37% of the samples while HBV/HCV coinfection was found in 19.2%. Among TP53 mutations, 10.5% occur at the common aflatoxin mutation hotspot, codon 249. No data regarding chronic alcoholism was available from the cases. In conclusion, in this first study of HCC and biomarkers in a Colombian population, the main HCC risk factor was HBV infection. PMID:22114738

Liver Full Reference Set Application: Hiro Yamada - Wako (2011) — EDRN Public Portal

Cancer.gov

Wako has received new 510(k) clearance for Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and Des-gamma-carboxy prothrombin (DCP) tests on an innovative μTASWako i30 analyzer from FDA. The AFP-L3 and DCP assayed on an older platform LiBASys have been cleared with indication of use for risk assessment of hepatocellular carcinoma (HCC) in patient at risk for the liver malignancy. Wako believes that early detection of HCC is critical for improving HCC patient outcome. Therefore, Wako is currently seeking collaborative opportunities to retrospectively measure clinical samples using the AFP-L3 and DCP for further determining of effectiveness of the HCC biomarkers in early detection which are collected prospectively during HCC surveillance. The Reference Sample Set in the EDRN biorepository are well characterized and studied. Access to these samples would allow Wako to quickly determine the clinical effectiveness of AFP-L3 and DCP in detecting early HCC

Tumor-adjacent tissue co-expression profile analysis reveals pro-oncogenic ribosomal gene signature for prognosis of resectable hepatocellular carcinoma.

PubMed

Grinchuk, Oleg V; Yenamandra, Surya P; Iyer, Ramakrishnan; Singh, Malay; Lee, Hwee Kuan; Lim, Kiat Hon; Chow, Pierce Kah-Hoe; Kuznetsov, Vladamir A

2018-01-01

Currently, molecular markers are not used when determining the prognosis and treatment strategy for patients with hepatocellular carcinoma (HCC). In the present study, we proposed that the identification of common pro-oncogenic pathways in primary tumors (PT) and adjacent non-malignant tissues (AT) typically used to predict HCC patient risks may result in HCC biomarker discovery. We examined the genome-wide mRNA expression profiles of paired PT and AT samples from 321 HCC patients. The workflow integrated differentially expressed gene selection, gene ontology enrichment, computational classification, survival predictions, image analysis and experimental validation methods. We developed a 24-ribosomal gene-based HCC classifier (RGC), which is prognostically significant in both PT and AT. The RGC gene overexpression in PT was associated with a poor prognosis in the training (hazard ratio = 8.2, P = 9.4 × 10 -6 ) and cross-cohort validation (hazard ratio = 2.63, P = 0.004) datasets. The multivariate survival analysis demonstrated the significant and independent prognostic value of the RGC. The RGC displayed a significant prognostic value in AT of the training (hazard ratio = 5.0, P = 0.03) and cross-validation (hazard ratio = 1.9, P = 0.03) HCC groups, confirming the accuracy and robustness of the RGC. Our experimental and bioinformatics analyses suggested a key role for c-MYC in the pro-oncogenic pattern of ribosomal biogenesis co-regulation in PT and AT. Microarray, quantitative RT-PCR and quantitative immunohistochemical studies of the PT showed that DKK1 in PT is the perspective biomarker for poor HCC outcomes. The common co-transcriptional pattern of ribosome biogenesis genes in PT and AT from HCC patients suggests a new scalable prognostic system, as supported by the model of tumor-like metabolic redirection/assimilation in non-malignant AT. The RGC, comprising 24 ribosomal genes, is introduced as a robust and reproducible prognostic model for stratifying HCC patient risks. The adjacent non-malignant liver tissue alone, or in combination with HCC tissue biopsy, could be an important target for developing predictive and monitoring strategies, as well as evidence-based therapeutic interventions, that aim to reduce the risk of post-surgery relapse in HCC patients. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Inhibitory effects of blockage of intermediate conductance Ca(2+)-activated K (+) channels on proliferation of hepatocellular carcinoma cells.

PubMed

Yang, Xiao-wei; Liu, Jin-wen; Zhang, Ru-chao; Yin, Qian; Shen, Wen-zhuang; Yi, Ji-lin

2013-02-01

The roles of intermediate conductance Ca(2+)-activated K(+) channel (IKCa1) in the pathogenesis of hepatocellular carcinoma (HCC) were investigated. Immunohistochemistry and Western blotting were used to detect the expression of IKCa1 protein in 50 HCC and 20 para-carcinoma tissue samples. Real-time PCR was used to detect the transcription level of IKCa1 mRNA in 13 HCC and 11 para-carcinoma tissue samples. The MTT assay was used to measure the function of IKCa1 in human HCC cell line HepG2 in vitro. TRAM-34, a specific blocker of IKCa1, was used to intervene with the function of IKCa1. As compared with para-carcinoma tissue, an over-expression of IKCa1 protein was detected in HCC tissue samples (P<0.05). The mRNA expression level of IKCa1 in HCC tissues was 2.17 times higher than that in para-carcinoma tissues. The proliferation of HepG2 cells was suppressed by TRAM-34 (0.5, 1.0, 2.0 and 4.0 μmol/L) in vitro (P<0.05). Our results suggested that IKCa1 may play a role in the proliferation of human HCC, and IKCa1 blockers may represent a potential therapeutic strategy for HCC.

Quantitative Tissue Proteomics Analysis Reveals Versican as Potential Biomarker for Early-Stage Hepatocellular Carcinoma.

PubMed

Naboulsi, Wael; Megger, Dominik A; Bracht, Thilo; Kohl, Michael; Turewicz, Michael; Eisenacher, Martin; Voss, Don Marvin; Schlaak, Jörg F; Hoffmann, Andreas-Claudius; Weber, Frank; Baba, Hideo A; Meyer, Helmut E; Sitek, Barbara

2016-01-04

Hepatocellular carcinoma (HCC) is one of the most aggressive tumors, and the treatment outcome of this disease is improved when the cancer is diagnosed at an early stage. This requires biomarkers allowing an accurate and early tumor diagnosis. To identify potential markers for such applications, we analyzed a patient cohort consisting of 50 patients (50 HCC and 50 adjacent nontumorous tissue samples as controls) using two independent proteomics approaches. We performed label-free discovery analysis on 19 HCC and corresponding tissue samples. The data were analyzed considering events known to take place in early events of HCC development, such as abnormal regulation of Wnt/b-catenin and activation of receptor tyrosine kinases (RTKs). 31 proteins were selected for verification experiments. For this analysis, the second set of the patient cohort (31 HCC and corresponding tissue samples) was analyzed using selected (multiple) reaction monitoring (SRM/MRM). We present the overexpression of ATP-dependent RNA helicase (DDX39), Fibulin-5 (FBLN5), myristoylated alanine-rich C-kinase substrate (MARCKS), and Serpin H1 (SERPINH1) in HCC for the first time. We demonstrate Versican core protein (VCAN) to be significantly associated with well differentiated and low-stage HCC. We revealed for the first time the evidence of VCAN as a potential biomarker for early-HCC diagnosis.

Overexpression of p42.3 promotes cell growth and tumorigenicity in hepatocellular carcinoma

PubMed Central

Sun, Wei; Dong, Wei-Wei; Mao, Lin-Lin; Li, Wen-Mei; Cui, Jian-Tao; Xing, Rui; Lu, You-Yong

2013-01-01

AIM: To investigate the association of p42.3 expression with clinicopathological characteristics and the biological function of p42.3 in human hepatocellular carcinoma (HCC). METHODS: We used reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR and western blotting to detect p42.3 mRNA and protein expression in hepatic cell lines. We examined primary HCC samples and matched adjacent normal tissue by immunohistochemistry to investigate the correlation between p42.3 expression and clinicopathological features. HepG2 cells were transfected with a pIRES2-EGFP-p42.3 expression vector to examine the function of the p42.3 gene. Transfected cells were analyzed for their viability and malignant transformation abilities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, and tumorigenicity assay in nude mice. RESULTS: p42.3 is differentially expressed in primary HCC tumors and cell lines. Approximately 69.6% (96/138) of cells were p42.3-positive in hepatic tumor tissues, while 30.7% (35/114) were p42.3-positive in tumor-adjacent normal tissues. Clinicopathological characteristics of the HCC specimens revealed a significant correlation between p42.3 expression and tumor differentiation (P = 0.031). However, p42.3 positivity was not related to tumor tumor-node-metastasis classification, hepatitis B virus status, or hepatoma type. Regarding p42.3 overexpression in stably transfected HepG2 cells, we discovered significant enhancement of cancer cell growth and colony formation in vitro, and significantly enhanced tumorigenicity in nude mice. Western blot analysis of cell cycle proteins revealed that enhanced p42.3 levels promote upregulation of proliferating cell nuclear antigen, cyclin B1 and mitotic arrest deficient 2. CONCLUSION: p42.3 promotes tumorigenicity and tumor growth in HCC and may be a potential target for future clinical cancer therapeutics. PMID:23704824

Hair cortisol in relation to acute and post-traumatic stress symptoms in children and adolescents.

PubMed

Straub, Joana; Klaubert, Lena Marie; Schmiedgen, Susann; Kirschbaum, Clemens; Goldbeck, Lutz

2017-11-01

We report on the preliminary results of two independent studies that (1) compare the hair cortisol concentrations (HCC) of healthy controls with patients displaying post-traumatic stress symptoms (PTSS, study 1+2), (2) investigate whether pre-trauma HCC are predictive for the development of acute stress symptoms (ASS) and PTSS (study 1) and (3) determine whether HCC correlate with PTSS in a clinical sample of children (study 2). In study 1, the clinical symptoms of 35 minors were examined one (T1) and seven weeks (T2) after surgery following an accident. Hair samples were taken after the accident that reflect cortisol secretion over the past three months before the accident (healthy controls). In study 2, HCC and PTSS symptoms were cross-sectionally assessed in 22 minors who had experienced a psychological trauma. The HCC of patients with PTSS were lower than the HCC of healthy controls (study 1+2). Secondary analyses showed that HCC were significantly lower in male PTSS patients than in male healthy controls, whereas the HCC in females were comparably low in both groups. Pre-trauma HCC did not predict the total ASS and PTSS scores (study 1) and HCC were not directly related to the total PTSS scores (study 2).

Management of hepatocellular carcinoma: Predictive value of immunohistochemical markers for postoperative survival

PubMed Central

Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Mei

2015-01-01

Hepatocellular carcinoma (HCC) accounts for over 90% of all primary liver cancers. With an ever increasing incidence trend year by year, it has become the third most common cause of death from cancer worldwide. Hepatic resection is generally considered to be one of the most effective therapies for HCC patients, however, there is a high risk of recurrence in postoperative HCC. In clinical practice, there exists an urgent need for valid prognostic markers to identify patients with prognosis, hence the importance of studies on prognostic markers in improving the prediction of HCC prognosis. This review focuses on the most promising immunohistochemical prognostic markers in predicting the postoperative survival of HCC patients. PMID:25624992

Correlation between smoking habit and surgical outcomes on viral-associated hepatocellular carcinomas

PubMed Central

Kai, Keita; Komukai, Sho; Koga, Hiroki; Yamaji, Koutaro; Ide, Takao; Kawaguchi, Atsushi; Aishima, Shinichi; Noshiro, Hirokazu

2018-01-01

AIM To investigate the association between smoking habits and surgical outcomes in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) (B-HCC) and hepatitis C virus (HCV)-related HCC (C-HCC) and clarify the clinicopathological features associated with smoking status in B-HCC and C-HCC patients. METHODS We retrospectively examined the cases of the 341 consecutive patients with viral-associated HCC (C-HCC, n = 273; B-HCC, n = 68) who underwent curative surgery for their primary lesion. We categorized smoking status at the time of surgery into never, ex- and current smoker. We analyzed the B-HCC and C-HCC groups’ clinicopathological features and surgical outcomes, i.e., disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS). Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. We also performed subset analyses in both patient groups comparing the current smokers to the other patients. RESULTS The multivariate analysis in the C-HCC group revealed that current-smoker status was significantly correlated with both OS (P = 0.0039) and DSS (P = 0.0416). In the B-HCC patients, no significant correlation was observed between current-smoker status and DFS, OS, or DSS in the univariate or multivariate analyses. The subset analyses comparing the current smokers to the other patients in both the C-HCC and B-HCC groups revealed that the current smokers developed HCC at significantly younger ages than the other patients irrespective of viral infection status. CONCLUSION A smoking habit is significantly correlated with the overall and disease-specific survivals of patients with C-HCC. In contrast, the B-HCC patients showed a weak association between smoking status and surgical outcomes. PMID:29358882

Correlation between smoking habit and surgical outcomes on viral-associated hepatocellular carcinomas.

PubMed

Kai, Keita; Komukai, Sho; Koga, Hiroki; Yamaji, Koutaro; Ide, Takao; Kawaguchi, Atsushi; Aishima, Shinichi; Noshiro, Hirokazu

2018-01-07

To investigate the association between smoking habits and surgical outcomes in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) (B-HCC) and hepatitis C virus (HCV)-related HCC (C-HCC) and clarify the clinicopathological features associated with smoking status in B-HCC and C-HCC patients. We retrospectively examined the cases of the 341 consecutive patients with viral-associated HCC (C-HCC, n = 273; B-HCC, n = 68) who underwent curative surgery for their primary lesion. We categorized smoking status at the time of surgery into never, ex- and current smoker. We analyzed the B-HCC and C-HCC groups' clinicopathological features and surgical outcomes, i.e ., disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS). Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. We also performed subset analyses in both patient groups comparing the current smokers to the other patients. The multivariate analysis in the C-HCC group revealed that current-smoker status was significantly correlated with both OS ( P = 0.0039) and DSS ( P = 0.0416). In the B-HCC patients, no significant correlation was observed between current-smoker status and DFS, OS, or DSS in the univariate or multivariate analyses. The subset analyses comparing the current smokers to the other patients in both the C-HCC and B-HCC groups revealed that the current smokers developed HCC at significantly younger ages than the other patients irrespective of viral infection status. A smoking habit is significantly correlated with the overall and disease-specific survivals of patients with C-HCC. In contrast, the B-HCC patients showed a weak association between smoking status and surgical outcomes.

Failure of Chemotherapy in Hepatocellular Carcinoma Due to Impaired and Dysregulated Primary Liver Drug Metabolizing Enzymes and Drug Transport Proteins: What to Do?

PubMed

Ul Islam, Salman; Ahmed, Muhammad Bilal; Shehzad, Adeeb; Ul-Islam, Mazhar; Lee, Young Sup

2018-05-28

Most of the drugs are metabolized in the liver by the action of drug metabolizing enzymes. In hepatocellular carcinoma (HCC), primary drug metabolizing enzymes are severely dysregulated, leading to failure of chemotherapy. Sorafenib is the only standard systemic drug available, but it still presents certain limitations, and much effort is required to understand who is responsive and who is refractory to the drug. Preventive and therapeutic approaches other than systemic chemotherapy include vaccination, chemoprevention, liver transplantation, surgical resection, and locoregional therapies. This review details the dysregulation of primary drug metabolizing enzymes and drug transport proteins of the liver in HCC and their influence on chemotherapeutic drugs. Furthermore, it emphasizes the adoption of safe alternative therapeutic strategies to chemotherapy. The future of HCC treatment should emphasize the understanding of resistance mechanisms and the finding of novel, safe, and efficacious therapeutic strategies, which will surely benefit patients affected by advanced HCC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Serum anti-Ku86 is a potential biomarker for early detection of hepatitis C virus-related hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nomura, Fumio, E-mail: fnomura@faculty.chiba-u.jp; Sogawa, Kazuyuki; Noda, Kenta

Highlights: Black-Right-Pointing-Pointer Overexpression of Ku86 in human liver cancer was shown by immunohistochemistry. Black-Right-Pointing-Pointer Serum anti-Ku86 was significantly elevated in early hepatocellular carcinoma. Black-Right-Pointing-Pointer Anti-Ku86 may be more sensitive than the conventional markers for early detection. Black-Right-Pointing-Pointer Serum anti-Ku86 significantly decreased after surgical resection of liver tumors. Black-Right-Pointing-Pointer Elevation of serum anti-Ku86 in other non-liver solid tumors was minimal. -- Abstract: Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is one of the most common cancers worldwide and the third most common cause of cancer-related death. Imaging studies including ultrasound and computed tomography are recommended for early detectionmore » of HCC, but they are operator dependent, costly and involve radiation. Therefore, there is a need for simple and sensitive serum markers for the early detection of hepatocellular carcinoma (HCC). In our recent proteomic studies, a number of proteins overexpressed in HCC tissues were identified. We thought if the serum autoantibodies to these overexpressed proteins were detectable in HCC patients. Of these proteins, we focused on Ku86, a nuclear protein involved in multiple biological processes and aimed to assess the diagnostic value of serum anti-Ku86 in the early detection of HCC. Serum samples were obtained prior to treatment from 58 consecutive patients with early or relatively early hepatitis C virus (HCV)-related HCC and 137 patients with HCV-related liver cirrhosis without evidence of HCC. Enzyme immunoassays were used to measure serum levels of autoantibodies. Serum levels of anti-Ku86 antibodies were significantly elevated in HCC patients compared to those in liver cirrhosis patients (0.41 {+-} 0.28 vs. 0.18 {+-} 0.08 Abs at 450 nm, P < 0001). Setting the cut-off level to give 90% specificity, anti-Ku86 was positive in 60.7% of stage I solitary tumor <2 cm in diameter, whereas the sensitivities of alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II) were 17.8% and 21.4%, respectively. The results of ROC analyses indicated the better performance of anti-Ku86 for early detection of HCC. Serum anti-Ku86 levels decreased after surgical resection of the tumors in the 12 HCC cases tested, Elevation of anti-Ku86 in solid tumors other than liver was minimal. Serum anti-Ku86 is a potential biomarker for early detection of HCV-related HCC. Further studies in a larger number of HCC patients with various etiologies are needed to further evaluate the diagnostic and pathophysiological roles of elevation of serum anti-Ku86 in early HCC.« less

Long non-coding RNA UBE2CP3 enhances HCC cell secretion of VEGFA and promotes angiogenesis by activating ERK1/2/HIF-1α/VEGFA signalling in hepatocellular carcinoma.

PubMed

Lin, Jinduan; Cao, Shunwang; Wang, Yu; Hu, Yanwei; Liu, Hongwei; Li, Jiehua; Chen, Jing; Li, Pan; Liu, Jumei; Wang, Qian; Zheng, Lei

2018-06-04

Angiogenesis is considered as an important process in the development of malignancies and is associated with cancer progression and metastasis. Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and is recognized as a typical angiogenic tumor. Thus, it is of great importance to study the underlying mechanism of angiogenesis in HCC. The long non-coding RNA (lncRNA) ubiquitin conjugating enzyme E2C pseudogene 3 (UBE2CP3) has been reported as an oncogene that promotes tumor metastasis in HCC. However, the role and underlying mechanisms of UBE2CP3 in HCC angiogenesis are still unclear. We measured the expression levels of UBE2CP3 by in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) in HCC patient samples. We also concomitantly used CD31/PAS double-staining to measure endothelial vessel (EV) density and used qRT-PCR to measure the CD31 mRNA level. HepG2 and SMMC-7721 cells were transfected with Lv-UBE2CP3 or Sh-UBE2CP3 virus to obtain stably over-expressing or knocking-down UBE2CP3 cell lines. The indirect effects of UBE2CP3 on ECs were studied by establishing a co-culture system using Transwell chambers with a 0.4-μm pore size. HCC cells and ECs in the co-culture system were separated, but the cytokines and growth factors were able to communicate with each other. Following exposed to HCC cells, ECs were collected for functional studies. Finally, we studied the function of UBE2CP3 in vivo by chick embryo chorioallantoic membrane (CAM) angiogenesis assays and nude mouse tumorigenicity assays. In this study, we found that UBE2CP3 expression was higher in HCC tissues than in para-tumor tissues and was up-regulated in tissues with high EV density. Functionally, we found that in the co-culture systems, HCC cells overexpressing UBE2CP3 promoted HUVEC proliferation, migration and tube formation via the activation of ERK/HIF-1α/p70S6K/VEGFA signalling, increasing the level of VEGFA in HCC cell supernatant. In addition, the opposite results appeared when the expression of UBE2CP3 in HCC cells was knocked down. Consistent with these results, CAM angiogenesis assays and nude mouse tumorigenicity assays showed that UBE2CP3 expression up-regulated EV density in vivo. Our study suggests that UBE2CP3 can enhance the interaction between HCC tumor cells and HUVECs and promote HCC tumorigenicity by facilitating angiogenesis.

Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence.

PubMed

Reyes, J D; Carr, B; Dvorchik, I; Kocoshis, S; Jaffe, R; Gerber, D; Mazariegos, G V; Bueno, J; Selby, R

2000-06-01

To describe our experience with total hepatectomy and liver transplantation as treatment for primary hepatoblastoma (HBL) and hepatocellular carcinoma (HCC) in children. A retrospective analysis of the perioperative course of 31 children with unresectable primary HBL (n = 12) and HCC (n = 19) who underwent transplantation between May 1989 and December 1998. Systemic (n = 18) and intraarterial (n = 7) neoadjuvant chemotherapy were administered; follow-up ranged from 1 to 185 months. For HBL, 1-year, 3-year, and 5-year posttransplantation survival rates were 92%, 92%, and 83%, respectively. Intravenous invasion, positive hilar lymph nodes, and contiguous spread did not have a significant adverse effect on outcome; distant metastasis was responsible for 2 deaths. Intraarterial chemotherapy was effective in all patients treated. For HCC, the overall 1-year, 3-year, and 5-year disease-free survival rates were 79%, 68%, and 63%, respectively. Vascular invasion, distant metastases, lymph node involvement, tumor size, and gender were significant risk factors for recurrence. Intraarterial chemotherapy was effective in 1 of 3 patients. Six patients died of recurrent HCC, and 3 deaths were unrelated to recurrent tumor. Liver transplantation for unresectable HBL and HCC can be curative. Risk factors for recurrence were significant only for HCC, with more advanced stages amenable to cure in the HBL group.

Deregulation of RB1 expression by loss of imprinting in human hepatocellular carcinoma.

PubMed

Anwar, Sumadi Lukman; Krech, Till; Hasemeier, Britta; Schipper, Elisa; Schweitzer, Nora; Vogel, Arndt; Kreipe, Hans; Lehmann, Ulrich

2014-08-01

The tumour suppressor gene RB1 is frequently silenced in many different types of human cancer, including hepatocellular carcinoma (HCC). However, mutations of the RB1 gene are relatively rare in HCC. A systematic screen for the identification of imprinted genes deregulated in human HCC revealed that RB1 shows imprint abnormalities in a high proportion of primary patient samples. Altogether, 40% of the HCC specimens (16/40) showed hyper- or hypomethylation at the CpG island in intron 2 of the RB1 gene. Re-analysis of publicly available genome-wide DNA methylation data confirmed these findings in two independent HCC cohorts. Loss of correct DNA methylation patterns at the RB1 locus leads to the aberrant expression of an alternative RB1-E2B transcript, as measured by quantitative real-time PCR. Demethylation at the intron 2 CpG island by DNMT1 knock-down or aza-deoxycytidine (DAC) treatment stimulated expression of the RB1-E2B transcript, accompanied by diminished RB1 main transcript expression. No aberrant DNA methylation was found at the RB1 locus in hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5) and their corresponding adjacent liver tissue specimens. Deregulated RB1 expression due to hyper- or hypomethylation in intron 2 of the RB1 gene is found in tumours without loss of heterozygosity and is associated with a decrease in overall survival (p = 0.032) if caused by hypermethylation of CpG85. This unequivocally demonstrates that loss of imprinting represents an important additional mechanism for RB1 pathway inactivation in human HCC, complementing well-described molecular defects. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A Novel Predictive Equation for Potential Diagnosis of Cholangiocarcinoma

PubMed Central

Kraiklang, Ratthaphol; Pairojkul, Chawalit; Khuntikeo, Narong; Imtawil, Kanokwan; Wongkham, Sopit; Wongkham, Chaisiri

2014-01-01

Cholangiocarcinoma (CCA) is the second most common-primary liver cancer. The difficulties in diagnosis limit successful treatment of CCA. At present, histological investigation is the standard diagnosis for CCA. However, there are some poor-defined tumor tissues which cannot be definitively diagnosed by general histopathology. As molecular signatures can define molecular phenotypes related to diagnosis, prognosis, or treatment outcome, and CCA is the second most common cancer found after hepatocellularcarcinoma (HCC), the aim of this study was to develop a predictive model which differentiates CCA from HCC and normal liver tissues. An in-house PCR array containing 176 putative CCA marker genes was tested with the training set tissues of 20 CCA and 10 HCC cases. The molecular signature of CCA revealed the prominent expression of genes involved in cell adhesion and cell movement, whereas HCC showed elevated expression of genes related to cell proliferation/differentiation and metabolisms. A total of 69 genes differentially expressed in CCA and HCC were optimized statistically to formulate a diagnostic equation which distinguished CCA cases from HCC cases. Finally, a four-gene diagnostic equation (CLDN4, HOXB7, TMSB4 and TTR) was formulated and then successfully validated using real-time PCR in an independent testing set of 68 CCA samples and 77 non-CCA controls. Discrimination analysis showed that a combination of these genes could be used as a diagnostic marker for CCA with better diagnostic parameters with high sensitivity and specificity than using a single gene marker or the usual serum markers (CA19-9 and CEA). This new combination marker may help physicians to identify CCA in liver tissues when the histopathology is uncertain. PMID:24586698

249 TP53 mutation has high prevalence and is correlated with larger and poorly differentiated HCC in Brazilian patients.

PubMed

Nogueira, Jeronimo A; Ono-Nita, Suzane K; Nita, Marcelo E; de Souza, Marcelo M T; do Carmo, Eliane P; Mello, Evandro S; Scapulatempo, Cristovan; Paranaguá-Vezozzo, Denise C; Carrilho, Flair J; Alves, Venancio A F

2009-06-26

Ser-249 TP53 mutation (249(Ser)) is a molecular evidence for aflatoxin-related carcinogenesis in Hepatocellular Carcinoma (HCC) and it is frequent in some African and Asian regions, but it is unusual in Western countries. HBV has been claimed to add a synergic effect on genesis of this particular mutation with aflatoxin. The aim of this study was to investigate the frequency of 249(Ser) mutation in HCC from patients in Brazil. We studied 74 HCC formalin fixed paraffin blocks samples of patients whom underwent surgical resection in Brazil. 249(Ser) mutation was analyzed by RFLP and DNA sequencing. HBV DNA presence was determined by Real-Time PCR. 249(Ser) mutation was found in 21/74 (28%) samples while HBV DNA was detected in 13/74 (16%). 249Ser mutation was detected in 21/74 samples by RFLP assay, of which 14 were confirmed by 249(Ser) mutant-specific PCR, and 12 by nucleic acid sequencing. All HCC cases with p53-249ser mutation displayed also wild-type p53 sequences. Poorly differentiated HCC was more likely to have 249(Ser) mutation (OR = 2.415, 95% CI = 1.001 - 5.824, p = 0.05). The mean size of 249(Ser) HCC tumor was 9.4 cm versus 5.5 cm on wild type HCC (p = 0.012). HBV DNA detection was not related to 249(Ser) mutation. Our results indicate that 249(Ser) mutation is a HCC important factor of carcinogenesis in Brazil and it is associated to large and poorly differentiated tumors.

MEK-ERK inhibition potentiates WAY-600-induced anti-cancer efficiency in preclinical hepatocellular carcinoma (HCC) models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Kaifeng, E-mail: kaifeng_wangdr@sina.com; Fan, Yaohua; Chen, Gongying

The search for novel anti-hepatocellular carcinoma (HCC) agents is important. Mammalian target of rapamycin (mTOR) hyper-activation plays a pivotal role in promoting HCC tumorigenesis and chemoresistance. The current preclinical study evaluated the potential anti-HCC activity by a potent mTOR kinase inhibitor, WAY-600. We showed that WAY-600 inhibited survival and proliferation of HCC cell lines (HepG2 and Huh7) and primary human HCC cells. Caspase-dependent apoptosis was activated by WAY-600 in above HCC cells. Reversely, caspase inhibitors largely attenuated WAY-600's lethality against HCC cells. At the signaling level, WAY-600 blocked mTOR complex 1/2 (mTORC1/2) assemble and activation, yet activated MEK-ERK pathway inmore » HCC cells. MEK-ERK inhibitors, PD-98059 and MEK-162, or MEK1/2 shRNA significantly potentiated WAY-600's cytotoxicity in HCC cells. Further studies showed that WAY-600 intraperitoneal (i.p.) administration in nude mice inhibited p-AKT Ser-473 and displayed significant anti-cancer activity against HepG2 xenografts. Remarkably, co-administration of MEK-162 further potentiated WAY-600's anti-HCC activity in vivo. These preclinical results demonstrate the potent anti-HCC activity by WAY-600, either alone or with MEK-ERK inhibitors. -- Highlights: •WAY-600 inhibits HCC cell survival and proliferation in vitro. •WAY-600 activates caspase-dependent apoptosis in HCC cells. •WAY-600 blocks mTORC1/2 activation, but activates MEK-ERK in HCC cells. •MEK-ERK inhibitors or MEK1/2 shRNA enhances WAY-600's cytotoxicity against HCC cells. •MEK-162 co-administration potentiates WAY-600-induced the anti-HepG2 tumor efficacy.« less

Novel Aspects of the Liver Microenvironment in Hepatocellular Carcinoma Pathogenesis and Development

PubMed Central

Tu, Thomas; Budzinska, Magdalena A.; Maczurek, Annette E.; Cheng, Robert; Di Bartolomeo, Anna; Warner, Fiona J.; McCaughan, Geoffrey W.; McLennan, Susan V.; Shackel, Nicholas A.

2014-01-01

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer that is derived from hepatocytes and is characterised by high mortality rate and poor prognosis. While HCC is driven by cumulative changes in the hepatocyte genome, it is increasingly recognised that the liver microenvironment plays a pivotal role in HCC propensity, progression and treatment response. The microenvironmental stimuli that have been recognised as being involved in HCC pathogenesis are diverse and include intrahepatic cell subpopulations, such as immune and stellate cells, pathogens, such as hepatitis viruses, and non-cellular factors, such as abnormal extracellular matrix (ECM) and tissue hypoxia. Recently, a number of novel environmental influences have been shown to have an equally dramatic, but previously unrecognized, role in HCC progression. Novel aspects, including diet, gastrointestinal tract (GIT) microflora and circulating microvesicles, are now being recognized as increasingly important in HCC pathogenesis. This review will outline aspects of the HCC microenvironment, including the potential role of GIT microflora and microvesicles, in providing new insights into tumourigenesis and identifying potential novel targets in the treatment of HCC. PMID:24871369

Aberrant expression of microRNAs and the miR-1/MET pathway in canine hepatocellular carcinoma.

PubMed

Lai, Y-C; Ushio, N; Rahman, M M; Katanoda, Y; Ogihara, K; Naya, Y; Moriyama, A; Iwanaga, T; Saitoh, Y; Sogawa, T; Sunaga, T; Momoi, Y; Izumi, H; Miyoshi, N; Endo, Y; Fujiki, M; Kawaguchi, H; Miura, N

2018-06-01

Canine hepatocellular carcinoma (HCC) is the most common primary hepatic tumour in dogs. MicroRNA (miRNA) dysregulation has been reported in human HCC and shown to have diagnostic and prognostic value; however, there are no data on miRNA expression in canine HCC. The aim of the present study was to investigate differentially expressed miRNAs in canine HCC. Analysis of miRNA expression in canine HCC tissues and cell lines by quantitative reverse transcription PCR showed that miR-1, miR-122, let-7a, and let-7g were downregulated, whereas miR-10b and miR-21 were upregulated in canine HCC. MET is one of the target genes of miR-1. MET was upregulated in canine HCC at the gene and protein levels, and a significant correlation between the concomitant downregulation of miR-1 and upregulation of MET was observed. Fast/intermediate-proliferating canine HCC cell lines had higher MET gene and protein expression levels than the slow-proliferating cell line. These findings suggest that miRNAs are differentially expressed in canine HCC, and that the miR-1/MET pathway may be associated with canine HCC cell proliferation. © 2018 John Wiley & Sons Ltd.

Indocyanine Green Fluorescence Navigation Thoracoscopic Metastasectomy for Pulmonary Metastasis of Hepatocellular Carcinoma.

PubMed

Kawakita, Naoya; Takizawa, Hiromitsu; Kondo, Kazuya; Sakiyama, Shoji; Tangoku, Akira

2016-12-20

Indocyanine green can selectively accumulate in primary hepatocellular carcinoma (HCC) and extrahepatic metastases. We report a patient who underwent resection of pulmonary metastasis of HCC using a thoracoscopic near-infrared imaging system and fluorescent navigation surgery. A 66-year-old man with suspicion of pulmonary metastasis of HCC was referred to our hospital. Indocyanine green was injected intravenously at a dose of 0.5 mg/kg body weight, 20 h before thoracoscopic surgery. An endoscopic indocyanine green near-infrared fluorescence imaging system showed clear blue fluorescence, indicating pulmonary metastasis of HCC in a lingular segment. We performed wide wedge resection using the fluorescence image for navigation to confirm the surgical margins. The specimen was histologically confirmed as a pulmonary metastasis of HCC. In conclusion, thoracoscopic indocyanine green near-infrared fluorescence imaging for pulmonary metastases of HCC is useful in identifying tumor locations and ensuring resection margins.

Deep convolutional neural network for the classification of hepatocellular carcinoma and intrahepatic cholangiocarcinoma

NASA Astrophysics Data System (ADS)

Midya, Abhishek; Chakraborty, Jayasree; Pak, Linda M.; Zheng, Jian; Jarnagin, William R.; Do, Richard K. G.; Simpson, Amber L.

2018-02-01

Liver cancer is the second leading cause of cancer-related death worldwide.1 Hepatocellular carcinoma (HCC) is the most common primary liver cancer accounting for approximately 80% of cases. Intrahepatic cholangiocarcinoma (ICC) is a rare liver cancer, arising in patients with the same risk factors as HCC, but treatment options and prognosis differ. The diagnosis of HCC is based primarily on imaging but distinguishing between HCC and ICC is challenging due to common radiographic features.2-4 The aim of the present study is to classify HCC and ICC in portal venous phase CT. 107 patients with resected ICC and 116 patients with resected HCC were included in our analysis. We developed a deep neural network by modifying a pre-trained Inception network by retraining the final layers. The proposed method achieved the best accuracy and area under the receiver operating characteristics curve of 69.70% and 0.72, respectively on the test data.

Carbonaceous content and water-soluble organic functionality of atmospheric aerosols at a semi-rural New England location

NASA Astrophysics Data System (ADS)

Shakya, Kabindra M.; Place, Philip F., Jr.; Griffin, Robert J.; Talbot, Robert W.

2012-02-01

Ambient aerosol samples (n = 287) collected at a semi-rural location, Thompson Farm (TF) in Durham, New Hampshire, from August 2007 to 2008 exhibited seasonal variation, characterized by the largest total carbon (TC) concentrations during winter (3.74 ± 2.55 μg C m-3) and the smallest during summer (1.21 ± 1.22 μg C m-3). On average, 92% of TC was organic (OC), of which 69% on average was observed to be water-soluble (WSOC). This study focuses on characterizing the WSOC functional groups using Proton Nuclear Magnetic Resonance spectroscopy on a subset of the samples (n = 108). Three aliphatic groups (H-C, H-C-C=, and H-C-O) are estimated to account for 79% of the characterized WSOC carbon mass. Pure aliphatic (H-C), oxygenated aliphatic (H-C-O), and unsaturated aliphatic (H-C-C=) groups were the dominant functional groups contributing to an average of 31%, 25%, and 23% of the WSOC carbon mass, respectively. The arylic group contributed an average of 21% of the WSOC carbon mass but exhibited large seasonal variation compared to the other groups. Precipitation affected mainly the WSOC and the H-C-C= functional group, which showed consistent decreases following rainfall events. Strong correlation between elemental carbon and OC and the dominance of air masses from the continental Midwest during winter shows that primary emissions (from local heating or industrial emissions) were the main sources during winter. Air masses originating from the continental Midwest were associated with the high levels of EC, primary OC, and H-C-O at TF. In contrast to winter, enhanced secondary formation and processed aerosols were dominant during other seasons.

Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors.

PubMed

Lin, Shi-Ming; Lin, Chun-Jung; Hsu, Chao-Wei; Tai, Dar-In; Sheen, I-Shyan; Lin, Deng-Yn; Liaw, Yun-Fan

2004-01-15

Hepatocellular carcinoma (HCC) recurrence after ablation therapy for primary tumors is common. To evaluate the effectiveness of interferon-alpha (IFN-alpha) in preventing HCC recurrence, 30 eligible patients were randomized into three groups: 11 patients treated with three mega units (MU) of IFN-alpha three times weekly for 24 months (IFN-alpha-continuous group), 9 patients treated with 3 MU of IFN-alpha daily for 10 days every month for 6 months followed by 3 MU of IFN-alpha daily for 10 days every 3 months for a further 18 months (IFN-alpha-intermittent group), and 10 patients who received no IFN-alpha therapy (control group). The three groups were comparable in terms of etiology, demographics, and laboratory data at entry and HCC characteristics. After a median follow-up of 27 months (range 4-53 months), 9 patients (90%) in the control group and 9 patients (45%) in 2 treatment groups (6 patients in the IFN-alpha-continuous group and 3 patients in the IFN-alpha-intermittent group) developed an HCC recurrence (P = 0.021). Cumulative HCC recurrence rates in the IFN-alpha-intermittent, IFN-alpha-continuous, and control groups were 22.2%, 27.3%, and 40% at the end of 1 year and 33.3%, 54.6%, and 90% at the end of 4 years (P = 0.0375), respectively (control vs. IFN-alpha-intermittent group, P = 0.0123; vs. IFN-alpha-continuous group, P = 0.0822). If both IFN-alpha groups were combined, the cumulative HCC recurrence rate of the patients treated with IFN-alpha and the control group was 25% and 40% at the end of 1 year and 47% and 90% at the end of 4 years, respectively (P = 0.0135). The data suggested that IFN-alpha therapy may reduce HCC recurrence after medical ablation therapy for primary tumors. Copyright 2003 American Cancer Society.

Tumor angiogenesis and its clinical significance in pediatric malignant liver tumor

PubMed Central

Sun, Xiao-Yi; Wu, Zai-De; Liao, Xiao-Feng; Yuan, Ji-Yan

2005-01-01

AIM: To investigate the expression of vascular endothelial growth factor (VEGF) and microvascular density (MVD) count in pediatric malignant liver tumor and their clinical significances. METHODS: Fourteen children with malignant liver tumors including seven hepatocellular carcinomas (HCCs), five hepatoblastomas, one malignant mesenchymoma and one rhabdomyosarcoma were studied. Twelve adult HCC samples served as control group. All samples were examined with streptavidin-biotin peroxidase (SP) immunohistochemical staining for VEGF expression and MVD count. RESULTS: VEGF positive expression in all pediatric malignant liver tumors was significantly higher than that in adult HCC (0.4971±0.14 vs 0.4027±0.03, P<0.05). VEGF expression in pediatric HCC group was also markedly higher than that in adult HCC group (0.5665±0.10 vs 0.4027±0.03, P<0.01) and pediatric non-HCC group (0.5665±0.10 vs 0.4276±0.15, P<0.05). The mean value of MVD in pediatric malignant liver tumors was significantly higher than that in adult HCC (33.66±12.24 vs 26.52±4.38, P<0.05). Furthermore, MVD in pediatric HCC group was significantly higher compared to that in adult HCC group (36.94±9.28 vs 26.52±4.38, P<0.05), but there was no significant difference compared to the pediatric non-HCC group (36.94±9.28 vs 30.37±14.61, P>0.05). All 7 children in HCC group died within 2 years, whereas the prognosis in pediatric non-HCC group was better, in which two patients survived more than 5 years. CONCLUSION: Children with malignant liver tumors, especially with HCC, may have extensive angiogenesis that induces a rapid tumor growth and leads to a poor prognosis. PMID:15655835

Global proteomic profiling in multistep hepatocarcinogenesis and identification of PARP1 as a novel molecular marker in hepatocellular carcinoma

PubMed Central

Wang, Jianguo; Xie, Haiyang; Li, Jie; Cao, Jili; Zhou, Lin; Zheng, Shusen

2016-01-01

The more accurate biomarkers have long been desired for hepatocellular carcinoma (HCC). Here, we characterized global large-scale proteomics of multistep hepatocarcinogenesis in an attempt to identify novel biomarkers for HCC. Quantitative data of 37874 sequences and 3017 proteins during hepatocarcinogenesis were obtained in cohort 1 of 75 samples (5 pooled groups: normal livers, hepatitis livers, cirrhotic livers, peritumoral livers, and HCC tissues) by iTRAQ 2D LC-MS/MS. The diagnostic performance of the top six most upregulated proteins in HCC group and HSP70 as reference were subsequently validated in cohort 2 of 114 samples (hepatocarcinogenesis from normal livers to HCC) using immunohistochemistry. Of seven candidate protein markers, PARP1, GS and NDRG1 showed the optimal diagnostic performance for HCC. PARP1, as a novel marker, showed comparable diagnostic performance to that of classic markers GS and NDRG1 in HCC (AUCs = 0.872, 0.856 and 0.792, respectively). A significant higher AUC of 0.945 was achieved when three markers combined. For diagnosis of HCC, the sensitivity and specificity were 88.2% and 81.0% when at least two of the markers were positive. Similar diagnostic values of PARP1, GS and NDRG1 were confirmed by immunohistochemistry in cohort 3 of 180 HCC patients. Further analysis indicated that PARP1 and NDRG1 were associated with some clinicopathological features, and the independent prognostic factors for HCC patients. Overall, global large-scale proteomics on spectrum of multistep hepatocarcinogenesis are obtained. PARP1 is a novel promising diagnostic/prognostic marker for HCC, and the three-marker panel (PARP1, GS and NDRG1) with excellent diagnostic performance for HCC was established. PMID:26883192

Studying liver cancer metastasis by in vivo imaging and flow cytometer

NASA Astrophysics Data System (ADS)

Wang, Chen; Gu, Zhengqin; Guo, Jin; Li, Yan; Liu, Guangda; Wei, Xunbin

2009-11-01

Primary liver cancer (hepatocellular carcinoma, or HCC) is associated with liver cirrhosis 60-80% of the time. Liver cancer is one of the most common malignancies in the world, with approximately 1,000,000 cases reported every year. About 80% of people with primary liver cancer are male. Although two-thirds of people have advanced liver disease when they seek medical help, one third of the patients have cancer that has not progressed beyond the liver. HCC may metastasize to the lung, bones, kidney, and many other organs. Surgical resection, liver transplantation, chemotherapy and radiation therapy are the foundation of current HCC therapies. However the outcomes are poor: the survival rate is almost zero for metastatic HCC patients. Molecular mechanisms of HCC metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of HCC cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern liver tumor cell spread through the microenvironment in vivo with real-time confocal near-infrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess liver tumor cell spreading and the circulation kinetics of liver tumor cells. A real- time quantitative monitoring of circulating liver tumor cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

Metastatic lung adenocarcinoma related α-Fetoprotein elevation in a patient with HBV-related cirrhosis.

PubMed

Hamamci, Mevlut; Karaahmet, Fatih; Akinci, Hakan; Kilincalp, Serta; Acıkgoz, Ruchan; Coban, Sahin; Yuksel, Ilhami

2015-12-01

HCC is the most common type of primary liver tumor. The Practice Guideline, AASLD, for HCC recommended surveillance of HBV carriers at high risk of HCC with US every 6-12 months. Laboratory surveillance option is the measurement of serum α-fetoprotein level which has long been used for the diagnosis of HCC. But, increased serum levels of α-fetoprotein are also seen in acute hepatitis, cirrhosis, and malignancies include yolk sac carcinoma, neuroblastoma, hepatoblastoma, gastric and lung carcinoma. Because of elevation α-fetoprotein in these malignancies, liver mass with an elevated α-fetoprotein does not directly indicate HCC. For these reason, clinicians evaluating patient with liver mass and HBV-related cirrhosis should be vigilant for other case of α-fetoprotein elevation. © Acta Gastro-Enterologica Belgica.

Environmental Exposures and Hepatocellular Carcinoma

PubMed Central

Wu, Hui-Chen

2013-01-01

Infection with hepatitis B and/or hepatitis C virus is a well-established risk factor for the development of hepatocellular carcinoma (HCC). However, it is now clear that certain occupational, environmental, and lifestyle factors also play a role in cancer development. Among these factors are smoking, alcohol consumption, workplace exposure to vinyl chloride, and exposure to polycylic aromatic hydrocarbons and aflatoxins. There is also evidence that several other chemical and infectious agents have a role in inducing HCC in humans. Epidemiologic studies and the use of biomarkers have provided essential data to demonstrate the importance of some of these factors in human risk, while animal studies have suggested that other chemicals may also play a role. Although immunization against hepatitis B virus infection remains the primary method of preventing HCC in regions of the world where this virus is a primary etiologic agent, there is currently no vaccine for hepatitis C virus. Thus, limiting exposure to other known risk factors remains an important mechanism in preventing HCC. PMID:26357611

Hepatitis-Associated Liver Cancer: Gaps and Opportunities to Improve Care

PubMed Central

McMahon, Brian; Block, Timothy; Cohen, Chari; Evans, Alison A.; Hosangadi, Anu; London, W. Thomas; Sherman, Morris

2016-01-01

The global burden of hepatocellular carcinoma (HCC; primary liver cancer) is increasing. HCC is often unaccompanied by clear symptomatology, causing patients to be unaware of their disease. Moreover, effective treatment for those with advanced disease is lacking. As such, effective surveillance and early detection of HCC are essential. However, current screening and surveillance guidelines are not being fully implemented. Some at-risk populations fall outside of the guidelines, and patients who are screened are often not diagnosed at an early enough stage for treatment to be effective. From March 17 to 19, 2015, the Hepatitis B Foundation sponsored a workshop to identify gaps and limitations in current approaches to the detection and treatment of HCC and to define research priorities and opportunities for advocacy. In this Commentary, we summarize areas for further research and action that were discussed throughout the workshop to improve the recognition of liver disease generally, improve the recognition of liver cancer risk, and improve the recognition that screening for HCC makes a life-saving difference. Participants agreed that primary prevention of HCC relies on prevention and treatment of viral hepatitis and other underlying etiologies. Earlier diagnosis (secondary prevention) needs to be substantially improved. Areas for attention include increasing practitioner awareness, better definition of at-risk populations, and improved performance of screening approaches (ultrasound, biomarkers for detection, risk stratification, targeted therapies). The heterogeneous nature of HCC makes it unlikely that a single therapeutic agent will be universally effective. Medical management will benefit from the development of new, targeted treatment approaches. PMID:26626106

Clinical outcome after pulmonary metastasectomy from primary hepatocellular carcinoma: Analysis of prognostic factors

PubMed Central

Kwon, Jong-Bum; Park, Khun; Kim, Young-Du; Seo, Jong-Hee; Moon, Seok-Whan; Cho, Deog-Gon; Kim, Yong-Whan; Kim, Dong-Goo; Yoon, Seung-Kew; Lim, Hyeon-Woo

2008-01-01

AIM: To review the surgical outcomes in terms of the surgical indications and relevant prognostic factors. METHODS: Sixteen patients underwent therapeutic lung surgery between March 1999 and May 2006. The observation period was terminated on May 31, 2007. The surgical outcomes and the clinicopathological factors were compared. RESULTS: There was no mortality or major morbidity encountered in this study. The mean follow-up period after metastasectomy was 26.7 ± 28.2 (range: 1-99 mo), and the median survival time was 20 mo. The 1- and 5-year survival rates were 56% and 26%, respectively. At the end of the follow-up, 1 patient died from hepatic failure without recurrence, 6 died from hepatic failure with a recurrent hepatocellular carcinoma (HCC), and 4 died from recurrent HCC with cachexia. Among several clinical factors, Kaplan-Meier analysis revealed that liver transplantation as a treatment for the primary lesion, grade of cell differentiation, and negative evidence HBV infection were independent predictive factors. On Cox’s proportional hazard model, there were no significant factors affecting survival after pulmonary metastasectomy in patients with HCC. CONCLUSION: A metastasectomy should be performed before other treatments in selected patients. Although not significant, patients with liver transplantation of a primary HCC survived longer. Liver transplantation might be the most beneficial modality that can offer patients better survival. A multi-institutional and collaborative study would be needed for identifying clinical prognostic factors predicting survival in patients with HCC and lung metastasis. PMID:18837090

Potentiality of immunotherapy against hepatocellular carcinoma

PubMed Central

Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Uemura, Yasushi; Nakatsura, Tetsuya

2015-01-01

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future. PMID:26420958

Potentiality of immunotherapy against hepatocellular carcinoma.

PubMed

Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Uemura, Yasushi; Nakatsura, Tetsuya

2015-09-28

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the new-found field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future.

 Economic growth leads to increase of obesity and associated hepatocellular carcinoma in developing countries.

PubMed

Seyda Seydel, G; Kucukoglu, Ozlem; Altinbasv, Akif; Demir, O Oguz; Yilmaz, Sezai; Akkiz, Hikmet; Otan, Emrah; Sowa, Jan-Peter; Canbay, Ali

2016-01-01

 Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer related death worldwide. In recent years, the prevalence of HCC has increased in both developing and developed countries. Most HCC cases develop in the presence of advanced chronic liver disease related to viral hepatitis. In particular hepatitis B virus and hepatitis C virus infections are considered as major HCC risk factors worldwide. However, current studies provide strong evidence for increasing numbers of HCC in nonalcoholic fatty liver disease (NAFLD). NAFLD represents the hepatic manifestation of metabolic syndrome which is based on obesity and insulin resistance. Epidemiologic data clearly demonstrates that NAFLD and obesity-related disorders are significant risk factors for tumor development in general and HCC in particular. As a consequence of life style changes towards higher calorie intake and less exercise, obesity and metabolic syndrome are spreading all over the world. Due to this increase in obesity and metabolic syndrome NAFLD-related HCC will become a major health care problem in the future. In conclusion, better understanding of the impact of NAFLD and obesity in the development of HCC will improve our treatment strategies of HCC and allow preventive measures.

A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Bo; Sun, Ding; Department of Hepatobiliary Surgery, First Affiliated Hospital of Soochow University, Suzhou, 215004

2015-12-25

Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primarymore » liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development. - Highlights: • Polymeric nanoparticle formulation of curcumin not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. • In combination with sorafenib, NanoCurcumin induced HCC cell apoptosis and cell cycle arrest. • NanoCurcumin and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. • NanoCurcumin and sorafenib significantly decreased the population of CD133-positive HCC cells.« less

Identification of serum monocyte chemoattractant protein-1 and prolactin as potential tumor markers in hepatocellular carcinoma.

PubMed

Wang, Who-Whong; Ang, Soo Fan; Kumar, Rajneesh; Heah, Charmain; Utama, Andi; Tania, Navessa Padma; Li, Huihua; Tan, Sze Huey; Poo, Desmond; Choo, Su Pin; Chow, Wan Cheng; Tan, Chee Kiat; Toh, Han Chong

2013-01-01

Early diagnosis of hepatocellullar carcinoma (HCC) remains a challenge. The current practice of serum alpha-fetoprotein (AFP) measurement is inadequate. Here we utilized a proteomic approach to identify novel serum biomarkers for distinguishing HCC patients from non-cancer controls. We profiled the serum proteins in a group of 58 resectable HCC patients and 11 non-HCC chronic hepatitis B (HBV) carrier samples from the Singapore General Hospital (SGH) using the RayBio® L-Series 507 Antibody Array and found 113 serum markers that were significantly modulated between HCC and control groups. Selected potential biomarkers from this list were quantified using a multiplex sandwich enzyme-linked immunosorbent assay (ELISA) array in an expanded SGH cohort (126 resectable HCC patients and 115 non-HCC chronic HBV carriers (NC group)), confirming that serum prolactin and monocyte chemoattractant protein-1 (MCP-1) were significantly upregulated in HCC patients. This finding of serum MCP-1 elevation in HCC patients was validated in a separate cohort of serum samples from the Mochtar Riady Institute for Nanotechnology, Indonesia (98 resectable HCC, 101 chronic hepatitis B patients and 100 asymptomatic HBV/HCV carriers) by sandwich ELISA. MCP-1 and prolactin levels were found to correlate with AFP, while MCP-1 also correlated with disease stage. Subsequent receiver operating characteristic (ROC) analysis of AFP, prolactin and MCP-1 in the SGH cohort and comparing their area under the ROC curve (AUC) indicated that neither prolactin nor MCP-1 on their own performed better than AFP. However, the combination of AFP+MCP-1 (AUC, 0.974) had significantly superior discriminative ability than AFP alone (AUC, 0.942; p<0.001). In conclusion, prolactin and MCP-1 are overexpressed in HCC and are conveniently quantifiable in patients' sera by ELISA. MCP-1 appears to be a promising complementary biomarker for HCC diagnosis and this MCP-1+AFP model should be further evaluated as potential biomarker on a larger scale in patients at-risk of HCC.

Identification of Serum Monocyte Chemoattractant Protein-1 and Prolactin as Potential Tumor Markers in Hepatocellular Carcinoma

PubMed Central

Kumar, Rajneesh; Heah, Charmain; Utama, Andi; Tania, Navessa Padma; Li, Huihua; Tan, Sze Huey; Poo, Desmond; Choo, Su Pin; Chow, Wan Cheng; Tan, Chee Kiat; Toh, Han Chong

2013-01-01

Early diagnosis of hepatocellullar carcinoma (HCC) remains a challenge. The current practice of serum alpha-fetoprotein (AFP) measurement is inadequate. Here we utilized a proteomic approach to identify novel serum biomarkers for distinguishing HCC patients from non-cancer controls. We profiled the serum proteins in a group of 58 resectable HCC patients and 11 non-HCC chronic hepatitis B (HBV) carrier samples from the Singapore General Hospital (SGH) using the RayBio® L-Series 507 Antibody Array and found 113 serum markers that were significantly modulated between HCC and control groups. Selected potential biomarkers from this list were quantified using a multiplex sandwich enzyme-linked immunosorbent assay (ELISA) array in an expanded SGH cohort (126 resectable HCC patients and 115 non-HCC chronic HBV carriers (NC group)), confirming that serum prolactin and monocyte chemoattractant protein-1 (MCP-1) were significantly upregulated in HCC patients. This finding of serum MCP-1 elevation in HCC patients was validated in a separate cohort of serum samples from the Mochtar Riady Institute for Nanotechnology, Indonesia (98 resectable HCC, 101 chronic hepatitis B patients and 100 asymptomatic HBV/HCV carriers) by sandwich ELISA. MCP-1 and prolactin levels were found to correlate with AFP, while MCP-1 also correlated with disease stage. Subsequent receiver operating characteristic (ROC) analysis of AFP, prolactin and MCP-1 in the SGH cohort and comparing their area under the ROC curve (AUC) indicated that neither prolactin nor MCP-1 on their own performed better than AFP. However, the combination of AFP+MCP-1 (AUC, 0.974) had significantly superior discriminative ability than AFP alone (AUC, 0.942; p<0.001). In conclusion, prolactin and MCP-1 are overexpressed in HCC and are conveniently quantifiable in patients’ sera by ELISA. MCP-1 appears to be a promising complementary biomarker for HCC diagnosis and this MCP-1+AFP model should be further evaluated as potential biomarker on a larger scale in patients at-risk of HCC. PMID:23874805

3-Tesla MRI Response to TACE in HCC (Liver Cancer)

ClinicalTrials.gov

2016-08-22

Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Stage A Adult Primary Liver Cancer (BCLC); Stage B Adult Primary Liver Cancer (BCLC)

Detection of Circulating Tumor Cells in Hepatocellular Carcinoma Using Antibodies against Asialoglycoprotein Receptor, Carbamoyl Phosphate Synthetase 1 and Pan-Cytokeratin

PubMed Central

Zhang, Yu; Liu, Huiying; Sun, Bin; Zhao, Linlin; Ge, Naijian; Qian, Haihua; Yang, Yefa; Wu, Mengchao; Yin, Zhengfeng

2014-01-01

Background Asialoglycoprotein receptor (ASGPR)-ligand-based separation combined with identification with Hep Par 1 or pan-cytokeratin (P-CK) antibody have been demonstrated to detect circulating tumor cells (CTCs) in hepatocellular carcinoma (HCC). The aim of this study was to develop an improved enrichment and identification system that allows the detection of all types of HCC CTCs. Methods The specificity of the prepared anti-ASGPR monoclonal antibody was characterized. HCC cells were bound by ASGPR antibody and subsequently magnetically isolated by second antibody-coated magnetic beads. Isolated HCC cells were identified by immunofluorescence staining using a combination of anti-P-CK and anti-carbamoyl phosphate synthetase 1 (CPS1) antibodies. Blood samples spiked with HepG2 cells were used to determine recovery and sensitivity. CTCs were detected in blood samples from HCC patients and other patients. Results ASGPR was exclusively expressed in human hepatoma cell line, normal hepatocytes and HCC cells in tissue specimens detected by the ASGPR antibody staining. More HCC cells could be identified by the antibody cocktail for CPS1 and P-CK compared with a single antibody. The current approach obtained a higher recovery rate of HepG2 cells and more CTC detection from HCC patients than the previous method. Using the current method CTCs were detected in 89% of HCC patients and no CTCs were found in the other test subjects. Conclusions Our anti-ASGPR antibody could be used for specific and efficient HCC CTC enrichment, and anti-P-CK combined with anti-CPS1 antibodies is superior to identification with one antibody alone in the sensitivity for HCC CTC detection. PMID:24763545

Osthole inhibits the tumorigenesis of hepatocellular carcinoma cells.

PubMed

Lin, Zhi-Kun; Liu, Jia; Jiang, Guo-Qiang; Tan, Guang; Gong, Peng; Luo, Hai-Feng; Li, Hui-Min; Du, Jian; Ning, Zhen; Xin, Yi; Wang, Zhong-Yu

2017-03-01

Hepatocellular carcinoma (HCC) accounts for approximately 90% of all cases of primary liver cancer, and the majority of patients with HCC are deprived of effective curative methods. Osthole is a Chinese herbal medicine which has been reported to possess various pharmacological functions, including hepatocellular protection. In the present study, we investigated the anticancer activity of osthole using HCC cell lines. We found that osthole inhibited HCC cell proliferation, induced cell cycle arrest, triggered DNA damage and suppressed migration in HCC cell lines. Furthermore, we demonstrated that osthole not only contributed to cell cycle G2/M phase arrest via downregulation of Cdc2 and cyclin B1 levels, but also induced DNA damage via an increase in ERCC1 expression. In addition, osthole inhibited the migration of HCC cell lines by significantly downregulating MMP-2 and MMP-9 levels. Finally, we demonstrated that osthole inhibited epithelial-mesenchymal transition (EMT) via increasing the expression of epithelial biomarkers E-cadherin and β-catenin, and significantly decreasing mesenchymal N-cadherin and vimentin protein expression. These results suggest that osthole may have potential chemotherapeutic activity against HCC.

Hepatic Stellate Cells Alter Liver Immune Environment to Promote Cancer | Center for Cancer Research

Cancer.gov

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for up to 90 percent of cases, and is the second most common cause of cancer-related deaths worldwide according to the World Health Organization’s 2014 World Cancer Report. Even when caught early, HCC often recurs, either from intra-liver metastases or new primary tumors, and recurrence is the leading cause of death for patients with HCC. The liver microenvironment is an important contributor to HCC initiation and progression and also likely plays a role in tumor recurrence. Xin Wei Wang, Ph.D., of CCR’s Laboratory of Human Carcinogenesis, and his colleagues wondered whether activated hepatic stellate cells (A-HSCs), stromal cells in the liver known to participate in repair following injury and in the development of fibrosis, contribute directly to HCC recurrence.

Oncolytic reovirus as a combined antiviral and anti-tumour agent for the treatment of liver cancer.

PubMed

Samson, Adel; Bentham, Matthew J; Scott, Karen; Nuovo, Gerard; Bloy, Abigail; Appleton, Elizabeth; Adair, Robert A; Dave, Rajiv; Peckham-Cooper, Adam; Toogood, Giles; Nagamori, Seishi; Coffey, Matthew; Vile, Richard; Harrington, Kevin; Selby, Peter; Errington-Mais, Fiona; Melcher, Alan; Griffin, Stephen

2018-03-01

Oncolytic viruses (OVs) represent promising, proinflammatory cancer treatments. Here, we explored whether OV-induced innate immune responses could simultaneously inhibit HCV while suppressing hepatocellular carcinoma (HCC). Furthermore, we extended this exemplar to other models of virus-associated cancer. Clinical grade oncolytic orthoreovirus (Reo) elicited innate immune activation within primary human liver tissue in the absence of cytotoxicity and independently of viral genome replication. As well as achieving therapy in preclinical models of HCC through the activation of innate degranulating immune cells, Reo-induced cytokine responses efficiently suppressed HCV replication both in vitro and in vivo. Furthermore, Reo-induced innate responses were also effective against models of HBV-associated HCC, as well as an alternative endogenous model of Epstein-Barr virus-associated lymphoma. Interestingly, Reo appeared superior to the majority of OVs in its ability to elicit innate inflammatory responses from primary liver tissue. We propose that Reo and other select proinflammatory OV may be used in the treatment of multiple cancers associated with oncogenic virus infections, simultaneously reducing both virus-associated oncogenic drive and tumour burden. In the case of HCV-associated HCC (HCV-HCC), Reo should be considered as an alternative agent to supplement and support current HCV-HCC therapies, particularly in those countries where access to new HCV antiviral treatments may be limited. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Studying tumor metastasis by in vivo imaging and flow cytometer

NASA Astrophysics Data System (ADS)

Wei, Xunbin; Guo, Jin; Liu, Guangda; Li, Yan; Chen, Yun; Zhang, Li; Tan, Yuan; Chen, Tong; Gu, Zhenqin; Wang, Chen

2009-02-01

Liver cancer is one of the most common malignancies in the world, with approximately 1,000,000 cases reported every year. This ranges from 15,000 cases in the United States to more than a 250,000 in China. About 80% of people with primary liver cancer are male. Although two-thirds of people have advanced liver disease when they seek medical help, one third of the patients have cancer that has not progressed beyond the liver. Primary liver cancer (hepatocellular carcinoma, or HCC) is associated with liver cirrhosis 60-80% of the time. HCC may metastasize to the lung, bones, kidney, and many other organs. Surgical resection, liver transplantation, chemotherapy and radiation therapy are the foundation of current HCC therapies. However the outcomes are poor-the survival rate is almost zero for metastatic HCC patients. Molecular mechanisms of HCC metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of HCC cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern liver tumor cell spread through the microenvironment in vivo in real-time confocal near-infrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess liver tumor cell spreading and the circulation kinetics of liver tumor cells. A real-time quantitative monitoring of circulating liver tumor cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

Effects of a 24-week course of interferon-α therapy after curative treatment of hepatitis C virus-associated hepatocellular carcinoma

PubMed Central

Jeong, Soo Cheol; Aikata, Hiroshi; Katamura, Yoshio; Azakami, Takahiro; Kawaoka, Tomokazu; Saneto, Hiromi; Uka, Kiminori; Mori, Nami; Takaki, Shintaro; Kodama, Hideaki; Waki, Koji; Imamura, Michio; Shirakawa, Hiroo; Kawakami, Yoshiiku; Takahashi, Shoichi; Chayama, Kazuaki

2007-01-01

AIM: To assess whether a 24-wk course of interferon (IFN) could prevent hepatocellular carcinoma (HCC) recurrence and worsening of liver function in patients with hepatitis C virus (HCV)-infected patients after receiving curative treatment for primary HCC. METHODS: Outcomes in 42 patients with HCV infection treated with IFN-α, after curative treatment for primary HCC (IFN group), were compared with 42 matched curatively treated historical controls not given IFN (non-IFN group). RESULTS: Although the rate of initial recurrence did not differ significantly between IFN group and non-IFN group (0%, 44%, 61%, and 67% vs 4.8%, 53%, 81%, and 87% at 1, 3, 5, and 7 years, P = 0.153, respectively), IFN group showed a lower rate than the non-IFN group for second recurrence (0%, 10.4%, 28%, and 35% vs 0%, 30%, 59%, and 66% at 1, 3, 5 and 7 years, P = 0.022, respectively). Among the IFN group, patients with sustained virologic response (SVR) were less likely to have a second HCC recurrence than IFN patients without an SVR, or non-IFN patients. Multivariate analysis identified the lack of SVR as the only independent risk factor for a second recurrence, while SVR and Child-Pugh class A independently favored overall survival. CONCLUSION: Most intrahepatic recurrences of HCV-related HCC occurred during persistent viral infection. Eradication of HCV is essential for the prevention of HCC recurrence and improvement of survival. PMID:17879404

Prognostic significance of kynurenine 3-monooxygenase and effects on proliferation, migration, and invasion of human hepatocellular carcinoma.

PubMed

Jin, Haojie; Zhang, Yurong; You, Haiyan; Tao, Xuemei; Wang, Cun; Jin, Guangzhi; Wang, Ning; Ruan, Haoyu; Gu, Dishui; Huo, Xisong; Cong, Wenming; Qin, Wenxin

2015-06-23

Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the kynurenine pathway of tryptophan degradation and plays a critical role in Huntington's and Alzheimer's diseases. This study aimed to examine the expression of KMO in human hepatocellular carcinoma (HCC) and investigate the relationship between its expression and prognosis of HCC patients. We first analyzed KMO expression in 120 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), and 205 clinical HCC specimens using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis showed that KMO expression was significantly higher in HCC tissues than that in normal liver tissues (all p < 0.05). Survival and recurrence analyses showed that KMO was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR) (both p<0.01). And in vitro studies revealed that KMO positively regulated proliferation, migration, and invasion of HCC cells. These results suggest that KMO exhibits tumor-promoting effects towards HCC and it may serve as a novel prognostic marker in HCC.

EVI1, a target gene for amplification at 3q26, antagonizes transforming growth factor-β-mediated growth inhibition in hepatocellular carcinoma

PubMed Central

Yasui, Kohichiroh; Konishi, Chika; Gen, Yasuyuki; Endo, Mio; Dohi, Osamu; Tomie, Akira; Kitaichi, Tomoko; Yamada, Nobuhisa; Iwai, Naoto; Nishikawa, Taichiro; Yamaguchi, Kanji; Moriguchi, Michihisa; Sumida, Yoshio; Mitsuyoshi, Hironori; Tanaka, Shinji; Arii, Shigeki; Itoh, Yoshito

2015-01-01

EVI1 (ecotropic viral integration site 1) is one of the most aggressive oncogenes associated with myeloid leukemia. We investigated DNA copy number aberrations in human hepatocellular carcinoma (HCC) cell lines using a high-density oligonucleotide microarray. We found that a novel amplification at the chromosomal region 3q26 occurs in the HCC cell line JHH-1, and that MECOM (MDS1 and EVI1 complex locus), which lies within the 3q26 region, was amplified. Quantitative PCR analysis of the three transcripts transcribed from MECOM indicated that only EVI1, but not the fusion transcript MDS1–EVI1 or MDS1, was overexpressed in JHH-1 cells and was significantly upregulated in 22 (61%) of 36 primary HCC tumors when compared with their non-tumorous counterparts. A copy number gain of EVI1 was observed in 24 (36%) of 66 primary HCC tumors. High EVI1 expression was significantly associated with larger tumor size and higher level of des-γ-carboxy prothrombin, a tumor marker for HCC. Knockdown of EVI1 resulted in increased induction of the cyclin-dependent kinase inhibitor p15INK4B by transforming growth factor (TGF)-β and decreased expression of c-Myc, cyclin D1, and phosphorylated Rb in TGF-β-treated cells. Consequently, knockdown of EVI1 led to reduced DNA synthesis and cell viability. Collectively, our results suggest that EVI1 is a probable target gene that acts as a driving force for the amplification at 3q26 in HCC and that the oncoprotein EVI1 antagonizes TGF-β-mediated growth inhibition of HCC cells. PMID:25959919

Circulating tumor DNA profiling reveals clonal evolution and real-time disease progression in advanced hepatocellular carcinoma.

PubMed

Cai, Zhi-Xiong; Chen, Geng; Zeng, Yong-Yi; Dong, Xiu-Qing; Lin, Min-Jie; Huang, Xin-Hui; Zhang, Da; Liu, Xiao-Long; Liu, Jing-Feng

2017-09-01

Circulating tumor DNA (ctDNA) provides a potential non-invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real-time track the therapeutic responses in the longitudinal monitoring. © 2017 UICC.

Sociodemographic, lifestyle, and psychosocial determinants of hair cortisol in a South London community sample.

PubMed

Fischer, Susanne; Duncko, Roman; Hatch, Stephani L; Papadopoulos, Andrew; Goodwin, Laura; Frissa, Souci; Hotopf, Matthew; Cleare, Anthony J

2017-02-01

Hypothalamic-pituitary-adrenal (HPA) measures are crucial for research into stress and stress-related disorders. Most HPA measures fluctuate depending on diurnal rhythms and state confounders. Hair cortisol concentrations (HCC) are less susceptible to such fluctuations, but less is known about trait-like confounders. Using a community sample, we tested the relationship between HCC and a range of variables including demographic variables, hair treatment, and medication, as well as psychosocial variables, namely childhood trauma, critical life events, and depressive symptoms. Hair samples were collected from 144 individuals from the South East London Community Health (SELCoH) study. Childhood trauma, life events, and depressive symptoms were measured, together with age, sex, ethnicity, relationship status, educational attainment, employment status, occupational social class, hair washing frequency, hair treatments, season reflected in the hair sample, hazardous drinking, smoking, medication intake, and body mass index. Hair samples reflecting the past 3 months were collected and analysed using immunoassays. First, correlations (continuous variables) and simple linear regressions (dichotomous variables) were conducted to identify sociodemographic, hair-related, and lifestyle determinants of HCC. Next, multiple linear regressions were conducted to test the relationship between psychosocial variables and HCC when controlling for the identified confounders. Age (r=-0.17, p=0.050), White British ethnicity (β=-0.19, p=0.023), heat-based treatments (β=-0.22, p=0.010), and winter season (β=-0.18, p=0.024) were associated with lower HCC, whereas summer season (β=0.24, p=0.024), painkillers (β=0.25, p=0.003), anxiolytics/antidepressants (β=0.21, p=0.014), and hormonal contraceptives (β=0.27, p=0.006) were associated with higher HCC. Controlling for these confounders, physical neglect during childhood (β=-0.17, p=0.057), war-related experiences (β=0.20, p=0.027), separation (β=0.18, p=0.054), and being the victim of a serious crime (β=-0.17, p=0.062) were linked with altered HCC. Our findings suggest that variation in HCC occurs according to sociodemographic, hair-related, and lifestyle variables, and that certain associations between stress and altered HCC can only be revealed when accounting for these confounders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identification of the collagen type 1 alpha 1 gene (COL1A1) as a candidate survival-related factor associated with hepatocellular carcinoma

PubMed Central

2014-01-01

Background Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death especially among Asian and African populations. It is urgent that we identify carcinogenesis-related genes to establish an innovative treatment strategy for this disease. Methods Triple-combination array analysis was performed using one pair each of HCC and noncancerous liver samples from a 68-year-old woman. This analysis consists of expression array, single nucleotide polymorphism array and methylation array. The gene encoding collagen type 1 alpha 1 (COL1A1) was identified and verified using HCC cell lines and 48 tissues from patients with primary HCC. Results Expression array revealed that COL1A1 gene expression was markedly decreased in tumor tissues (log2 ratio –1.1). The single nucleotide polymorphism array showed no chromosomal deletion in the locus of COL1A1. Importantly, the methylation value in the tumor tissue was higher (0.557) than that of the adjacent liver tissue (0.008). We verified that expression of this gene was suppressed by promoter methylation. Reactivation of COL1A1 expression by 5-aza-2′-deoxycytidine treatment was seen in HCC cell lines, and sequence analysis identified methylated CpG sites in the COL1A1 promoter region. Among 48 pairs of surgical specimens, 13 (27.1%) showed decreased COL1A1 mRNA expression in tumor sites. Among these 13 cases, 10 had promoter methylation at the tumor site. The log-rank test indicated that mRNA down-regulated tumors were significantly correlated with a poor overall survival rate (P = 0.013). Conclusions Triple-combination array analysis successfully identified COL1A1 as a candidate survival-related gene in HCCs. Epigenetic down-regulation of COL1A1 mRNA expression might have a role as a prognostic biomarker of HCC. PMID:24552139

mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peng, Xingang, E-mail: pengxinggang26@sina.com; Zhang, Donghui, E-mail: zhangdonghuiyx@sina.com; Li, Zhengling, E-mail: lizhenglingzz@sina.com

Histone deacetylases (HDACs) hyper-activity in hepatocellular carcinoma (HCC) is often associated with patients’ poor prognosis. Our previous study has shown that resminostat, a novel HDAC inhibitor (HDACi), activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway in HCC cells. Here we explored the potential resminostat resistance factor by focusing on mammalian target of rapamycin (mTOR). We showed that AZD-2014, a novel mTOR kinase inhibitor, potentiated resminostat-induced cytotoxicity and proliferation inhibition in HCC cells. Molecularly, AZD-2014 enhanced resminostat-induced mPTP apoptosis pathway activation in HCC cells. Inhibition of this apoptosis pathway, by the caspase-9 specific inhibitor Ac-LEHD-CHO, the mPTP blockers (sanglifehrin A/cyclosporine A),more » or by shRNA-mediated knockdown of mPTP component cyclophilin-D (Cyp-D), significantly attenuated resminostat plus AZD-2014-induced cytotoxicity and apoptosis in HCC cells. Significantly, mTOR shRNA knockdown or kinase-dead mutation (Asp-2338-Ala) also sensitized HCC cells to resminostat, causing profound cytotoxicity and apoptosis induction. Together, these results suggest that mTOR could be a primary resistance factor of resminostat. Targeted inhibition of mTOR may thus significantly sensitize HCC cells to resminostat. - Highlights: • AZD-2014 potentiates resminostat’s cytotoxicity against HCC cells. • AZD-2014 facilitates resminostat-induced HCC cell apoptosis. • AZD-2014 augments resminostat-induced mitochondrial apoptosis pathway activation. • mTOR shRNA or kinase-dead mutation significantly sensitizes HCC cells to resminostat.« less

Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fu, Meili; Shi, Wenhong; Li, Zhengling

Over-expression and aberrant activation of histone deacetylases (HDACs) are often associated with poor prognosis of hepatocellular carcinoma (HCC). Here, we evaluated the potential anti-hepatocellular carcinoma (HCC) cell activity by resminostat, a novel pan HDAC inhibitor (HDACi). We demonstrated that resminostat induced potent cytotoxic and anti-proliferative activity against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, resminostat treatment in HCC cells activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway, which was evidenced by physical association of cyclophilin-D and adenine nucleotide translocator 1 (ANT-1), mitochondrial depolarization, cytochrome C release and caspase-9 activation. Intriguingly, the mPTP blockers (sanglifehrinmore » A and cyclosporine A), shRNA knockdown of cyclophilin-D or the caspase-9 inhibitor dramatically attenuated resminostat-induced HCC cell apoptosis and cytotoxicity. Reversely, HCC cells with exogenous cyclophilin-D over-expression were hyper-sensitive to resminostat. Intriguingly, a low concentration of resminostat remarkably potentiated sorafenib-induced mitochondrial apoptosis pathway activation, leading to a profound cytotoxicity in HCC cells. The results of this preclinical study indicate that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy. - Highlights: • Resminostat inhibits human HCC cell survival and proliferation. • Resminostat activates mPTP-dependent mitochondrial apoptosis pathway in HCC cells. • Resminostat potentiates sorafenib-induced mitochondrial apoptosis pathway activation. • mPTP or caspase-9 inhibition attenuates apoptosis by resminostat or plus sorafenib.« less

An evaluation of distal hair cortisol concentrations collected at delivery.

PubMed

Orta, Olivia R; Tworoger, Shelley S; Terry, Kathryn L; Coull, Brent A; Gelaye, Bizu; Kirschbaum, Clemens; Sanchez, Sixto E; Williams, Michelle A

2018-04-04

Distal hair segments collected at delivery may allow for the assessment of maternal cortisol secretion in early pregnancy, an important time window for fetal development. Therefore, an investigation of the validity of distal hair cortisol concentrations is warranted. We examined the concordance between proximal and distal hair cortisol concentrations (HCC), both representing the first trimester of pregnancy. The study population was comprised of a random sample of 97 women participating in the Pregnancy Outcomes Maternal and Infant Study, a prospective cohort study of pregnant women attending prenatal clinics in Lima, Peru. Each participant provided two hair samples: once at enrollment [mean gestational age (GA) = 13.1 weeks] and again at full-term delivery (mean GA = 39.0 weeks). Hair segments reflecting the first trimester were: 3 cm hair segments closest to the scalp on the first hair sample (proximal) and 6-9 cm from the scalp on the second hair sample (distal). HCC was determined using Luminescence Immunoassay. A subset (N = 28) had both hair segments additionally analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS). HCC values were log-transformed (logHCC), and proximal-distal differences tested using paired sample t-tests. Concordance was evaluated within and across assay types. LogHCC, measured using immunoassay, in distal hair segments was lower compared to proximal hair segments (1.35 versus 1.64 respectively; p = .02). No difference was observed using LC-MS/MS (1.99 versus 1.83, respectively; p=.33). Proximal-distal concordance was low within assay (immunoassay: Pearson = 0.27 and κ = 0.10; LC-MS/MS: Pearson = 0.37 and κ = 0.07). High correlation was observed across assays for both distal (Pearson = 0.78, p < .001; κ = 0.64) and proximal segments (Pearson = 0.96, p < .001; κ = 0.75). In conclusion, distal first-trimester hair segments collected at delivery have lower absolute HCC compared to HCC in proximal first trimester hair segments collected in early pregnancy, and are poorly concordant with HCC in proximal segments. Findings may inform the design of future studies.

The establishment and characterization of the first canine hepatocellular carcinoma cell line, which resembles human oncogenic expression patterns

PubMed Central

Boomkens, Sacha Y; Spee, Bart; IJzer, Jooske; Kisjes, Ronald; Egberink, Herman F; van den Ingh, Ted SGAM; Rothuizen, Jan; Penning, Louis C

2004-01-01

Background Hepatocellular carcinoma (HCC) is one of the most worldwide frequent primary carcinomas resulting in the death of many cirrhotic patients. Unfortunately, the molecular mechanisms of this cancer are not well understood; therefore, we need a good model system to study HCC. The dog is recognized as a promising model for human medical research, namely compared with rodents. The objective of this study was to establish and characterize a spontaneous canine tumor cell line as a potential model for studies on HCC. Results Histomorphological, biochemical, molecular biological and quantitative assays were performed to characterize the canine HCC cell line that originated from a dog with a spontaneous liver tumor. Morphological investigations provided strong evidence for the hepatocytic and neoplastic nature of the cell line, while biochemical assays showed that they produced liver-specific enzymes. PCR analysis confirmed expression of ceruloplasmin, alpha-fetoprotein and serum albumin. Quantitative RT-PCR showed that the canine HCC cell line resembles human HCC based on the measurements of expression profiles of genes involved in cell proliferation and apoptosis. Conclusions We have developed a novel, spontaneous tumor liver cell line of canine origin that has many characteristics of human HCC. Therefore, the canine HCC cell line might be an excellent model for comparative studies on the molecular pathogenesis of HCC. PMID:15566568

Hepatitis B virus mutation may play a role in hepatocellular carcinoma recurrence: A systematic review and meta-regression analysis.

PubMed

Zhou, Hua-ying; Luo, Yue; Chen, Wen-dong; Gong, Guo-zhong

2015-06-01

A number of studies have confirmed that antiviral therapy with nucleotide analogs (NAs) can improve the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative therapy. However, what factors affected the prognosis of HBV-HCC after removal of the primary tumor and inhibition of HBV replication? A meta-regression analysis was conducted to explore the prognostic factor for this subgroup of patients. MEDLINE, EMBASE, Web of Science, and Cochrane library were searched from January 1995 to February 2014 for clinical trials evaluating the effect of NAs on the prognosis of HBV-HCC after curative therapy. Data were extracted for host, viral, and intervention information. Single-arm meta-analysis was performed to assess overall survival (OS) rates and HCC recurrence. Meta-regression analysis was carried out to explore risk factors for 1-year OS rate and HCC recurrence for HBV-HCC patients after curative therapy and antiviral therapy. Fourteen observational studies with 1284 patients met the inclusion criteria. Influential factors for prognosis of HCC were mainly baseline HBeAg positivity, cirrhotic stage, advanced Tumor-Node-Metastasis (TNM) stage, macrovascular invasion, and antiviral agent type. The 1-year OS rate decreased by more than four times (coefficient -4.45, P<0.001) and the 1-year HCC recurrence increased by more than one time (coefficient 1.20, P=0.003) when lamivudine was chosen for HCC after curative therapy, relative to entecavir for HCC. HBV mutation may play a role in HCC recurrence. Entecavir or tenofovir, a high genetic barrier to resistance, should be recommended for HBV-HCC patients. © 2015 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Is hypercortisolism in anorexia nervosa detectable using hair samples?

PubMed

Ritschel, Franziska; Clas, Sabine; Geisler, Daniel; Haas, Verena; Seidel, Maria; Steding, Julius; Roessner, Veit; Kirschbaum, Clemens; Ehrlich, Stefan

2018-03-01

Anorexia nervosa (AN) is a severe mental disorder accompanied by extensive metabolic and endocrine abnormalities. It has been associated with hypercortisolism using short-term measurement methods such as 24 h-urine, saliva, and blood. The aim of this study was to examine whether the proposed hypercortisolism in acutely underweight AN (acAN) is also reflected in a long-term measure: hair cortisol (HCC). To gain further insight, we compared hair cortisol to a well-established classical cortisol measure (24 h-urine; UCC) longitudinally in acAN. Hair samples were collected and analyzed using a LC-MS/MS-based method to provide a monthly cortisol value. We compared HCC in samples of 40 acAN with 40 pairwise age-matched healthy controls (HC) as well as 23 long-term recovered AN participants (recAN) with 23 pairwise age-matched HC (cross-sectional design). In the second part, UCC collected weekly during 14 weeks of weight-restoration therapy in 16 acAN was compared with the (time-corresponding) HCC using linear mixed models and bivariate correlations (longitudinal design). No group differences in HCC occurred comparing acAN and recAN to HC (cross-sectional study). The longitudinal analysis revealed a decrease of UCC but not HCC with weight gain. Furthermore, there was no overall significant association between UCC and HCC. Only in the last four weeks of weight-restoration therapy we found a significant moderate correlation between UCC and HCC. HCC did not reflect the expected hypercortisolism in acAN and did not decrease during short-term weight-restoration. Time-corresponding measurements of UCC and HCC were not consistently associated in our longitudinal analysis of acAN undergoing inpatient treatment. Given the drastic metabolic disturbances in acutely underweight AN our findings could be interpreted as disturbed cortisol incorporation or altered activity of 11-β-HSD-enzymes in the hair follicle. Copyright © 2017. Published by Elsevier Ltd.

Expression of K19 and K7 in dysplastic nodules and hepatocellular carcinoma.

PubMed

Bae, Jun Sang; Choi, Ha Na; Noh, Sang Jae; Park, Byung Hyun; Jang, Kyu Yun; Park, Cheol Keun; Moon, Woo Sung

2012-08-01

Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumors characterized by a multistep process of tumor development. Nodular lesions that differ from the surrounding liver parenchyma and are characterized by cytological or structural atypia are termed dysplastic nodules (DNs). DNs are well-known precancerous HCC lesions. Expression of keratin (K) 19 and K7, molecular markers of hepatic progenitor cells and cholangiocytes, has been reported in certain HCCs. However, it remains unclear whether K19-positive HCC cells are derived from true hepatic progenitor cells or mature cells that have undergone a dedifferentiation or a transdifferentiation process. In total, 107 tissue sections (13 low-grade DNs, 15 high-grade DNs, 27 small HCCs and 52 large HCCs) from resected liver samples and 132 HCC tissue microarray (TMA) cores were subjected to immunohistochemical analysis for K19 and K7. Clinicopathological data of the HCC patients were evaluated. K19 expression was found in 0% of DNs, 19% of small HCCs (≤2 cm), 8% of large HCCs (>2 cm) and 8% of TMA samples. K7 expression was found in 14% of DNs, 41% of small HCCs, 15% of large HCCs and 6% of TMA samples. Among the five K19-positive small HCCs, four were distinctly nodular and one tumor was an infiltrative type. No vaguely nodular HCC was positive for K19. K19 expression was significantly associated with histological grade (P=0.023), serum α-fetoprotein level (P=0.001) and K7 expression (P=0.001) in HCC. K19 expression was an independent prognostic factor for overall survival in non-viral HCC patients (P=0.003). K19 expression is extremely rare in DNs and occurs in progressed small HCCs. Our results suggest that K19 expression may be an acquired feature of carcinoma cells during HCC progression in certain HCCs.

Identification of DNA-PKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells.

PubMed

Cheng, Long; Liu, Yuan-Yuan; Lu, Pei-Hua; Peng, Yi; Yuan, Qiang; Gu, Xin-Shi; Jin, Yong; Chen, Min-Bin; Bai, Xu-Ming

2017-04-25

The current study tested the anti-hepatocellular carcinoma (HCC) cell activity of TIC10, a first-in-class small-molecule tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) inducer. TIC10 exerted potent anti-proliferative and pro-apoptotic actions in primary and established human HCC cells. TIC10 blocked Akt-Erk activation, leading to Foxo3a nuclear translocation, as well as TRAIL and death receptor-5 (DR5) transcription in HCC cells. We propose that DNA-PKcs is a major resistance factor of TIC10 possibly via inhibiting Foxo3a nuclear translocation. DNA-PKcs inhibition, knockdown or mutation facilitated TIC10-induced Foxo3a nuclear translocation, TRAIL/DR5 expression and cell apoptosis. Reversely, exogenous DNA-PKcs over-expression inhibited above actions by TIC10. In vivo, oral administration of TIC10 significantly inhibited HepG2 tumor growth in nude mice, which was further potentiated with Nu7026 co-administration. Thus, TIC10 shows promising anti-HCC activity, alone or together with DNA-PKcs inhibitors.

Consensus Development from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014)

PubMed Central

Hsu, Chiun; Chen, Bang-Bin; Chen, Chien-Hung; Ho, Ming-Chih; Cheng, Jason Chia-Hsien; Kokudo, Norihiro; Murakami, Takamichi; Yeo, Winnie; Seong, Jinsil; Jia, Ji-Dong; Han, Kwan-Hyub; Cheng, Ann-Lii

2015-01-01

A key mission of the Asia-Pacific Primary Liver Cancer Expert (APPLE) Association is to ensure a coherent view for management of hepatocellular carcinoma (HCC) and to advance new treatment for this difficult disease. At the 5th APPLE meeting, held in July 2014 in Taipei, Taiwan, an APPLE consensus development program was established to facilitate discussion among experts in the Asia-Pacific region on pertinent issues for HCC management, including (1) surgery for intermediate/advanced-stage disease, (2) prevention of HCC recurrence after curative treatment, (3) optimizing imaging diagnosis, (4) radiotherapy: current practice and future clinical trials, and (5) the role of cytotoxic chemotherapy. A pre-congress questionnaire was undertaken with the consensus development committee members to help understand the current practice patterns for HCC in the Asia-Pacific region and to identify issues relating to optimal patient care and further clinical trials for which consensus needs to be developed. In this report, the results of the questionnaire are presented, and the pertinent issues identified by each consensus group for further discussion and consensus development are summarized. PMID:26020032

Postoperative Outcomes for Patients with Non-B Non-C Hepatocellular Carcinoma: A Subgroup Analysis of Patients with a History of Hepatitis B Infection.

PubMed

Omichi, Kiyohiko; Shindoh, Junichi; Yamamoto, Satoshi; Matsuyama, Yutaka; Akamatsu, Nobuhisa; Arita, Junichi; Kaneko, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Kokudo, Norihiro

2015-12-01

Hepatocellular carcinoma (HCC) not associated with active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, termed non-B non-C HCC (nBnC-HCC), is reportedly correlated with better survival outcomes than HBV- or HCV-related HCC. However, the nBnC-HCC population includes patients with a history of HBV infection possessing anti-hepatitis B core antibodies (HBcAb), and the oncologic significance of this finding remains unclear. A retrospective review of the data for 562 patients who underwent curative resection for primary HCC was performed. The clinical outcomes were compared among the following four groups: HBV group (HBsAg-positive), HCV group (HCVAb-positive), HBcAb-positive nBnC-HCC group, and pure nBnC-HCC group (negative for these viral markers). The HBcAb-positive nBnC-HCC group showed better overall survival (OS) and recurrence-free survival (RFS) rates than the HBV, HCV, and pure nBnC-HCC groups (5-year OS 89.4 vs 68.4, 62.0, and 66.2 %; P = 0.003; 5-year RFS 53.8 vs 31.4, 28.1, and 33.6 %; P = 0.01). A multivariate analysis confirmed that a history of HBV is associated with a lower risk of OS (hazard ratio [HR] 0.23; 95 % confidence interval [CI] 0.09-0.56; P = 0.001) and RFS (HR 0.45; 95 % CI 0.27-0.73; P = 0.001). The HBcAb-positive nBnC-HCC group was associated with a higher incidence of well-differentiated HCC (33 vs 15 %; P = 0.03) and lower plasma des-gamma-carboxyprothrombin concentration (72 vs 357 mAu/mL; P = 0.047) than the pure nBnC group. The subgroup of patients with a history of HBV infection may have better survival outcomes after resection of HCC than the HBV/HCV-related or pure nBnC-HCC patients.

2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma

PubMed Central

2015-01-01

The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC. PMID:25918260

2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma.

PubMed

2015-05-23

The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.

Paired assessment of liver telomere lengths in hepatocellular cancer is a reliable predictor of disease persistence.

PubMed

Feng, Wendu; Yu, Decai; Li, Binghua; Luo, Ou-Yang; Xu, Tiancheng; Cao, Yajuan; Ding, Yitao

2017-04-30

In the present study, we used a small series of highly defined patients, where we had matched timed peripheral blood samples (PBS), as well as paired liver biopsies obtained during collection of blood samples from patients with diagnosed hepatocellular carcinoma (HCC) and compared the correlation between the changes of telomere lengths in these defined samples. Patients included had either HCC alone or in conjunction with either pre-existing hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. PCR-based assay incorporating primers to the telomeric hexamer repeats to polymerize and detect telomeric DNA was used. The average telomere length for each independent assessment was measured by seeing the differences in the intensity of the sample's telomere signal (T) to the signal from a single-copy gene (S-, β-globin) to estimate the standard ratio. Our results provide the first convincing evidence that PBS may be utilized to assay telomere shortening as a predictor for disease persistence in HCC resulting after HBV or HCV infection, but not in non-infectious cause-stimulated HCC. These findings provide incipient opportunity to develop telomere length assessment as a biomarker tool for prediction of HCC in patients with HBV or HCV infection, as well as to gauge responses to chemotherapy and other treatment modalities. © 2017 The Author(s).

Protein induced by vitamin K absence or antagonist-II (PIVKA-II) specifically increased in Italian hepatocellular carcinoma patients.

PubMed

Viggiani, Valentina; Palombi, Sara; Gennarini, Giuseppina; D'Ettorre, Gabriella; De Vito, Corrado; Angeloni, Antonio; Frati, Luigi; Anastasi, Emanuela

2016-10-01

As a marker for Hepatocellular Carcinoma (HCC), Protein Induced by Vitamin K Absence II (PIVKA-II) seems to be superior to alpha fetoprotein (AFP). To better characterize the role of PIVKA-II, both AFP and PIVKA-II have been measured in Italian patients with diagnosis of HCC compared with patients affected by non-oncological liver pathologies. Sixty serum samples from patients with HCC, 60 samples from patients with benign liver disease and 60 samples obtained from healthy blood donors were included in the study. PIVKA-II and AFP were measured by LUMIPULSE(®) G1200 (Fujirebio-Europe, Belgium). We considered as PIVKA-II cutoff 70 mAU/ml (mean +3SD) of the values observed in healthy subjects. The evaluation of PIVKA-II showed a positivity of 70% in patients with HCC and 5% in patients with benign diseases (p < 0.0001) whereas high levels of AFP were observed in 55% of HCC patients and in 47% of patients with benign diseases. The combined Receiver Operating Characteristic (ROC) analysis of the two analytes revealed a higher sensitivity (75%) compared to those observed for the individual biomarkers. In conclusion, we demonstrate that as a marker for HCC, PIVKA-II is more specific for HCC and less prone to elevation during chronic liver diseases. The combination of the two biomarkers, evaluated by the ROC analysis, improved the specificity compared to a single marker. These data suggest that the combined analysis of the two markers could be a useful tool in clinical practice.

Co-expression network analysis identified six hub genes in association with metastasis risk and prognosis in hepatocellular carcinoma

PubMed Central

Feng, Juerong; Zhou, Rui; Chang, Ying; Liu, Jing; Zhao, Qiu

2017-01-01

Hepatocellular carcinoma (HCC) has a high incidence and mortality worldwide, and its carcinogenesis and progression are influenced by a complex network of gene interactions. A weighted gene co-expression network was constructed to identify gene modules associated with the clinical traits in HCC (n = 214). Among the 13 modules, high correlation was only found between the red module and metastasis risk (classified by the HCC metastasis gene signature) (R2 = −0.74). Moreover, in the red module, 34 network hub genes for metastasis risk were identified, six of which (ABAT, AGXT, ALDH6A1, CYP4A11, DAO and EHHADH) were also hub nodes in the protein-protein interaction network of the module genes. Thus, a total of six hub genes were identified. In validation, all hub genes showed a negative correlation with the four-stage HCC progression (P for trend < 0.05) in the test set. Furthermore, in the training set, HCC samples with any hub gene lowly expressed demonstrated a higher recurrence rate and poorer survival rate (hazard ratios with 95% confidence intervals > 1). RNA-sequencing data of 142 HCC samples showed consistent results in the prognosis. Gene set enrichment analysis (GSEA) demonstrated that in the samples with any hub gene highly expressed, a total of 24 functional gene sets were enriched, most of which focused on amino acid metabolism and oxidation. In conclusion, co-expression network analysis identified six hub genes in association with HCC metastasis risk and prognosis, which might improve the prognosis by influencing amino acid metabolism and oxidation. PMID:28430663

FAM83D activates the MEK/ERK signaling pathway and promotes cell proliferation in hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Dong; Han, Sheng; Peng, Rui

2015-03-06

Publicly available microarray data suggests that the expression of FAM83D (Family with sequence similarity 83, member D) is elevated in a wide variety of tumor types, including hepatocellular carcinoma (HCC). However, its role in the pathogenesis of HCC has not been elucidated. Here, we showed that FAM83D was frequently up-regulated in HCC samples. Forced FAM83D expression in HCC cell lines significantly promoted their proliferation and colony formation while FAM83D knockdown resulted in the opposite effects. Mechanistic analyses indicated that FAM83D was able to activate the MEK/ERK signaling pathway and promote the entry into S phase of cell cycle progression. Takenmore » together, these results demonstrate that FAM83D is a novel oncogene in HCC development and may constitute a potential therapeutic target in HCC. - Highlights: • FAM83D is up-regulated in HCC tissues and cell lines. • Ectopic expression of FAM83D promotes HCC cell proliferation and colony formation. • Depletion of FAM83D inhibits HCC cell proliferation and colony formation. • FAM83D activates the MEK/ERK signaling pathway in HCC.« less

Prognostic significance of kynurenine 3-monooxygenase and effects on proliferation, migration, and invasion of human hepatocellular carcinoma

PubMed Central

Jin, Haojie; Zhang, Yurong; You, Haiyan; Tao, Xuemei; Wang, Cun; Jin, Guangzhi; Wang, Ning; Ruan, Haoyu; Gu, Dishui; Huo, Xisong; Cong, Wenming; Qin, Wenxin

2015-01-01

Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the kynurenine pathway of tryptophan degradation and plays a critical role in Huntington’s and Alzheimer’s diseases. This study aimed to examine the expression of KMO in human hepatocellular carcinoma (HCC) and investigate the relationship between its expression and prognosis of HCC patients. We first analyzed KMO expression in 120 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), and 205 clinical HCC specimens using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis showed that KMO expression was significantly higher in HCC tissues than that in normal liver tissues (all p < 0.05). Survival and recurrence analyses showed that KMO was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR) (both p<0.01). And in vitro studies revealed that KMO positively regulated proliferation, migration, and invasion of HCC cells. These results suggest that KMO exhibits tumor-promoting effects towards HCC and it may serve as a novel prognostic marker in HCC. PMID:26099564

[Association between hair cortisol concentration and overweight and obesity in 6-9 years old childhood].

PubMed

Hu, J J; Duan, X N; Fang, J; Xu, N; Wan, Y H; Su, P Y; Tao, F B; Sun, Y

2017-12-06

Objective: To determine the possible relations between hair cortisol concentration (HCC) as a biomarker of chronic stress and childhood overweight and obesity. Methods: Children from grade 1 to 3 from 2 primary schools in Bengbu were invited to participate in the study; and those who suffer from mental disorders, endocrine diseases and those who took hormone drugs were excluded. Parental questionnaire was implemented to collect information on physical activity, screen time, sleep duration, sugar-beverage consumption, as well as socio-economic status. Height and weight were examined. Eligible hair samples from 1 263 children (598 boys and 665 girls) were obtained, and the cortisol content was determined. Multivariate logistic regression model analysis was recruited to examine the association between HCC quartiles and overweight and obesity among boys and girls, respectively. Results: HCC in P (50) ( P (25)- P (75)) among girls and boys was separately 11.86 (10.57-13.15) and 11.71 (10.54-13.09) µg/kg ( Z=- 0.886, P= 0.376); HCC in P (50) ( P (25)- P (75)) among non-overweight, overweight and obesity boys was separately 11.62 (10.45-12.82), 12.24 (10.88-13.55) and 12.30 (10.99-13.53) µg/kg (χ(2)=8.24, P= 0.016); HCC in P (50) ( P (25)- P (75)) among non-overweight, overweight and obesity girls was separately 11.35 (10.06-12.62), 12.07 (11.04-13.21) and 12.59 (11.12-13.63) µg/kg (χ(2)=36.16, P< 0.001). After age, physical activity, screen time, sleep duration, sugared beverages and socio-economic status adjusted, compared with HCC in Q 1 level, girls whose HCC in Q 2, Q 3 Q 4 level had higher rates in overweight, with OR (95 %CI ) at 1.10 (1.04-3.32), 2.59 (1.51-4.45) and 3.16 (1.79-5.57), respectively. Girls with HCC in Q 3 and Q 4 level had higher rates in obesity, with OR (95 %CI ) at 2.22 (1.16-4.26) and 5.62 (3.04-10.41). Among boys, highest quartiles in HCC was risk factor for overweight, OR (95 %CI ) was 2.14 (1.18-3.90). Conclusion: Hair cortisol had a significant relation with overweight and obesity in 6-9 years old childhood especially among girls.

Liver Rapid Reference Set Application: Hiro Yamada - Wako (2011) — EDRN Public Portal

Cancer.gov

Measure clinical effectiveness of AFP-L3 and DCP for early detection of HCC in patient samples collected prospectively during surveillance. However since such samples are not readily available in the USA the reference set samples are well characterized and studied, gaining access to these samples will allow Wako to quickly measure clinical effectiveness of AFP-L3 and DCP in detecting early HCC.

Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas.

PubMed

Zhou, Guoying; Sprengers, Dave; Boor, Patrick P C; Doukas, Michail; Schutz, Hannah; Mancham, Shanta; Pedroza-Gonzalez, Alexander; Polak, Wojciech G; de Jonge, Jeroen; Gaspersz, Marcia; Dong, Haidong; Thielemans, Kris; Pan, Qiuwei; IJzermans, Jan N M; Bruno, Marco J; Kwekkeboom, Jaap

2017-10-01

Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell-mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non-small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4 + and CD8 + T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8 + and CD4 + T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8 + and CD4 + T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8 + TIL, compared with other CD8 + TIL. Compared with TIL that did not express these inhibitory receptors, CD8 + and CD4 + TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8 + and CD4 + TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chinese herbal medicine-derived compounds for cancer therapy: a focus on hepatocellular carcinoma.

PubMed

Hu, Yangyang; Wang, Shengpeng; Wu, Xu; Zhang, Jinming; Chen, Ruie; Chen, Meiwan; Wang, Yitao

2013-10-07

Hepatocellular carcinoma (HCC) as the major histological subtype of primary liver cancer remains one of the most common malignancies worldwide. Due to the complicated molecular pathogenesis of HCC, the option for effective systemic treatment is quite limited. There exists a critical need to explore and evaluate possible alternative strategies for effective control of HCC. With a long history of clinical use, Chinese herbal medicine (CHM) is emerging as a noticeable choice for its multi-level, multi-target and coordinated intervention effects against HCC. With the aids of phytochemistry and molecular biological approaches, in the past decades many CHM-derived compounds have been carefully studied through both preclinical and clinical researches and have shown great potential in novel anti-HCC natural product development. The present review aimed at providing the most recent developments on anti-HCC compounds derived from CHM, especially their underlying pharmacological mechanisms. A systematic search of anti-HCC compounds from CHM was carried out focusing on literatures published both in English (PubMed, Scopus, Web of Science and Medline) and in Chinese academic databases (Wanfang and CNKI database). In this review, we tried to give a timely and comprehensive update about the anti-HCC effects and targets of several representative CHM-derived compounds, namely curcumin, resveratrol, silibinin, berberine, quercetin, tanshinone II-A and celastrol. Their mechanisms of anti-HCC behaviors, potential side effects or toxicity and future research directions were discussed. Herbal compounds derived from CHM are of much significance in devising new drugs and providing unique ideas for the war against HCC. We propose that these breakthrough findings may have important implications for targeted-HCC therapy and modernization of CHM. Copyright © 2013. Published by Elsevier Ireland Ltd.

Development of Glycoprotein Capture-Based Label-Free Method for the High-throughput Screening of Differential Glycoproteins in Hepatocellular Carcinoma*

PubMed Central

Chen, Rui; Tan, Yexiong; Wang, Min; Wang, Fangjun; Yao, Zhenzhen; Dong, Liwei; Ye, Mingliang; Wang, Hongyang; Zou, Hanfa

2011-01-01

A robust, reproducible, and high throughput method was developed for the relative quantitative analysis of glycoprotein abundances in human serum. Instead of quantifying glycoproteins by glycopeptides in conventional quantitative glycoproteomics, glycoproteins were quantified by nonglycosylated peptides derived from the glycoprotein digest, which consists of the capture of glycoproteins in serum samples and the release of nonglycopeptides by trypsin digestion of captured glycoproteins followed by two-dimensional liquid chromatography-tandem MS analysis of released peptides. Protein quantification was achieved by comparing the spectrum counts of identified nonglycosylated peptides of glycoproteins between different samples. This method was demonstrated to have almost the same specificity and sensitivity in glycoproteins quantification as capture at glycopeptides level. The differential abundance of proteins present at as low as nanogram per milliliter levels was quantified with high confidence. The established method was applied to the analysis of human serum samples from healthy people and patients with hepatocellular carcinoma (HCC) to screen differential glycoproteins in HCC. Thirty eight glycoproteins were found with substantial concentration changes between normal and HCC serum samples, including α-fetoprotein, the only clinically used marker for HCC diagnosis. The abundance changes of three glycoproteins, i.e. galectin-3 binding protein, insulin-like growth factor binding protein 3, and thrombospondin 1, which were associated with the development of HCC, were further confirmed by enzyme-linked immunosorbent assay. In conclusion, the developed method was an effective approach to quantitatively analyze glycoproteins in human serum and could be further applied in the biomarker discovery for HCC and other cancers. PMID:21474793

Overexpression of the RD RNA binding protein in hepatitis C virus-related hepatocellular carcinoma.

PubMed

Iida, Michihisa; Iizuka, Norio; Tsunedomi, Ryouichi; Tsutsui, Masahiro; Yoshida, Shin; Maeda, Yoshinari; Tokuhisa, Yoshihiro; Sakamoto, Kazuhiko; Yoshimura, Kiyoshi; Tamesa, Takao; Oka, Masaaki

2012-08-01

Hepatocellular carcinoma (HCC) often exhibits a poor prognosis due to metastatic spread caused by portal vein invasion (PVI). In the present study, we attempted to identify a novel therapeutic target related to PVI of HCC. Based on pooled genomic data, we identified RD RNA binding protein (RDBP), a member of the negative elongation factor (NELF) transcription elongation regulatory complex, to be preferentially overexpressed in HCC with PVI. We used quantitative reverse transcription polymerase chain reaction (RT-PCR) and immuno-histochemical analyses to investigate the relationship between RDBP mRNA and protein with metastatic potential in sample sets of hepatitis C virus (HCV)-related HCC and corresponding non-HCC liver tissues. We also used the small interfering RNA technique to examine the role of RDBP in invasion and proliferation of HCC cells in vitro. Our data showed that both mRNA and protein levels of RDBP were significantly higher in HCC compared to non-HCC liver tissue, and that these levels were also significantly higher in HCC with PVI compared to HCC without PVI. Multivariate analysis revealed that RDBP protein levels were an independent risk factor for early intrahepatic recurrence of HCC within 2 years of surgery. Knockdown of RDBP protein significantly inhibited the proliferation and invasion of cells in vitro. These data demonstrate that RDBP is related to the metastatic potential of HCC, suggesting a possible candidate for prevention of HCC cell metastasis.

Preventive antitumor activity against hepatocellular carcinoma (HCC) induced by immunization with fusions of dendritic cells and HCC cells in mice.

PubMed

Homma, S; Toda, G; Gong, J; Kufe, D; Ohno, T

2001-11-01

The prevention of recurrence of hepatocellular carcinoma (HCC) after treatment is very important for improvement of the prognosis of HCC patients. Dendritic cells (DCs) are potent antigen-presenting cells that can prime naive T cells to induce a primary immune response. We attempted to induce preventive antitumor immunity against HCC by immunizing BALB/c mice with fusions of DCs and HCC cells. Murine bone marrow-derived DCs and a murine HCC cell line. BNL cells, were fused by treatment with 50% polyethyleneglvcol (PEG). Fusion efficacy was assessed by the analysis of fusions of BNL cells stained with red fluorescent dye and DCs stained with green fluorescent dye. Mice injected intravenously with DC/BNL fusions were challenged by BNL cell inoculation. About 30% of the PEG-treated non-adherent cells with both fluorescences were considered to be fusion cells. The cell fraction of DC/BNL fusions showed phenotypes of DCs, MHC class II, CD80, CD86, and intercellular adhesion molecule (ICAM)-1, which were not expressed on BNL cells. Mice immunized with the fusions were protected against the inoculation of BNL tumor cells, whereas injection with a mixture of DCs and BNL cells not treated with PEG did not provide significant resistance against BNL cell inoculation. Splenocytes from DC/BNL fusion-immunized mice showed lytic activity against BNL cells. These results demonstrate that immunization with fusions of DCs and HCC cells is capable of inducing preventive antitumor immunity against HCC.

Socioeconomic status, hair cortisol and internalizing symptoms in parents and children.

PubMed

Ursache, Alexandra; Merz, Emily C; Melvin, Samantha; Meyer, Jerrold; Noble, Kimberly G

2017-04-01

Socioeconomic disadvantage is consistently linked with higher risk for internalizing problems, and stress is likely one important mechanism explaining this increased risk. Few studies have examined socioeconomic differences in hair cortisol, a novel biomarker of long-term adrenocortical activity and chronic stress. Moreover, no studies have examined whether differences in hair cortisol might explain socioeconomic disparities in internalizing problems. To address these gaps, we first examined relations of socioeconomic status (SES; family income and parental education) to variation in both parents' and children's hair cortisol concentrations (HCC) and then tested whether HCC and perceptions of stress mediated relations of SES to parents' and children's internalizing symptoms. Participants were a socioeconomically diverse sample of 35 parents and 26 children (ages 5-7). Parents completed questionnaires, and hair samples were collected from parents and children. Parents reported on children's internalizing symptoms on average 2 years after the initial visit. Results demonstrated that lower parental education was associated with higher HCC for both parents and children. Effects for child HCC held even after controlling for parent HCC. Lower family income was associated with higher parent HCC, but not child HCC. This relation was nonlinear, such that the relation between HCC and income was strongest among the most disadvantaged parents. Furthermore, associations of SES with parental anxiety were significantly mediated by parental perceptions of stress and marginally mediated by parent HCC. These findings suggest that socioeconomic disadvantage is associated with greater accumulation of cortisol in hair in parents and children, and that both perceived and biological markers of stress capture important facets of the experiences that underlie socioeconomic disparities in adult anxiety. Copyright © 2017 Elsevier Ltd. All rights reserved.

2014 Korean Liver Cancer Study Group-National Cancer Center Korea practice guideline for the management of hepatocellular carcinoma.

PubMed

2015-01-01

The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.

2014 Korean Liver Cancer Study Group-National Cancer Center Korea Practice Guideline for the Management of Hepatocellular Carcinoma

PubMed Central

2015-01-01

The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC. PMID:25995680

Liver stem/progenitor cells in the canals of Hering: cellular origin of hepatocellular carcinoma with bile duct tumor thrombi?

PubMed

Peng, Ningfu; Li, Lequn; Cai, Xiang; Tan, Shaozao; Wu, Ting

2010-12-01

It is generally believed that the invasion of hepatocellular carcinoma (HCC) into the biliary tree ultimately leads to the formation of bile duct tumor thrombi (BDTT). However, recent studies revealed that primary tumor might be small, even undetectable, and there was no histopathologic evidence of direct tumor invasion into bile duct wall in some patients. During the last decade, efforts on stem cell biology may shed light on the pathogenesis of BDTT. Presently, accumulating evidence supports the following notions: (1) the canals of Hering (CoH) are the most likely origin of liver stem/progenitor cells (LSPCs) in adult livers; (2) similar signalling pathways may regulate self-renewal in LSPCs and liver cancer cells, and a substantial proportion of liver tumors may often originate from the transformation of LSPCs; and (3) liver cancer contains rare cells with stem cell-like properties, which could derive from malignant transformation of LSPCs. Herein, we propose that HCC with BDTT, especially with small or undetectable primary lesion and/or no histopathologic evidence for bile duct invasion, might arise from LSPCs residing in the CoH and, possibly, some primary lesions are formed firstly within the intrahepatic biliary tree. When "tumor thrombi" extends mainly along bile duct, there might be "BDTT" alone; when it invades into surrounding parenchyma, there might often be small "primary tumor" with "BDTT". If this holds true, the putative type may be a particular subset of HCC, and most importantly it would facilitate our understanding of stem-cell origin of HCC.

Analysis of differentially co-expressed genes based on microarray data of hepatocellular carcinoma.

PubMed

Wang, Y; Jiang, T; Li, Z; Lu, L; Zhang, R; Zhang, D; Wang, X; Tan, J

2017-01-01

Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death worldwide. Although great progress in diagnosis and management of HCC have been made, the exact molecular mechanisms remain poorly understood. The study aims to identify potential biomarkers for HCC progression, mainly at transcription level. In this study, chip data GSE 29721 was utilized, which contains 10 HCC samples and 10 normal adjacent tissue samples. Differentially expressed genes (DEGs) between two sample types were selected by t-test method. Following, the differentially co-expressed genes (DCGs) and differentially co-expressed Links (DCLs) were identified by DCGL package in R with the threshold of q < 0.25. Afterwards, pathway enrichment analysis of the DCGs was carried out by DAVID. Then, DCLs were mapped to TRANSFAC database to reveal associations between relevant transcriptional factors (TFs) and their target genes. Quantitative real-time RT-PCR was performed for TFs or genes of interest. As a result, a total of 388 DCGs and 35,771 DCLs were obtained. The predominant pathways enriched by these genes were Cytokine-cytokine receptor interaction, ECM-receptor interaction and TGF-β signaling pathway. Three TF-target interactions, LEF1-NCAM1, EGR1-FN1 and FOS-MT2A were predicted. Compared with control, expressions of the TF genes EGR1, FOS and ETS2 were all up-regulated in the HCC cell line, HepG2; while LEF1 was down-regulated. Except NCAM1, all the target genes were up-regulated in HepG2. Our findings suggest these TFs and genes might play important roles in the pathogenesis of HCC and may be used as therapeutic targets for HCC management.

A Highly Sensitive and Robust Method for Hepatitis B Virus Covalently Closed Circular DNA Detection in Single Cells and Serum.

PubMed

Huang, Jing-Tao; Yang, Ying; Hu, Yi-Min; Liu, Xing-Hui; Liao, Mei-Yan; Morgan, Roy; Yuan, Er-Feng; Li, Xia; Liu, Song-Mei

2018-05-01

Despite implications of persistence of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in the development of hepatocellular carcinoma (HCC), little is known about serum cccDNA in HBV-infected diseases. We developed a cccDNA-selective droplet digital PCR (ddPCR) to assess cccDNA content and dynamics across different stages of HCC development. One hundred forty-seven serum samples and 35 formalin-fixed, paraffin-embedded tumor tissues were derived from patients with HCC or HBV hepatitis/cirrhosis. After specific amplification and selective digestion, probe-based ddPCR was used to quantify cccDNA copy numbers in single cells and clinical samples. The cccDNA in single HepG2.2.15 cells ranged from 0 to 10.8 copies/cell. Compared with non-HCC patients, HCC patients showed a higher cccDNA-positive rate (89.9% versus 53.2%; P = 4.22 × 10 -6 ) and increased serum cccDNA contents (P = 0.002 and P = 0.041 for hepatitis and cirrhosis patients, respectively). Serum cccDNA ranged from 84 to 1.07 × 10 5 copies/mL. Quantification of serum cccDNA and HBV-DNA was an effective way to discriminate HCC patients from non-HCC patients, with areas under the curve of receiver operating characteristic of 0.847 (95% CI, 0.759-0.935; sensitivity, 74.5%; specificity, 93.7%). cccDNA-selective ddPCR is sensitive to detect cccDNA in single cells and different clinical samples. Combined analysis of serum cccDNA and HBV-DNA may be a promising strategy for HBV-induced HCC surveillance and antiviral therapy evaluation. Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

[Expression of ATAD2 in different liver lesions and its clinical significance].

PubMed

Liu, F; Zhou, X; Ji, H H; Li, H; Xiang, F G

2017-05-20

Objective: To examine the expression of ATAD2 in different liver lesions and its clinical significance. Methods: ATAD2 expression in 60 hepatocellular carcinoma (HCC) surgical specimens (49 of which have concurrent liver cirrhosis), 43 HCC biopsy specimens, 2 high-grade liver dysplastic nodule specimens, 3 low-grade liver dysplastic nodule specimens, 50 liver cirrhosis tissue samples, and 20 normal liver tissue samples were measured using immunohistochemistry. The F-test, q-test, t-test, and chi-square test were used for statistical analysis of data. Results: ATAD2 was expressed in 56 HCC surgical specimens (93.33%), 35 HCC biopsy specimens (81.40%), and 2 high-grade liver dysplastic nodule specimens (2/2), but not in the low-grade liver dysplastic nodule, liver cirrhosis tissue, and normal liver tissue samples. The mean expression of ATAD2 was significantly higher in HCC tissues than in high-grade and low-grade liver dysplastic nodule tissues, liver cirrhosis tissue, and normal liver tissue ( F = 22.96, q = 3.138, 3.972, 12.272, and 9.101, respectively, all P < 0.01). There were no significant differences in the mean expression and positive expression rate of ATAD2 between HCC surgical and biopsy specimens ( t = 1.40, P > 0.05; χ ² = 3.47, P >0.05). Of the 35 HCC biopsy specimens that expressed ATAD2, the mean ATAD2 expression was ≥1% in 35 specimens (100%), ≥3% in 27 specimens (77.14%), and ≥5 % in 23 specimens (65.71%). In addition, among the pathological grade I-II HCC biopsy specimens, the mean ATAD2 expression was ≥1% in 28 specimens (100%), ≥3% in 22 specimens (62.86%), and ≥5% in 19 specimens (54.29%). Moreover, ATAD2 expression in HCC was associated with serum alpha-fetoprotein level, presence of hepatitis B virus surface antigen (HBsAg), and presence of concurrent liver cirrhosis ( t = 2.09, 2.30, and 2.18, respectively, all P < 0.05). Conclusion: ATAD2 may play an important role in HCC tumorigenesis, and may be involved in malignant transformation of cells. ATAD2 expression can be a valuable marker for differentiating the nature of lesions in liver biopsy tissues during clinical practice.

Predictors for microinvasion of small hepatocellular carcinoma ≤ 2 cm.

PubMed

Yamashita, Yo-ichi; Tsuijita, Eiji; Takeishi, Kazuki; Fujiwara, Megumu; Kira, Shinsuke; Mori, Masaki; Aishima, Shinichi; Taketomi, Akinobu; Shirabe, Ken; Ishida, Terutoshi; Maehara, Yoshihiko

2012-06-01

Hepatocellular carcinoma (HCC) ≤ 2 cm in diameter is considered to have a low potential for malignancy. A retrospective review was undertaken of 149 patients with primary solitary HCC ≤ 2 cm who underwent initial hepatic resection between 1994 and 2010. The independent predictors of the microinvasion (MI) such as portal venous, hepatic vein, or bile duct infiltration and/or intrahepatic metastasis were identified by multivariate analysis. Prognosis of patients with HCC ≤ 2 cm accompanied by MI was compared to that of patients with HCC ≤ 2 cm without MI. Forty-three patients with HCC ≤ 2 cm had MI in patients (28.9%). Three independent predictors of the MI were revealed: invasive gross type (simple nodular type with extranodular growth or confluent multinodular type), des-γ-carboxy prothrombin (DCP) >100 mAU/ml, and poorly differentiated. Disease-free survival rates of patients with HCC ≤ 2 cm with MI (3 year 44%) were significantly worse than those for HCC ≤ 2 cm without MI (3 year 72%). This disadvantage of disease-free survival rate of patients with HCC ≤ 2 cm with MI could be dissolved by hepatic resection with a wide tumor margin of ≥ 5 mm (P = 0.04). Even in cases of HCC ≤ 2 cm, patients who are suspected of having invasive gross type tumors in preoperative imaging diagnosis or who have a high DCP level (>100 mAU/ml) are at risk for MI. Therefore, in such patients, hepatic resection with a wide tumor margin should be recommended.

Synthesis and physicochemical studies of amyloidogenic hexapeptides derived from human cystatin C.

PubMed

Iłowska, Emilia; Sawicka, Justyna; Szymańska, Aneta

2018-06-01

Human cystatin C (hCC) is a low molecular mass protein that belongs to the cystatin superfamily. It is an inhibitor of extracellular cysteine proteinases, present in all human body fluids. At physiological conditions, hCC is a monomer, but it has a tendency to dimerization. Naturally occurring hCC mutant, with leucine in position 68 substituted by glutamine (L68Q), is directly involved in the formation of amyloid deposits, independently of other proteins. This process is the primary cause of hereditary cerebral amyloid angiopathy, observed mainly in the Icelandic population. Oligomerization and fibrillization processes of hCC are not explained equally well, but it is proposed that domain swapping is involved in both of them. Research carried out on the fibrillization process led to new hypothesis about the existence of a steric zipper motif in amyloidogenic proteins. In the hCC sequence, there are 2 fragments which may play the role of a steric zipper: the loop L1 region and the C-terminal fragment. In this work, we focused on the first of these. Nine hexapeptides covering studied hCC fragment were synthesized, and their fibrillogenic potential was assessed using an array of biophysical methods. The obtained results showed that the studied hCC fragment has strong profibrillogenic propensities because it contains 2 fragments fulfilling the requirements for an effective steric zipper located next to each other, forming 1 super-steric zipper motif. This hCC fragment might therefore be responsible for the enhanced amyloidogenic properties of dimeric or partially unfolded hCC. Copyright © 2018 European Peptide Society and John Wiley & Sons, Ltd.

Regulation and function of the atypical cadherin FAT1 in hepatocellular carcinoma.

PubMed

Valletta, Daniela; Czech, Barbara; Spruss, Thilo; Ikenberg, Kristian; Wild, Peter; Hartmann, Arndt; Weiss, Thomas S; Oefner, Peter J; Müller, Martina; Bosserhoff, Anja-Katrin; Hellerbrand, Claus

2014-06-01

In human cancers, giant cadherin FAT1 may function both, as an oncogene and a tumor suppressor. Here, we investigated the expression and function of FAT1 in hepatocellular carcinoma (HCC). FAT1 expression was increased in human HCC cell lines and tissues compared with primary human hepatocytes and non-tumorous liver tissue as assessed by quantitative PCR and western blot analysis. Combined immunohistochemical and tissue microarray analysis showed a significant correlation of FAT1 expression with tumor stage and proliferation. Suppression of FAT1 expression by short hairpin RNA impaired proliferation and migration as well as apoptosis resistance of HCC cells in vitro. In nude mice, tumors formed by FAT1-suppressed HCC cells showed a delayed onset and more apoptosis compared with tumors of control cells. Both hepatocyte growth factor and hypoxia-mediated hypoxia-inducible factor 1 alpha activation were identified as strong inducers of FAT1 in HCC. Moreover, demethylating agents induced FAT1 expression in HCC cells. Hypoxia lead to reduced levels of the methyl group donor S-adenosyl-L-methionine (SAM) and hypoxia-induced FAT1 expression was inhibited by SAM supplementation in HCC cells. Together, these findings indicate that FAT1 expression in HCC is regulated via promotor methylation. FAT1 appears as relevant mediator of hypoxia and growth receptor signaling to critical tumorigenic pathways in HCC. This knowledge may facilitate the rational design of novel therapeutics against this highly aggressive malignancy. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Development and application of a fluorescence protein microarray for detecting serum alpha-fetoprotein in patients with hepatocellular carcinoma.

PubMed

Zhang, Aiying; Yin, Chengzeng; Wang, Zhenshun; Zhang, Yonghong; Zhao, Yuanshun; Li, Ang; Sun, Huanqin; Lin, Dongdong; Li, Ning

2016-12-01

Objective To develop a simple, effective, time-saving and low-cost fluorescence protein microarray method for detecting serum alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC). Method Non-contact piezoelectric print techniques were applied to fluorescence protein microarray to reduce the cost of prey antibody. Serum samples from patients with HCC and healthy control subjects were collected and evaluated for the presence of AFP using a novel fluorescence protein microarray. To validate the fluorescence protein microarray, serum samples were tested for AFP using an enzyme-linked immunosorbent assay (ELISA). Results A total of 110 serum samples from patients with HCC ( n = 65) and healthy control subjects ( n = 45) were analysed. When the AFP cut-off value was set at 20 ng/ml, the fluorescence protein microarray had a sensitivity of 91.67% and a specificity of 93.24% for detecting serum AFP. Serum AFP quantified via fluorescence protein microarray had a similar diagnostic performance compared with ELISA in distinguishing patients with HCC from healthy control subjects (area under receiver operating characteristic curve: 0.906 for fluorescence protein microarray; 0.880 for ELISA). Conclusion A fluorescence protein microarray method was developed for detecting serum AFP in patients with HCC.

Development and application of a fluorescence protein microarray for detecting serum alpha-fetoprotein in patients with hepatocellular carcinoma

PubMed Central

Zhang, Aiying; Yin, Chengzeng; Wang, Zhenshun; Zhang, Yonghong; Zhao, Yuanshun; Li, Ang; Sun, Huanqin; Lin, Dongdong

2016-01-01

Objective To develop a simple, effective, time-saving and low-cost fluorescence protein microarray method for detecting serum alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC). Method Non-contact piezoelectric print techniques were applied to fluorescence protein microarray to reduce the cost of prey antibody. Serum samples from patients with HCC and healthy control subjects were collected and evaluated for the presence of AFP using a novel fluorescence protein microarray. To validate the fluorescence protein microarray, serum samples were tested for AFP using an enzyme-linked immunosorbent assay (ELISA). Results A total of 110 serum samples from patients with HCC (n = 65) and healthy control subjects (n = 45) were analysed. When the AFP cut-off value was set at 20 ng/ml, the fluorescence protein microarray had a sensitivity of 91.67% and a specificity of 93.24% for detecting serum AFP. Serum AFP quantified via fluorescence protein microarray had a similar diagnostic performance compared with ELISA in distinguishing patients with HCC from healthy control subjects (area under receiver operating characteristic curve: 0.906 for fluorescence protein microarray; 0.880 for ELISA). Conclusion A fluorescence protein microarray method was developed for detecting serum AFP in patients with HCC. PMID:27885040

Hepatocellular carcinoma presenting as uterine metastasis.

PubMed

Kang, Woo Dae; Kim, Cheol Hong; Cho, Moon Kyung; Kim, Jong Woon; Lee, Ji Shin; Kim, Yoon Ha; Choi, Ho Sun; Kim, Seok Mo

2008-09-01

Metastatic extragenital cancer that spreads to the uterus is rare. When it occurs, the extragenital primary disease is often in the breast or gastrointestinal tract. We report here on a case of hepatocellular carcinoma (HCC) that metastasis to the uterus. The patient was admitted for evaluation of a pelvic mass. The serum alpha-fetoprotein level was highly elevated. Magnetic resonance imaging of the abdomen and pelvis showed hepatic and uterine masses. The patient underwent surgical treatment. The histopathologic findings and immunohistochemical staining results of the uterine mass were characteristics of metastatic HCC. The endometrium and both ovaries were free of tumor. Up to now, there have been only two cases of uterine metastasis from HCC reported in the English literature. This case is the first documented instance of a metastatic uterine tumor from HCC that spared both ovaries.

Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region.

PubMed

Zhu, Ran Xu; Seto, Wai-Kay; Lai, Ching-Lung; Yuen, Man-Fung

2016-05-23

Hepatocellular carcinoma (HCC) is the predominant primary liver cancer in many countries and is the third most common cause of cancer-related death in the Asia-Pacific region. The incidence of HCC is higher in men and in those over 40 years old. In the Asia-Pacific region, chronic hepatitis B virus and hepatitis C virus infections are the main etiological agents; in particular, chronic hepatitis B infection (CHB) is still the major cause in all Asia-Pacific countries except for Japan. Over the past two decades, the incidence of HCC has remained stable in countries in the region except for Singapore and Hong Kong, where the incidence for both sexes is currently decreasing. Chronic hepatitis C infection (CHC) is an important cause of HCC in Japan, representing 70% of HCCs. Over the past several decades, the prevalence of CHC has been increasing in many Asia-Pacific countries, including Australia, New Zealand, and India. Despite advancements in treatment, HCC is still an important health problem because of the associated substantial mortality. An effective surveillance program could offer early diagnosis and hence better treatment options. Antiviral treatment for both CHB and CHC is effective in reducing the incidence of HCC.

Genetics and epigenetics of liver cancer.

PubMed

Ozen, Cigdem; Yildiz, Gokhan; Dagcan, Alper Tunga; Cevik, Dilek; Ors, Aysegul; Keles, Umur; Topel, Hande; Ozturk, Mehmet

2013-05-25

Hepatocellular carcinoma (HCC) represents a major form of primary liver cancer in adults. Chronic infections with hepatitis B (HBV) and C (HCV) viruses and alcohol abuse are the major factors leading to HCC. This deadly cancer affects more than 500,000 people worldwide and it is quite resistant to conventional chemo- and radiotherapy. Genetic and epigenetic studies on HCC may help to understand better its mechanisms and provide new tools for early diagnosis and therapy. Recent literature on whole genome analysis of HCC indicated a high number of mutated genes in addition to well-known genes such as TP53, CTNNB1, AXIN1 and CDKN2A, but their frequencies are much lower. Apart from CTNNB1 mutations, most of the other mutations appear to result in loss-of-function. Thus, HCC-associated mutations cannot be easily targeted for therapy. Epigenetic aberrations that appear to occur quite frequently may serve as new targets. Global DNA hypomethylation, promoter methylation, aberrant expression of non-coding RNAs and dysregulated expression of other epigenetic regulatory genes such as EZH2 are the best-known epigenetic abnormalities. Future research in this direction may help to identify novel biomarkers and therapeutic targets for HCC. Copyright © 2013 Elsevier B.V. All rights reserved.

Long-term outcomes after hepatic resection combined with radiofrequency ablation for initially unresectable multiple and bilobar liver malignancies.

PubMed

Qiu, Jianguo; Chen, Shuting; Wu, Hong

2014-05-01

Hepatic resection (HRE) combined with radiofrequency ablation (RFA) offers a surgical option to a group of patients with multiple and bilobar liver malignancies who are traditionally unresectable for inadequate functional hepatic reserve. The aims of the present study were to assess the perioperative outcomes, recurrence, and long-term survival rates for patients treated with HRE plus RFA in the management of primary hepatocellular carcinoma (HCC) and metastatic liver cancer (MLC). Data from all consecutive patients with primary and secondary hepatic malignancies who were treated with HRE combined with RFA between 2007 and 2013 were prospectively collected and retrospectively reviewed. A total of 112 patients, with 368 hepatic tumors underwent HRE combined with ultrasound-guided RFA, were included in the present study. There were 40 cases of HCC with 117 tumors and 72 cases of MLC with 251 metastases. Most cases of liver metastases originated from the gastrointestinal tract (44, 61.1%). Other uncommon lesions included breast cancer (5, 6.9%), pancreatic cancer (3, 4.2%), lung cancer (4, 5.6%), cholangiocarcinoma (4, 5.6%), and so on. The ablation success rates were 93.3% for HCC and 96.7% for MLC. The 1-, 2-, 3-, 4-, and 5-y overall recurrence rates were 52.5%, 59.5%, 72.3%, 75%, and 80% for the HCC group and 44.4%, 52.7%, 56.1%, 69.4%, and 77.8% for the MLC group, respectively. The 1-, 2-, 3-, 4-, and 5-y overall survival rates for the HCC patients were 67.5%, 50%, 32.5%, 22.5%, and 12.5% and for the MLC patients were 66.5%, 55.5%, 50%, 30.5%, and 19.4%, respectively. The corresponding recurrence-free survival rates for the HCC patients were 52.5%, 35%, 22.5%, 15%, and 10% and for the MLC patients were 58.3%, 41.6%, 23.6%, 16.9%, and 12.5%, respectively. HRE combined with RFA provides an effective treatment approach for patients with primary and secondary liver malignancies who are initially unsuitable for radical resection, with high local tumor control rates and promising survival data. Copyright © 2014 Elsevier Inc. All rights reserved.

Spermine oxidase is up-regulated and promotes tumor growth in hepatocellular carcinoma.

PubMed

Hu, Tingting; Sun, Dalong; Zhang, Jie; Xue, Ruyi; Janssen, Harry L A; Tang, Wenqing; Dong, Ling

2018-06-20

The polyamine catabolic enzyme, spermine oxidase (SMOX) is up-regulated in chronic inflammatory conditions and linked to increased reactive oxygen species (ROS) and DNA damage in various forms of cancers. The present study aims to explore the expression pattern and biological function of SMOX in hepatocellular carcinoma (HCC). We used qRT-PCR, Western blotting and immunohistochemistry to examine SMOX expression in four HCC cell lines and 120 cases of HCC clinical samples, and the clinical significance of SMOX was analyzed. The biological function of SMOX on HCC cells were detected both in vitro and in vivo. It showed that SMOX was overexpressed in HCC cell lines and clinical HCC tissues. Moreover, SMOX expression levels were gradually increased in normal liver, chronic hepatitis and HCC tissues. Increased SMOX expression was correlated with poor clinical features of HCC. Patients with positive SMOX expression in tumor tissues indicated worse overall survival (P = 0.008) and shorter relapse-free survival (P = 0.002). Knockdown of SMOX inhibited HCC cell proliferation, arrested cell cycle at S phase and resulted in an increase of apoptosis. The in vivo study showed that inhibition of SMOX in HCC cells significantly repressed tumor growth in nude mice. Furthermore, we demonstrated that SMOX may exert its function by regulating PI3K/Akt signaling pathway. Our data indicated that SMOX upregulation may be a critical oncogene in HCC and might serve as a valuable prognostic marker and potential therapeutic target for HCC. This article is protected by copyright. All rights reserved.

Cirrhosis is Under-recognized in Patients Subsequently Diagnosed with Hepatocellular Cancer

PubMed Central

Walker, Megan; El-Serag, Hashem B.; Sada, Yvonne; Mittal, Sahil; Ying, Jun; Duan, Zhigang; Richardson, Peter; Davila, Jessica A.; Kanwal, Fasiha

2015-01-01

Background Most clinical practice guidelines recommend screening for HCC in patients with cirrhosis. However, patients with compensated cirrhosis are often asymptomatic and may remain unrecognized for years. Aims To determine the extent to which cirrhosis is unrecognized in a US Veteran population with HCC and to evaluate the association between lack of cirrhosis recognition and stage of HCC at diagnosis. Methods We reviewed the electronic medical records of a random sample of HCC cases diagnosed in the national Veterans Affairs system between 2005 and 2011. We conducted multivariable analyses adjusting for patients’ demographics, comorbidity, etiology of underlying disease, and healthcare utilization including HCC surveillance. Results Of 1201 patients with HCC and cirrhosis, 24.6% had unrecognized cirrhosis prior to HCC diagnosis. Older patients (>65yr, odds ratio [OR] 2.32), African Americans (OR 1.93), patients with alcoholic or NAFLD liver disease (OR 1.69 and 4.77 respectively), HIV (OR 3.02), and fewer comorbidities (Deyo 0 vs. 3, OR 2.42) had significantly higher odds of having unrecognized cirrhosis than comparison groups. Furthermore, patients with unrecognized cirrhosis were 6.5 times more likely to have advanced stage HCC at diagnosis. The effect of cirrhosis recognition on HCC stage remained significant after adjusting for pre-specified covariates (OR 3.37). Conclusions In one fourth of patients, cirrhosis was unrecognized prior to HCC diagnosis, and this group was significantly more likely to have advanced stage HCC. These findings emphasize the importance of timely evaluation for cirrhosis in at-risk populations as a critical step to improving outcomes for HCC patients. PMID:26784271

BAG3 and HIF-1 α coexpression detected by immunohistochemistry correlated with prognosis in hepatocellular carcinoma after liver transplantation.

PubMed

Xiao, Heng; Tong, Rongliang; Cheng, Shaobing; Lv, Zhen; Ding, Chaofeng; Du, Chengli; Xie, Haiyang; Zhou, Lin; Wu, Jian; Zheng, Shusen

2014-01-01

The objective is to determine the effects of BAG3 and HIF-1 α expression on the prognosis of HCC patients after liver transplantation. Samples from 31 patients with HCC receiving liver transplantation were collected for this study. The immunohistochemistry was used to detect the expression of BAG3 and HIF-1 α of HCC samples. According to the immunohistochemistry results, BAG3 and HIF-1 α staining were significantly associated with tumor TNM stage (P = 0.004, P = 0.012). A significant association between high BAG3/HIF-1 α levels and a shorter overall survival was detected, so as the combined BAG3 and HIF-1 α analysis. The results suggested that the expression level of BAG3 and HIF-1 α is efficient prognostic parameters in patients with HCC after liver transplantation.

Hsa_circ_0001649: A circular RNA and potential novel biomarker for hepatocellular carcinoma.

PubMed

Qin, Meilin; Liu, Gang; Huo, Xisong; Tao, Xuemei; Sun, Xiaomeng; Ge, Zhouhong; Yang, Juan; Fan, Jia; Liu, Lei; Qin, Wenxin

2016-01-01

It has been shown that circular RNA (circRNA) is associated with human cancers, however, few studies have been reported in hepatocellular carcinoma (HCC). To estimate clinical values of a circular RNA, Hsa_circ_0001649, in HCC. Expression level of hsa_circ_0001649 was detected in HCC and paired adjacent liver tissues by real-time quantitative reverse transcription-polymerase chain reactions (qRT-PCRs). Differences in expression level of hsa_circ_0001649 were analyzed using the paired t-test. Tests were performed between clinical information and hsa_circ_0001649 expression level by analysis of variance (ANOVA) or welch t-test and a receiver operating characteristics (ROC) curve was established to estimate the value of hsa_circ_0001649 expression as a biomarker in HCC. hsa_circ_0001649 expression was significantly downregulated in HCC tissues (p = 0.0014) based on an analysis of 89 paired samples of HCC and adjacent liver tissues and the area under the ROC curve (AUC) was 0.63. Furthermore, hsa_circ_0001649 expression was correlated with tumor size (p = 0.045) and the occurrence of tumor embolus (p = 0.017) in HCC. We first found hsa_circ_0001649 was significantly downregulated in HCC. Our findings indicate hsa_circ_0001649 might serve as a novel potential biomarker for HCC and may function in tumorigenesis and metastasis of HCC.

[Elevated expression of CLOCK is associated with poor prognosis in hepatocellular carcinoma].

PubMed

Li, Bo; Yang, Xiliang; Li, Jiaqi; Yang, Yi; Yan, Zhaoyong; Zhang, Hongxin; Mu, Jiao

2018-02-01

Objective To evaluate the expression of circadian locomotor output cycles kaput (CLOCK) and its effects on cell growth in hepatocellular carcinoma (HCC). Methods The expression of CLOCK in 158 pairs of human HCC tissues and matched noncancerous samples was detected by immunohistochemical (IHC) staining. The expression of CLOCK in HCC patients was also verified using the data from GEO and TCGA (a total of 356 cases). The relationship between CLOCK expression and clinicopathological features of HCC patients was analyzed by single factor statistical analysis. Kaplan-Meier survival curves of HCC patients were drawn to study the relationship between the expression level of CLOCK and the survival state. The effect of CLOCK on the growth of HepG2 cells was detected by MTS assay. Results The expression of CLOCK in HCC tissues was significantly higher than that in the adjacent tissues, and the up-regulation of CLOCK expression in HCC tissue was also confirmed in the public data of HCC (356 cases). HCC patients were divided into low CLOCK expression group and high CLOCK expression group. Univariate analysis showed that the expression of CLOCK was related to tumor size, TNM stage, and portal vein invasion in HCC patients. HCC patients with low CLOCK expression had longer overall survival time and relapse-free survival time than those with high CLOCK expression. The proliferation of cells significantly decreased after the expression of CLOCK was knocked down in HepG2 cells. Conclusion The expression of CLOCK in HCC tissues was much higher than that in normal liver tissues, and the high expression of CLOCK indicated the poor prognosis. The knockdown of CLOCK in HCC cells could inhibit the proliferation of HepG2 cells.

Heat Stress-Induced PI3K/mTORC2-Dependent AKT Signaling Is a Central Mediator of Hepatocellular Carcinoma Survival to Thermal Ablation Induced Heat Stress

PubMed Central

Thompson, Scott M.; Callstrom, Matthew R.; Jondal, Danielle E.; Butters, Kim A.; Knudsen, Bruce E.; Anderson, Jill L.; Lien, Karen R.; Sutor, Shari L.; Lee, Ju-Seog; Thorgeirsson, Snorri S.; Grande, Joseph P.; Roberts, Lewis R.; Woodrum, David A.

2016-01-01

Thermal ablative therapies are important treatment options in the multidisciplinary care of patients with hepatocellular carcinoma (HCC), but lesions larger than 2–3 cm are plagued with high local recurrence rates and overall survival of these patients remains poor. Currently no adjuvant therapies exist to prevent local HCC recurrence in patients undergoing thermal ablation. The molecular mechanisms mediating HCC resistance to thermal ablation induced heat stress and local recurrence remain unclear. Here we demonstrate that the HCC cells with a poor prognostic hepatic stem cell subtype (Subtype HS) are more resistant to heat stress than HCC cells with a better prognostic hepatocyte subtype (Subtype HC). Moreover, sublethal heat stress rapidly induces phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dependent-protein kinase B (AKT) survival signaling in HCC cells in vitro and at the tumor ablation margin in vivo. Conversely, inhibition of PI3K/mTOR complex 2 (mTORC2)-dependent AKT phosphorylation or direct inhibition of AKT function both enhance HCC cell killing and decrease HCC cell survival to sublethal heat stress in both poor and better prognostic HCC subtypes while mTOR complex 1 (mTORC1)-inhibition has no impact. Finally, we showed that AKT isoforms 1, 2 and 3 are differentially upregulated in primary human HCCs and that overexpression of AKT correlates with worse tumor biology and pathologic features (AKT3) and prognosis (AKT1). Together these findings define a novel molecular mechanism whereby heat stress induces PI3K/mTORC2-dependent AKT survival signaling in HCC cells and provide a mechanistic rationale for adjuvant AKT inhibition in combination with thermal ablation as a strategy to enhance HCC cell killing and prevent local recurrence, particularly at the ablation margin. PMID:27611696

Stress Hormone Cortisol Enhances Bcl2 Like-12 Expression to Inhibit p53 in Hepatocellular Carcinoma Cells.

PubMed

Wu, Weizhong; Liu, Sanguang; Liang, Yunfei; Zhou, Zegao; Bian, Wei; Liu, Xueqing

2017-12-01

The pathogenesis of hepatocellular carcinoma (HC) is unclear. It is suggested that psychological stress associates with the pathogenesis of liver cancer. Bcl2-like protein 12 (Bcl2L12) suppresses p53 protein. This study tests a hypothesis that the major stress hormone, cortisol, inhibits the expression of p53 in HC cells (HCC) via up regulating the expression of Bcl2L12. Peripheral blood samples were collected from patients with HC to be analyzed for the levels of cortisol. HCC were cultured to assess the role of cortisol in the regulation of the expression of Bcl2L12 and p53 in HCC. We observed that the serum cortisol levels were higher in HC patients. Expression of Bcl2L12 in HCC was correlated with serum cortisol. Cortisol enhanced the Bcl2L12 expression in HCC. Bcl2L12 binding to the TP53 promoter was correlated with p53 expression in HCC. Cortisol increased the Bcl2L12 expression in HCC to inhibit p53 expression. Stress hormone cortisol suppresses p53 in HCC via enhancing Bcl2L12 expression in HCC. The results suggest that cortisol may be a therapeutic target for the treatment of HC.

Survival Benefits of Small Anatomical Resection of the Liver for Patients with Hepatocellular Carcinoma and Impaired Liver Function, Based on New-Era Imaging Studies.

PubMed

Sakoda, Masahiko; Ueno, Shinichi; Iino, Satoshi; Hiwatashi, Kiyokazu; Minami, Koji; Kawasaki, Yota; Kurahara, Hiroshi; Mataki, Yuko; Maemura, Kosei; Shinchi, Hiroyuki; Natsugoe, Shoji

2016-01-01

It has been reported that anatomical resection of the liver may be preferred for primary hepatocellular carcinoma (HCC), and is at least recommended for systematic removal of a segment confined by tumor-bearing portal tributaries. However, nonanatomical resection (NAR) is often selected because of the patient's background, impairment of liver function, and tumor factors. The aims of the present study were to retrospectively compare the recurrence-free survival (RFS) rates for cases of partial resection (PR) and for small anatomical resection (SAR), which is regarded as NAR for primary HCC with impaired liver function. So-called NAR was performed for a primary and solitary (≤ 5cm) HCC in 47 patients; the patients were classified into PR (n=25) and SAR (n=22) groups. Clinicopathological factors, survival data, and recurrence patterns were compared between groups. There were no significant differences in the preoperative characteristics between the two groups. Operative time was significantly longer in the SAR group than in the PR group. There was no significant difference in the postoperative morbidity and tumor pathological characteristics between the two groups. The RFS of the SAR group was significantly better than those of the PR group. Although there was no significant difference in the pattern of recurrence between the two groups, the rate of intrahepatic recurrence in the same segment as the initial tumor tended to be higher in the PR group than in the SAR group. Multivariate analysis revealed that only the PR operative procedure was significant independent risk factor for poorer RFS. Compared with PR, SAR effectively improves the rate of RFS after surgery for a primary and solitary HCC with impaired liver function.

Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma.

PubMed

Liu, Furong; Zeng, Gucheng; Zhou, Shaotang; He, Xiaoshun; Sun, Nianfeng; Zhu, Xiaofeng; Hu, Anbin

2018-05-01

The immunosuppression of tumor-infiltrating lymphocytes (TILs) is associated with rapid progression of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). T cell Ig- and mucin-domain-containing molecule-3 (Tim-3) and programmed cell death 1 (PD-1) are important inhibitory molecules expressed on the surface of T cells, but their roles in the function of TILs in HBV-HCC are poorly understood. We aimed to study the roles of these two markers in HBV-HCC. Ninety patients with pathologically confirmed HBV-associated HCC were enrolled in our study. Blood samples, paired fresh tumor tissues and adjacent tissues were collected, and isolating peripheral blood mononuclear cells, TILs and adjacent-infiltrating lymphocytes were isolated from these samples. The patients were followed-up to allow survival analysis. Tim-3 or/and PD-1 was up-regulated expressed on CD4 + and CD8 + TILs in HBV-HCC patients and a higher proportion of TILs expressed PD-1 alone. Tim-3 + and PD-1 + TILs greatly decreased secretion of IFN-? and TNF-a. Expression of Tim-3 and PD-1 on TILs negatively correlated with disease-free survival of HCC patients. Direct blockade of Tim-3 and PD-1 in vitro significantly enhanced TILs proliferation and secretion of IFN-? and TNF-a. Expression of Tim-3 and/or PD-1 on TILs impairs their function and correlates negatively with disease-free survival in HBV-HCC. Direct blockade of Tim-3 and PD-1 restores anti-tumor effects of TILs, which suggests a potential target for novel immunotherapy in HBV-HCC. Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Hair Cortisol Concentrations in Adolescent Girls with Anorexia Nervosa are Lower Compared to Healthy and Psychiatric Controls.

PubMed

Föcker, Manuel; Stalder, Tobias; Kirschbaum, Clemens; Albrecht, Muriel; Adams, Frederike; de Zwaan, Martina; Hebebrand, Johannes; Peters, Triinu; Albayrak, Özgür

2016-11-01

In anorexia nervosa (AN) hypercortisolism has been described using urine, plasma and saliva samples as short-term markers for the hypothalamic-pituitary-adrenal (HPA)-axis. Here, for the first time, we analyse hair cortisol concentration (HCC) as a marker for long-term integrated cortisol secretion in female patients with AN compared to female healthy controls (HC) and female psychiatric controls (PC). HCC was assessed in 22 female adolescent psychiatric inpatients with AN compared to 20 female HC and to 117 female PC of the same age range. For further analyses we examined the associations of age and body mass index (BMI) with HCC. Log HCC was lower in AN-patients compared to HC (p = 0.030). BMI-standard deviation scores (SDS) but not age correlated with log HCC (BMI-SDS: r = 0.19, bias corrected accelerated 95% confidence interval: [.04, .34], p = 0.015; age: r = 0.10, bias corrected accelerated 95% confidence interval: [-.07, .25], p = 0.213) when combining AN, HC and PC samples. We find lower HCC in AN, compared to HC and PC, respectively. Based on the relationship between HCC and BMI-SDS across AN, HC and PC, we argue that HCC might not capture endocrine alterations because of AN pathology-related processes but rather shows consistent relationships with BMI, which extent even to the very low range of BMI values, as present in AN patients. Alternatively, incorporation of cortisol into the hair follicle might have been compromised because of trophic hair follicle disturbances that had been reported in AN patients, previously. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

A signature of six genes highlights defects on cell growth and specific metabolic pathways in murine and human hepatocellular carcinoma.

PubMed

Schröder, Paul C; Segura, Víctor; Riezu, José Ignacio; Sangro, Bruno; Mato, José M; Prieto, Jesús; Santamaría, Enrique; Corrales, Fernando J

2011-09-01

Hepatocellular carcinoma (HCC) represents a major health problem as it afflicts an increasing number of patients worldwide. Albeit most of the risk factors for HCC are known, this is a deadly syndrome with a life expectancy at the time of diagnosis of less than 1 year. Definition of the molecular principles governing the neoplastic transformation of the liver is an urgent need to facilitate the clinical management of patients, based on innovative methods to detect the disease in its early stages and on more efficient therapies. In the present study, we have combined the analysis of a murine model and human samples of HCC to identify genes differentially expressed early in the process of hepatocarcinogenesis, using a microarray-based approach. Expression of 190 genes was impaired in murine HCC from which 65 were further validated by low-density array real-time polymerase chain reaction (RT-PCR). The expression of the best 45 genes was then investigated in human samples resulting in 18 genes in which expression was significantly modified in HCC. Among them, JUN, methionine adenosyltransferase 1A and 2A, phosphoglucomutase 1, and acyl CoA dehydrogenase short/branched chain indicate defective cell proliferation as well as one carbon pathway, glucose and fatty acid metabolism, both in HCC and cirrhotic liver, a well-known preneoplastic condition. These alterations were further confirmed in public transcriptomic datasets from other authors. In addition, vasodilator-stimulated phosphoprotein, an actin-associated protein involved in cytoskeleton remodeling, was also found to be increased in the liver and serum of cirrhotic and HCC patients. In addition to revealing the impairment of central metabolic pathways for liver homeostasis, further studies may probe the potential value of the reported genes for the early detection of HCC.

Immunohistochemical and Biochemical Expression Patterns of TTF-1, RAGE, GLUT-1 and SOX2 in HCV-Associated Hepatocellular Carcinomas

PubMed Central

Aboushousha, Tarek; Mamdouh, Samah; Hamdy, Hussam; Helal, Noha; Khorshed, Fatma; Safwat, Gehan; Seleem, Mohamed

2018-01-01

Objective: To investigate the expression of TTF-1, RAGE, GLUT1 and SOX2 in HCV-associated HCCs and in surrounding non-tumorous liver tissue. Material and Methods: Tissue material from partial hepatectomy cases for HCC along with corresponding serum samples and 30 control serum samples from healthy volunteers were studied. Biopsies were classified into: non-tumor hepatic tissue (36 sections); HCC (33 sections) and liver cell dysplasia (LCD) (15 sections). All cases were positive for HCV. Immunohistochemistry (IHC), gene extraction and quantitative real-time reverse-transcription assays (qRT-PCR) were applied. Results: By IHC, LCD and HCC showed significantly high percentages of positive cases with all markers. SOX2 showed significant increase with higher HCC grades, while RAGE demonstrated an inverse relation and GLUT-1 and TTF-1 lacked any correlation. In nontumorous-HCV tissue, we found significantly high TTF-1, low RAGE and negative SOX2 expression. RAGE, GLUT-1 and SOX2 show non-significant elevation positivity in high grade HCV compared to low grade lesions. TTF-1, RAGE and SOX2 exhibited low expression in cirrhosis compared to fibrosis. Biochemical studies on serum and tissue extracts revealed significant down-regulation of RAGE, GLUT-1 and SOX2 genes, as well as significant up-regulation of the TTF-1 gene in HCC cases compared to controls. All studied genes show significant correlation with HCC grade. In non-tumor tissue, only TTF-1 gene expression had a significant correlation with the fibrosis score. Conclusion: Higher expression of TTF-1, RAGE, GLUT-1 and SOX2 in HCC and dysplasia compared to non-tumor tissues indicates up-regulation of these markers as early events during the development of HCV-associated HCC. PMID:29373917

Immunohistochemical and Biochemical Expression Patterns of TTF-1, RAGE, GLUT-1 and SOX2 in HCV-Associated Hepatocellular Carcinomas

PubMed

Aboushousha, Tarek; Mamdouh, Samah; Hamdy, Hussam; Helal, Noha; Khorshed, Fatma; Safwat, Gehan; Seleem, Mohamed

2018-01-27

Objective: To investigate the expression of TTF-1, RAGE, GLUT1 and SOX2 in HCV-associated HCCs and in surrounding non-tumorous liver tissue. Material and Methods: Tissue material from partial hepatectomy cases for HCC along with corresponding serum samples and 30 control serum samples from healthy volunteers were studied. Biopsies were classified into: non-tumor hepatic tissue (36 sections); HCC (33 sections) and liver cell dysplasia (LCD) (15 sections). All cases were positive for HCV. Immunohistochemistry (IHC), gene extraction and quantitative real-time reverse-transcription assays (qRT-PCR) were applied. Results: By IHC, LCD and HCC showed significantly high percentages of positive cases with all markers. SOX2 showed significant increase with higher HCC grades, while RAGE demonstrated an inverse relation and GLUT-1 and TTF-1 lacked any correlation. In nontumorous-HCV tissue, we found significantly high TTF-1, low RAGE and negative SOX2 expression. RAGE, GLUT-1 and SOX2 show non-significant elevation positivity in high grade HCV compared to low grade lesions. TTF-1, RAGE and SOX2 exhibited low expression in cirrhosis compared to fibrosis. Biochemical studies on serum and tissue extracts revealed significant down-regulation of RAGE, GLUT-1 and SOX2 genes, as well as significant up-regulation of the TTF-1 gene in HCC cases compared to controls. All studied genes show significant correlation with HCC grade. In non-tumor tissue, only TTF-1 gene expression had a significant correlation with the fibrosis score. Conclusion: Higher expression of TTF-1, RAGE, GLUT-1 and SOX2 in HCC and dysplasia compared to non-tumor tissues indicates up-regulation of these markers as early events during the development of HCV-associated HCC. Creative Commons Attribution License

Associations of hair cortisol concentration with self-reported measures of stress and mental health-related factors in a pooled database of diverse community samples.

PubMed

Wells, Samantha; Tremblay, Paul F; Flynn, Andrea; Russell, Evan; Kennedy, James; Rehm, Jürgen; Van Uum, Stan; Koren, Gideon; Graham, Kathryn

2014-07-01

A pooled database from diverse community samples was used to examine the associations of hair cortisol concentration (HCC) with self-reported stress and stress-linked mental health measures, including depression, anxiety, alcohol and drug use, disability and experiences with aggression. As part of innovative research using a mobile laboratory to study community mental health, data were pooled from five sub-studies: a random sample of the general population (n = 70), people who had received treatment for a mental health and/or substance use problem (n = 78), family members of people treated for mental health and/or substance use problems (n = 49), community volunteers who sometimes felt sad or blue or thought they drank too much (n = 83) and young adults in intimate partner relationships (n = 44). All participants completed a computerized questionnaire including standard measures of perceived stress, chronic stress, depression, anxiety, hazardous drinking, tobacco use, prescription drug use, illicit drug use, disability and intimate partner aggression. HCC was significantly associated with use of antidepressants, hazardous drinking, smoking and disability after adjusting for sub-study and potential confounders (sex, body-mass index, use of glucocorticoids and hair dyed). In addition, preliminary analyses suggest a significant curvilinear relationship between HCC and perceived stress; specifically, HCC increased with higher perceived stress but decreased at the highest level of stress. Overall, HCC was associated with mental health-related variables mainly reflecting substance use or experiencing a disability. The relationship between HCC and self-reported stress is unclear and needs further research.

The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition.

PubMed

Aleksandrova, Krasimira; Bamia, Christina; Drogan, Dagmar; Lagiou, Pagona; Trichopoulou, Antonia; Jenab, Mazda; Fedirko, Veronika; Romieu, Isabelle; Bueno-de-Mesquita, H Bas; Pischon, Tobias; Tsilidis, Kostas; Overvad, Kim; Tjønneland, Anne; Bouton-Ruault, Marie-Christine; Dossus, Laure; Racine, Antoine; Kaaks, Rudolf; Kühn, Tilman; Tsironis, Christos; Papatesta, Eleni-Maria; Saitakis, George; Palli, Domenico; Panico, Salvatore; Grioni, Sara; Tumino, Rosario; Vineis, Paolo; Peeters, Petra H; Weiderpass, Elisabete; Lukic, Marko; Braaten, Tonje; Quirós, J Ramón; Luján-Barroso, Leila; Sánchez, María-José; Chilarque, Maria-Dolores; Ardanas, Eva; Dorronsoro, Miren; Nilsson, Lena Maria; Sund, Malin; Wallström, Peter; Ohlsson, Bodil; Bradbury, Kathryn E; Khaw, Kay-Tee; Wareham, Nick; Stepien, Magdalena; Duarte-Salles, Talita; Assi, Nada; Murphy, Neil; Gunter, Marc J; Riboli, Elio; Boeing, Heiner; Trichopoulos, Dimitrios

2015-12-01

Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms. We aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer-hepatocellular carcinoma (HCC). We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination. The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and total bilirubin, which-in combination-attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively. These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury.

The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition123

PubMed Central

Aleksandrova, Krasimira; Bamia, Christina; Drogan, Dagmar; Lagiou, Pagona; Trichopoulou, Antonia; Jenab, Mazda; Fedirko, Veronika; Romieu, Isabelle; Bueno-de-Mesquita, H Bas; Pischon, Tobias; Tsilidis, Kostas; Overvad, Kim; Tjønneland, Anne; Bouton-Ruault, Marie-Christine; Dossus, Laure; Racine, Antoine; Kaaks, Rudolf; Kühn, Tilman; Tsironis, Christos; Papatesta, Eleni-Maria; Saitakis, George; Palli, Domenico; Panico, Salvatore; Grioni, Sara; Tumino, Rosario; Vineis, Paolo; Peeters, Petra H; Weiderpass, Elisabete; Lukic, Marko; Braaten, Tonje; Quirós, J Ramón; Luján-Barroso, Leila; Sánchez, María-José; Chilarque, Maria-Dolores; Ardanas, Eva; Dorronsoro, Miren; Nilsson, Lena Maria; Sund, Malin; Wallström, Peter; Ohlsson, Bodil; Bradbury, Kathryn E; Khaw, Kay-Tee; Wareham, Nick; Stepien, Magdalena; Duarte-Salles, Talita; Assi, Nada; Murphy, Neil; Gunter, Marc J; Riboli, Elio; Boeing, Heiner; Trichopoulos, Dimitrios

2015-01-01

Background: Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms. Objective: We aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer—hepatocellular carcinoma (HCC). Design: We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination. Results: The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and total bilirubin, which—in combination—attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively. Conclusion: These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury. PMID:26561631

Biochemical and molecular evidences for the antitumor potential of Ginkgo biloba leaves extract in rodents.

PubMed

Ahmed, Hanaa H; Shousha, Wafaa Gh; El-Mezayen, Hatem A; El-Toumy, Sayed A; Sayed, Alaa H; Ramadan, Aesha R

2017-01-01

Hepatocellular carcinoma (HCC) is one of the deadliest primary cancers, with a 5-year survival rate of 10% or less. This study was undertaken to elucidate the underlying biochemical and molecular mechanisms in favor of N-nitrosodiethylamine-induced hepatocellular carcinoma. Furthermore, the aim of this work was extended to explore the efficacy of Ginkgo biloba leaves extract in deterioration of HCC in rats. In the current study, HCC group experienced significant downregulation of ING-3 gene expression and upregulation of Foxp-1 gene expression in liver. Treatment of HCC groups with Ginkgo biloba leaves extract resulted in upregulation of ING-3 and downregulation of Foxp-1 gene expression in liver. In addition, there was significant increase in serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and glypican-3 (GPC-3) levels in HCC group versus the negative control group. In contrast, the groups with HCC subjected to either high or low dose of Ginkgo biloba leaves extract elicited significant reduction (P<0.05) of AFP, CEA and GPC-3 in serum compared to the untreated HCC rats. Besides, histological examination of liver tissue sections of rats in HCC group revealed typical anaplasia. Interestingly, treatment with Ginkgo biloba leaves extract elicited marked improvement in the histological feature of liver tissue in HCC groups. In conclusion, this research indicated that the carcinogenic potency of N-nitrosodiethylamine targeted multiple systems on the cellular and molecular levels. In addition, the results of the current study shed light on the promising anticancer activity of Ginkgo biloba leaves extract in treatment of hepatocellular carcinoma induced chemically in the experimental model through its apoptotic and antiproliferative properties.

Delivery of miR-375 and doxorubicin hydrochloride by lipid-coated hollow mesoporous silica nanoparticles to overcome multiple drug resistance in hepatocellular carcinoma

PubMed Central

Xue, Huiying; Yu, Zhaoyang; Liu, Yong; Yuan, Weigang; Yang, Tan; You, Jia; He, Xingxing; Lee, Robert J; Li, Lei; Xu, Chuanrui

2017-01-01

Multidrug resistance (MDR) due to overexpression of P-glycoprotein (P-gp) is a major obstacle that hinders the treatment of hepatocellular carcinoma (HCC). It has been shown that miR-375 inhibits P-gp expression via inhibition of astrocyte elevated gene-1 (AEG-1) expression in HCC, and induces apoptosis in HCC cells by targeting AEG-1 and YAP1. In this study, we prepared lipid-coated hollow mesoporous silica nanoparticles (LH) containing doxorubicin hydrochloride (DOX) and miR-375 (LHD/miR-375) to deliver the two agents into MDR HCC cells in vitro and in vivo. We found that LHD/miR-375 overcame drug efflux and delivered miR-375 and DOX into MDR HepG2/ADR cells or HCC tissues. MiR-375 delivered by LHD/miR-375 was taken up through phagocytosis and clathrin- and caveolae-mediated endocytosis. Following release from late endosomes, it repressed the expression of P-gp in HepG2/ADR cells. The synergistic effects of miR-375 and hollow mesoporous silica nanoparticles (HMSN) resulted in a profound increase in the uptake of DOX by the HCC cells and prevented HCC cell growth. Enhanced antitumor effects of LHD/miR-375 were also validated in HCC xenografts and primary tumors; however, no significant toxicity was observed. Mechanistic studies also revealed that miR-375 and DOX exerted a synergistic antitumor effect by promoting apoptosis. Our study illustrates that delivery of miR-375 using HMSN is a feasible approach to circumvent MDR in the management of HCC. It, therefore, merits further development for potential clinical application. PMID:28769563

Autophagy prevention sensitizes AKTi-1/2-induced anti-hepatocellular carcinoma cell activity in vitro and in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Qi; Yang, Manyi; Qu, Zhan

Molecule-targeted therapy has become the research focus for hepatocellular carcinoma (HCC). Persistent PI3K-AKT activation is often detected in HCC, representing a valuable oncotarget for treatment. Here, we tested the anti-HCC activity by a potent AKT inhibitor: AKT inhibitor 1/2 (AKTi-1/2). In both established (HepG2 and Huh-7) and primary human HCC cells, treatment with AKTi-1/2 inhibited cell survival and proliferation, but induced cell apoptosis. AKTi-1/2 blocked AKT-mTOR activation, yet simultaneously provoked cytoprotective autophagy in HCC cells. The latter was evidenced by ATG-5 and Beclin-1 upregulation, p62 downregulation as well as LC3B-GFP puncta formation. Autophagy inhibition, via pharmacological inhibitors (3-methyladenine, ammonium chloride,more » and bafilomycin A1) or Beclin-1 siRNA knockdown, significantly potentiated AKTi-1/2-induced HepG2 cell death and apoptosis. In nude mice, AKTi-1/2 intraperitoneal injection inhibited HepG2 tumor growth. Significantly, its anti-tumor activity in vivo was further sensitized when combined with Beclin-1 shRNA knockdown in HepG2 tumors. Together, these results demonstrate that autophagy activation serves as a main resistance factor of AKTi-1/2 in HCC cells. Autophagy prevention therefore sensitizes AKTi-1/2-induced anti-HCC activity in vitro and in vivo. - Highlights: • AKTi-1/2 inhibits human HCC cells in vitro. • Autophagy inhibitors sensitize AKTi-1/2-induced HCC cell death and apoptosis. • Beclin-1 siRNA potentiates AKTi-1/2-induced HepG2 cell death and apoptosis. • Beclin-1 knockdown augments AKTi-1/2-induced anti-HepG2 tumor activity in vivo.« less

Donor miR-196a-2 polymorphism is associated with hepatocellular carcinoma recurrence after liver transplantation in a Han Chinese population.

PubMed

Xu, Xiao; Ling, Qi; Wang, Jianguo; Xie, Haiyang; Wei, Xuyong; Lu, Di; Hu, Qichao; Zhang, Xuanyu; Wu, Liming; Zhou, Lin; Zheng, Shusen

2016-02-01

Recurrence of hepatocellular carcinoma (HCC) is one of the leading causes of death after liver transplantation (LT). We aim to evaluate the association of donor and recipient single nucleotide polymorphisms (SNPs) with the risk of HCC recurrence after LT. A total of 155 adult patients who underwent primary LT for HCC were enrolled. Ten SNPs associated with HCC susceptibility were genotyped. Patients who received donor livers with the rs11614913 homozygous CC variant presented significantly higher recurrence rates of HCC (41.7 vs. 15.3%, p = 0.009) and lower cumulative tumor-free survival (p = 0.005) than those who received TT wild-type donor livers. The donor rs11614913 genetic variant was an independent risk factor for HCC recurrence (odds ratio = 2 per each C allele, p < 0.05) and could significantly improve the predictive abilities of clinical models (Milan, UCSF and Hangzhou criteria). Donor livers homozygous for rs11614913 CC were associated with a higher miR-196a expression than TT (p = 0.002). In a lentiviral infection of mouse liver and orthotopic mouse model of HCC, the liver miR-196a overexpression group showed a significantly larger tumor size than the control group (p = 0.001). There is a close association between the tumor size and expression of miR-196a in the liver (r = 0.693, p = 0.001). In conclusion, the donor miR-196a-2 rs11614913 polymorphism is associated with HCC recurrence after LT and improves the predictive value of clinical models. The overexpression of miR-196a in the liver might provide a tumor-favorable environment for the development of HCC. © 2015 UICC.

Hepatic Stellate Cells Alter Liver Immune Environment to Promote Cancer | Center for Cancer Research

Cancer.gov

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for up to 90 percent of cases, and is the second most common cause of cancer-related deaths worldwide according to the World Health Organization’s 2014 World Cancer Report. Even when caught early, HCC often recurs, either from intra-liver metastases or new primary tumors, and recurrence is the

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

PubMed Central

Li, Min; Zhang, Weiyue; Wang, Birong; Gao, Yang; Song, Zifang; Zheng, Qi Chang

2016-01-01

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high morbidity and mortality worldwide. Chemotherapy is recommended to patients with intermediate or advanced stage cancer. However, the conventional chemotherapy yields low desired response rates due to multidrug resistance, fast clearance rate, nonspecific delivery, severe side effects, low drug concentration in cancer cells, and so on. Nanoparticle-mediated targeted drug delivery system can surmount the aforementioned obstacles through enhanced permeability and retention effect and active targeting as a novel approach of therapeutics for HCC in recent years. The active targeting is triggered by ligands on the delivery system, which recognize with and internalize into hepatoma cells with high specificity and efficiency. This review focuses on the latest targeted delivery systems for HCC and summarizes the ligands that can enhance the capacity of active targeting, to provide some insight into future research in nanomedicine for HCC. PMID:27920520

Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals.

PubMed

Prenner, Stacey B; VanWagner, Lisa B; Flamm, Steven L; Salem, Riad; Lewandowski, Robert J; Kulik, Laura

2017-06-01

The approval of all-oral direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) has led to the expansion of therapy to include patients with cirrhosis who have hepatocellular carcinoma (HCC). Data on the use of DAAs in HCV+ patients with HCC is limited. The aim of this study was to assess the efficacy of all-oral-DAA regimens in HCV+ cirrhotic patients who have or had HCC compared to those without HCC. A retrospective cohort study was conducted on all cirrhotic patients who were treated for HCV with DAAs at our institution between January 2014 and November 2015. A total of 421 HCV+ patients with cirrhosis were identified, of whom 33% had active or a history of HCC. Failure to achieve sustained virologic response (SVR) occurred in 21% of patients with HCC compared to 12% of patients without HCC (p=0.009). Of the 29 patients with HCC who did not achieve SVR, 27 (93%) occurred when an active tumor was present. DAA therapy in the presence of an inactive tumor or after removal of tumor (resection/transplant) resulted in excellent SVR rates, similar to those without HCC (p<0.0001). In multivariable analysis, the primary predictor of DAA treatment failure was the presence of active HCC at the time of HCV treatment initiation (adjusted odds ratio=8.5, 95% confidence interval=3.90-18.49). The presence of active HCC tumor at the initiation of HCV therapy is significantly associated with all-oral DAA treatment failure. HCV treatment after curative therapies for HCC resulted in excellent SVR. The new medications for hepatitis C have excellent cure rates. However, our study shows that in patients with both liver cancer and hepatitis C, they do not achieve these cure rates. Patients with liver cancer are almost 8 times more likely to fail hepatitis C treatment than patients without liver cancer. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Biomarker Discovery for Early Detection of Hepatocellular Carcinoma in Hepatitis C–infected Patients*

PubMed Central

Mustafa, Mehnaz G.; Petersen, John R.; Ju, Hyunsu; Cicalese, Luca; Snyder, Ned; Haidacher, Sigmund J.; Denner, Larry; Elferink, Cornelis

2013-01-01

Chronic hepatic disease damages the liver, and the resulting wound-healing process leads to liver fibrosis and the subsequent development of cirrhosis. The leading cause of hepatic fibrosis and cirrhosis is infection with hepatitis C virus (HCV), and of the patients with HCV-induced cirrhosis, 2% to 5% develop hepatocellular carcinoma (HCC), with a survival rate of 7%. HCC is one of the leading causes of cancer-related death worldwide, and the poor survival rate is largely due to late-stage diagnosis, which makes successful intervention difficult, if not impossible. The lack of sensitive and specific diagnostic tools and the urgent need for early-stage diagnosis prompted us to discover new candidate biomarkers for HCV and HCC. We used aptamer-based fractionation technology to reduce serum complexity, differentially labeled samples (six HCV and six HCC) with fluorescent dyes, and resolved proteins in pairwise two-dimensional difference gel electrophoresis. DeCyder software was used to identify differentially expressed proteins and spots picked, and MALDI-MS/MS was used to determine that ApoA1 was down-regulated by 22% (p < 0.004) in HCC relative to HCV. Differential expression quantified via two-dimensional difference gel electrophoresis was confirmed by means of 18O/16O stable isotope differential labeling with LC-MS/MS zoom scans. Technically independent confirmation was demonstrated by triple quadrupole LC-MS/MS selected reaction monitoring (SRM) assays with three peptides specific to human ApoA1 (DLATVYVDVLK, WQEEMELYR, and VSFLSALEEYTK) using 18O/16O-labeled samples and further verified with AQUA peptides as internal standards for quantification. In 50 patient samples (24 HCV and 26 HCC), all three SRM assays yielded highly similar differential expression of ApoA1 in HCC and HCV patients. These results validated the SRM assays, which were independently confirmed by Western blotting. Thus, ApoA1 is a candidate member of an SRM biomarker panel for early diagnosis, prognosis, and monitoring of HCC. Future multiplexing of SRM assays for other candidate biomarkers is envisioned to develop a biomarker panel for subsequent verification and validation studies. PMID:24008390

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Wenyao, E-mail: wangwy117@163.com; Zhang, Hongfei; Wang, Lichao

microRNAs (miRNAs) play key regulatory roles in various biological processes. In this study, we aimed to determine the expression and biological roles of miR-613 in hepatocellular carcinoma (HCC). Compared with non-cancerous liver tissues, miR-613 was significantly downregulated in HCC tissues. Ectopic expression of miR-613 significantly suppressed the proliferation and invasion of Hep3B and SMMC-7721 HCC cells. Bioinformatic and luciferase reporter analysis identified doublecortin-like kinase 1 (DCLK1) as a direct target of miR-613. Overexpression of miR-613 inhibited the expression of DCLK1 in HCC cells. There was a significant inverse correlation between miR-613 and DCLK1 protein expression in HCC samples. Small interferingmore » RNA-mediated silencing of DCLK1 phenocopied the suppressive effects of miR-613 in HCC cells. Rescue experiments demonstrated that co-transfection of DCLK1 lacking the 3′-untranslated region partially prevented miR-613-induced suppression of HCC cell proliferation and invasion. In vivo studies confirmed that miR-613 overexpression retarded the growth of Hep3B xenograft tumors in nude mice, coupled with a reduction in the percentage of Ki67-positive tumor cells and DCLK1 protein expression. In conclusion, we provide first evidence for the suppressive activity of miR-613 in HCC, which is causally linked to targeting of DCLK1. Restoration of miR-613 may provide a potential therapeutic strategy for HCC. - Highlights: • miR-613 inhibits the aggressive phenotypes of HCC cells. • DCLK1 is a direct target of miR-613 in HCC. • miR-613 impairs HCC tumorigenesis in vivo.« less

From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world

PubMed Central

Dimitroulis, Dimitrios; Damaskos, Christos; Valsami, Serena; Davakis, Spyridon; Garmpis, Nikolaos; Spartalis, Eleftherios; Athanasiou, Antonios; Moris, Demetrios; Sakellariou, Stratigoula; Kykalos, Stylianos; Tsourouflis, Gerasimos; Garmpi, Anna; Delladetsima, Ioanna; Kontzoglou, Konstantinos; Kouraklis, Gregory

2017-01-01

Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma. PMID:28839428

From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world.

PubMed

Dimitroulis, Dimitrios; Damaskos, Christos; Valsami, Serena; Davakis, Spyridon; Garmpis, Nikolaos; Spartalis, Eleftherios; Athanasiou, Antonios; Moris, Demetrios; Sakellariou, Stratigoula; Kykalos, Stylianos; Tsourouflis, Gerasimos; Garmpi, Anna; Delladetsima, Ioanna; Kontzoglou, Konstantinos; Kouraklis, Gregory

2017-08-07

Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma.

Contrast-enhanced harmonic ultrasound imaging in ablation therapy for primary hepatocellular carcinoma.

PubMed

Minami, Yasunori; Kudo, Masatoshi

2009-12-31

The success rate of percutaneous radiofrequency (RF) ablation for hepatocellular carcinoma (HCC) depends on correct targeting via an imaging technique. However, RF electrode insertion is not completely accurate for residual HCC nodules because B-mode ultrasound (US), color Doppler, and power Doppler US findings cannot adequately differentiate between treated and viable residual tumor tissue. Electrode insertion is also difficult when we must identify the true HCC nodule among many large regenerated nodules in cirrhotic liver. Two breakthroughs in the field of US technology, harmonic imaging and the development of second-generation contrast agents, have recently been described and have demonstrated the potential to dramatically broaden the scope of US diagnosis of hepatic lesions. Contrast-enhanced harmonic US imaging with an intravenous contrast agent can evaluate small hypervascular HCC even when B-mode US cannot adequately characterize tumor. Therefore, contrast-enhanced harmonic US can facilitate RF ablation electrode placement in hypervascular HCC, which is poorly depicted by B-mode US. The use of contrast-enhanced harmonic US in ablation therapy for liver cancer is an efficient approach.

Tumor-associated autoantibodies are useful biomarkers in immunodiagnosis of α-fetoprotein-negative hepatocellular carcinoma.

PubMed

Wang, Ting; Liu, Mei; Zheng, Su-Jun; Bian, Dan-Dan; Zhang, Jin-Yan; Yao, Jia; Zheng, Qing-Fen; Shi, A-Meng; Li, Wen-Han; Li, Lu; Chen, Yu; Wang, Jin-Hai; Duan, Zhong-Ping; Dong, Lei

2017-05-21

To determine the prevalence and diagnostic value of autoantibodies in α-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC). Fifty-six serum samples from AFP-negative HCC cases, 86 from AFP-positive HCC cases, 168 from chronic liver disease cases, and 59 from normal human controls were included in this study. Autoantibodies to nucleophosmin (NPM)1, 14-3-3zeta and mouse double minute 2 homolog (MDM2) proteins in AFP-negative HCC serum were evaluated by enzyme-linked immunosorbent assay. Partially positive sera were further evaluated by western blotting. Immunohistochemistry was used to detect the expression of three tumor-associated antigens (TAAs) in AFP-negative HCC and normal control tissues. The frequency of autoantibodies to the three TAAs in AFP-negative HCC sera was 21.4%, 19.6% and 19.6%, which was significantly higher than in the chronic liver disease cases and normal human controls ( P < 0.01) as well as AFP-positive HCC cases. The sensitivity of the three autoantibodies for diagnosis of AFP-negative HCC ranged from 19.6% to 21.4%, and the specificity was approximately 95%. When the three autoantibodies were combined, the sensitivity reached 30.4% and the specificity reached 91.6%. Autoantibodies to NPM1, 14-3-3zeta and MDM2 may be useful biomarkers for immunodiagnosis of AFP-negative HCC.

Tumor-associated autoantibodies are useful biomarkers in immunodiagnosis of α-fetoprotein-negative hepatocellular carcinoma

PubMed Central

Wang, Ting; Liu, Mei; Zheng, Su-Jun; Bian, Dan-Dan; Zhang, Jin-Yan; Yao, Jia; Zheng, Qing-Fen; Shi, A-Meng; Li, Wen-Han; Li, Lu; Chen, Yu; Wang, Jin-Hai; Duan, Zhong-Ping; Dong, Lei

2017-01-01

AIM To determine the prevalence and diagnostic value of autoantibodies in α-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC). METHODS Fifty-six serum samples from AFP-negative HCC cases, 86 from AFP-positive HCC cases, 168 from chronic liver disease cases, and 59 from normal human controls were included in this study. Autoantibodies to nucleophosmin (NPM)1, 14-3-3zeta and mouse double minute 2 homolog (MDM2) proteins in AFP-negative HCC serum were evaluated by enzyme-linked immunosorbent assay. Partially positive sera were further evaluated by western blotting. Immunohistochemistry was used to detect the expression of three tumor-associated antigens (TAAs) in AFP-negative HCC and normal control tissues. RESULTS The frequency of autoantibodies to the three TAAs in AFP-negative HCC sera was 21.4%, 19.6% and 19.6%, which was significantly higher than in the chronic liver disease cases and normal human controls (P < 0.01) as well as AFP-positive HCC cases. The sensitivity of the three autoantibodies for diagnosis of AFP-negative HCC ranged from 19.6% to 21.4%, and the specificity was approximately 95%. When the three autoantibodies were combined, the sensitivity reached 30.4% and the specificity reached 91.6%. CONCLUSION Autoantibodies to NPM1, 14-3-3zeta and MDM2 may be useful biomarkers for immunodiagnosis of AFP-negative HCC. PMID:28596685

Biomarker MicroRNAs for Diagnosis, Prognosis and Treatment of Hepatocellular Carcinoma: A Functional Survey and Comparison

PubMed Central

Shen, Sijia; Lin, Yuxin; Yuan, Xuye; Shen, Li; Chen, Jiajia; Chen, Luonan; Qin, Lei; Shen, Bairong

2016-01-01

Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors with high incidence and mortality rate. Precision and effective biomarkers are therefore urgently needed for the early diagnosis and prognostic estimation. MicroRNAs (miRNAs) are important regulators which play functions in various cellular processes and biological activities. Accumulating evidence indicated that the abnormal expression of miRNAs are closely associated with HCC initiation and progression. Recently, many biomarker miRNAs for HCC have been identified from blood or tissues samples, however, the universality and specificity on clinicopathological features of them are less investigated. In this review, we comprehensively surveyed and compared the diagnostic, prognostic, and therapeutic roles of HCC biomarker miRNAs in blood and tissues based on the cancer hallmarks, etiological factors as well as ethnic groups, which will be helpful to the understanding of the pathogenesis of biomarker miRNAs in HCC development and further provide accurate clinical decisions for HCC diagnosis and treatment. PMID:27917899

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

PubMed Central

Huang, De; Li, Tingting; Wang, Lin; Zhang, Long; Yan, Ronghui; Li, Kui; Xing, Songge; Wu, Gongwei; Hu, Lan; Jia, Weidong; Lin, Sheng-Cai; Dang, Chi V; Song, Libing; Gao, Ping; Zhang, Huafeng

2016-01-01

Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma (HCC) cells under nutrition deprivation conditions. Mechanistically, 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting ketolytic enzyme whose expression is suppressed in normal adult liver tissues, is re-induced by serum starvation-triggered mTORC2-AKT-SP1 signaling in HCC cells. Moreover, we observe that enhanced ketolysis in HCC is critical for repression of AMPK activation and protects HCC cells from excessive autophagy, thereby enhancing tumor growth. Importantly, analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality. Taken together, we uncover here a novel metabolic adaptation by which nutrition-deprived HCC cells employ ketone bodies for energy supply and cancer progression. PMID:27644987

Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma

NASA Astrophysics Data System (ADS)

Xu, Rui-Hua; Wei, Wei; Krawczyk, Michal; Wang, Wenqiu; Luo, Huiyan; Flagg, Ken; Yi, Shaohua; Shi, William; Quan, Qingli; Li, Kang; Zheng, Lianghong; Zhang, Heng; Caughey, Bennett A.; Zhao, Qi; Hou, Jiayi; Zhang, Runze; Xu, Yanxin; Cai, Huimin; Li, Gen; Hou, Rui; Zhong, Zheng; Lin, Danni; Fu, Xin; Zhu, Jie; Duan, Yaou; Yu, Meixing; Ying, Binwu; Zhang, Wengeng; Wang, Juan; Zhang, Edward; Zhang, Charlotte; Li, Oulan; Guo, Rongping; Carter, Hannah; Zhu, Jian-Kang; Hao, Xiaoke; Zhang, Kang

2017-11-01

An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive `liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.

Metformin inhibits early stage diethylnitrosamine-induced hepatocarcinogenesis in rats

PubMed Central

JO, WOORI; YU, EUN-SIL; CHANG, MINSUN; PARK, HYUN-KYU; CHOI, HYUN-JI; RYU, JAE-EUN; JANG, SUNGWOONG; LEE, HYO-JU; JANG, JA-JUNE; SON, WOO-CHAN

2016-01-01

Antitumor effects of metformin have recently emerged despite its original use for type II diabetes. In the present study, the effects of metformin on the development and recurrence of hepatocellular carcinoma (HCC) were investigated using the diethylnitrosamine (DEN)-induced rat model of HCC. Tumor foci were characterized by gross examination and by histopathological characteristics, including proliferation, hepatic progenitor cell content and the expression of hepatocarcinoma-specific molecular markers. Potential target molecules of metformin were investigated to determine the molecular mechanism underlying the inhibitory effects of metformin on chemically induced liver tumorigenesis. The antitumor effects of metformin were increased by the reduction of surface nodules and decreased the incidence of altered hepatocellular foci, hepatocellular adenoma and carcinoma. Also, decreased expression levels of glutathione S-transferase placental form, proliferating cell nuclear antigen and cytokeratin 8 described the inhibitory effects of metformin on HCC. In the present study, Wistar rats receiving treatment with DEN were administered metformin for 16 weeks. In addition, metformin suppressed liver tumorigenesis via an AMPK-dependent pathway. These results suggested that metformin has promising effects on the early stage of HCC in rats. Therefore, metformin may be used for the prevention of HCC recurrence following primary chemotherapy for HCC and/or for high-risk patients, including chronic hepatitis and cirrhosis. PMID:26548419

EF24 Suppresses Invasion and Migration of Hepatocellular Carcinoma Cells In Vitro via Inhibiting the Phosphorylation of Src

PubMed Central

Tin, Lamtin; Wu, Yiqi; Jin, Yinji; Jin, Xiaoming; Zhang, Fengmin

2016-01-01

Diphenyl difluoroketone (EF24), a curcumin analog, is a promising anticancer compound that exerts its effects by inhibiting cell proliferation and inducing apoptosis. However, the efficacy of EF24 against cancer metastasis, particularly in hepatocellular carcinoma (HCC), remains elusive. In this study, the effect of EF24 on HCCLM-3 and HepG2 cell migration and invasion was detected by wound healing and transwell assay, respectively. The results revealed that EF24 suppressed the migration and invasion of both HCCLM-3 and HepG2 cells. Furthermore, EF24 treatment decreased the formation of filopodia on the cell surface and inhibited the phosphorylation of Src in both cell lines, which may help contribute towards understanding the mechanism underlying the suppressive effect of EF24 on HCC migration and invasion. Additionally, the expression of total- and phosphorylated-Src in primary HCC tissues and their paired lymph node metastatic tissues was detected, and phosphorylated-Src was found to be associated with HCC lymph node metastasis. The results of this study suggest that Src is a novel and promising therapeutic target in HCC and provide evidence to support the hypothesis that EF24 may be a useful therapeutic agent for the treatment of HCC. PMID:27999817

EF24 Suppresses Invasion and Migration of Hepatocellular Carcinoma Cells In Vitro via Inhibiting the Phosphorylation of Src.

PubMed

Zhao, Ran; Tin, Lamtin; Zhang, Yuhua; Wu, Yiqi; Jin, Yinji; Jin, Xiaoming; Zhang, Fengmin; Li, Xiaobo

2016-01-01

Diphenyl difluoroketone (EF24), a curcumin analog, is a promising anticancer compound that exerts its effects by inhibiting cell proliferation and inducing apoptosis. However, the efficacy of EF24 against cancer metastasis, particularly in hepatocellular carcinoma (HCC), remains elusive. In this study, the effect of EF24 on HCCLM-3 and HepG2 cell migration and invasion was detected by wound healing and transwell assay, respectively. The results revealed that EF24 suppressed the migration and invasion of both HCCLM-3 and HepG2 cells. Furthermore, EF24 treatment decreased the formation of filopodia on the cell surface and inhibited the phosphorylation of Src in both cell lines, which may help contribute towards understanding the mechanism underlying the suppressive effect of EF24 on HCC migration and invasion. Additionally, the expression of total- and phosphorylated-Src in primary HCC tissues and their paired lymph node metastatic tissues was detected, and phosphorylated-Src was found to be associated with HCC lymph node metastasis. The results of this study suggest that Src is a novel and promising therapeutic target in HCC and provide evidence to support the hypothesis that EF24 may be a useful therapeutic agent for the treatment of HCC.

A Case of Hypertensive Crisis without a Surge in Adrenal Hormones after Radiofrequency Ablation as a Treatment for Primary Hepatocellular Carcinoma.

PubMed

Lee, Kyung Jin; Ryu, Soo Hyung

2017-10-25

Radiofrequency ablation (RFA) is a minimally invasive procedure that has been considered as a relatively safe treatment for patients with small hepatocellular carcinoma (HCC). However, RFA has been shown to be associated with complications including mechanical and thermal damage. A 74-year-old man with hepatitis C virus-associated HCC was admitted to our hospital. Abdominal computed tomography revealed two lobulated-HCC in segments 4 and 5. He had no medical history of hypertension and cardiac disease. During RFA, blood pressure was elevated to 200/140 mmHg. There was no evidence of pulmonary embolism, aortic dissection, or ischemic heart disease. Laboratory findings for catecholamine surge were all within normal limits. After continuous intravenous nitroglycerin and oral beta-blocker treatment, patient's blood pressure gradually decreased and back within the normal range. Hypertensive crisis after RFA treatment for HCC is rare. Most reported cases of hypertensive crisis during RFA were related to adrenal gland injury with a release of catecholamine. In our case, the site of HCC was not close to the adrenal gland, and there was no evidence of catecholamine surge. Herein, we report a very rare case of hypertensive crisis without a surge in adrenal hormones after RFA treatment for HCC.

Notch1 Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression*

PubMed Central

Wang, Chunmei; Qi, Runzi; Li, Nan; Wang, Zhengxin; An, Huazhang; Zhang, Qinghua; Yu, Yizhi; Cao, Xuetao

2009-01-01

Notch signaling plays a critical role in regulating cell proliferation, differentiation, and apoptosis. Our previous study showed that overexpression of Notch1 could inhibit human hepatocellular carcinoma (HCC) cell growth by arresting the cell cycle and inducing apoptosis. HCC cells are resistant to apoptotic induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), so new therapeutic approaches have been explored to sensitize HCC cells to TRAIL-induced apoptosis. We are wondering whether and how Notch1 signaling can enhance the sensitivity of HCC cells to TRAIL-induced apoptosis. In this study, we found that overexpression of ICN, the constitutive activated form of Notch1, up-regulated p53 protein expression in HCC cells by inhibiting proteasome degradation. p53 up-regulation was further observed in human primary hepatocellular carcinoma cells after activation of Notch signaling. Inhibition of the Akt/Hdm2 pathway by Notch1 signaling was responsible for the suppression of p53 proteasomal degradation, thus contributing to the Notch1 signaling-mediated up-regulation of p53 expression. Accordingly, Notch1 signaling could make HCC cells more sensitive to TRAIL-induced apoptosis, whereas Notch1 signaling lost the synergistic promotion of TRAIL-induced apoptosis in p53-silenced HepG2 HCC cells and p53-defective Hep3B HCC cells. The data suggest that enhancement of TRAIL-induced apoptosis by Notch1 signaling is dependent upon p53 up-regulation. Furthermore, Notch1 signaling could enhance DR5 expression in a p53-dependent manner. Taken together, Notch1 signaling sensitizes TRAIL-induced apoptosis in HCC cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. Thus, our results suggest that activation of Notch1 signaling may be a promising approach to improve the therapeutic efficacy of TRAIL-resistant HCC. PMID:19376776

Assessment of tumor vascularization with functional computed tomography perfusion imaging in patients with cirrhotic liver disease.

PubMed

Li, Jin-Ping; Zhao, De-Li; Jiang, Hui-Jie; Huang, Ya-Hua; Li, Da-Qing; Wan, Yong; Liu, Xin-Ding; Wang, Jin-E

2011-02-01

Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and early diagnosis is critical for patient outcome. In patients with HCC, it is mostly based on liver cirrhosis, developing from benign regenerative nodules and dysplastic nodules to HCC lesions, and a better understanding of its vascular supply and the hemodynamic changes may lead to early tumor detection. Angiogenesis is essential for the growth of primary and metastatic tumors due to changes in vascular perfusion, blood volume and permeability. These hemodynamic and physiological properties can be measured serially using functional computed tomography perfusion (CTP) imaging and can be used to assess the growth of HCC. This study aimed to clarify the physiological characteristics of tumor angiogenesis in cirrhotic liver disease by this fast imaging method. CTP was performed in 30 volunteers without liver disease (control subjects) and 49 patients with liver disease (experimental subjects: 27 with HCC and 22 with cirrhosis). All subjects were also evaluated by physical examination, laboratory screening and Doppler ultrasonography of the liver. The diagnosis of HCC was made according to the EASL criteria. All patients underwent contrast-enhanced ultrasonography, pre- and post-contrast triple-phase CT and CTP study. A mathematical deconvolution model was applied to provide hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS), hepatic arterial index (HAI), hepatic arterial perfusion (HAP) and hepatic portal perfusion (HPP) data. The Mann-Whitney U test was used to determine differences in perfusion parameters between the background cirrhotic liver parenchyma and HCC and between the cirrhotic liver parenchyma with HCC and that without HCC. In normal liver, the HAP/HVP ratio was about 1/4. HCC had significantly higher HAP and HAI and lower HPP than background liver parenchyma adjacent to the HCC. The value of HBF at the tumor rim was significantly higher than that in the controls. HBF, HBV, HAI, HAP and HPP, but not MTT and PS, were significantly higher in the cirrhotic liver parenchyma involved with HCC than those of the controls. Perfusion parameters were not significantly different between the controls and the cirrhotic liver parenchyma not involved with HCC. CTP can clearly distinguish tumor from cirrhotic liver parenchyma and controls and can provide quantitative information about tumor-related angiogenesis, which can be used to assess tumor vascularization in cirrhotic liver disease.

Molecular imaging and therapy targeting copper metabolism in hepatocellular carcinoma

PubMed Central

Wachsmann, Jason; Peng, Fangyu

2016-01-01

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Significant efforts have been devoted to identify new biomarkers for molecular imaging and targeted therapy of HCC. Copper is a nutritional metal required for the function of numerous enzymatic molecules in the metabolic pathways of human cells. Emerging evidence suggests that copper plays a role in cell proliferation and angiogenesis. Increased accumulation of copper ions was detected in tissue samples of HCC and many other cancers in humans. Altered copper metabolism is a new biomarker for molecular cancer imaging with position emission tomography (PET) using radioactive copper as a tracer. It has been reported that extrahepatic mouse hepatoma or HCC xenografts can be localized with PET using copper-64 chloride as a tracer, suggesting that copper metabolism is a new biomarker for the detection of HCC metastasis in areas of low physiological copper uptake. In addition to copper modulation therapy with copper chelators, short-interference RNA specific for human copper transporter 1 (hCtr1) may be used to suppress growth of HCC by blocking increased copper uptake mediated by hCtr1. Furthermore, altered copper metabolism is a promising target for radionuclide therapy of HCC using therapeutic copper radionuclides. Copper metabolism has potential as a new theranostic biomarker for molecular imaging as well as targeted therapy of HCC. PMID:26755872

Involvement of miR-485-5p in hepatocellular carcinoma progression targeting EMMPRIN.

PubMed

Sun, Xiangjun; Liu, Yonglei; Li, Ming; Wang, Mingchun; Wang, Yutong

2015-05-01

EMMPRIN plays important roles in cancer development, which includes EMMPRIN 1, 2, 3, and 4 isoforms. EMMPRIN2 is the main component in human cancers, but its regulation by miRNAs is still unclear. In this study, we will investigate the mechanism of EMMPRIN regulation in hepatocellular carcinoma (HCC) by miRNAs. Through RT-PCR, we found that EMMPRIN2 was the main isoform in HCC cells. EMMPRIN2 was down-regulated significantly by predicted miRNAs and miR-485-5p was one of the miRNA that regulated EMMPRIN in HCC cell lines. It was verified that EMMPRIN was a target gene of miR-485-5p by using luciferase analysis assay. We found that miR-485-5p was significantly downregulated in HCC tissues and that its expression was inversely correlated with the TNM stage and metastasis in HCC samples. Results of cellular functions in HCC showed that miR-485-5p could inhibit cell proliferation and metastasis. Additionally, miR-485-5p overexpression suppressed HCC growth in vivo by down-regulation of EMMPRIN. Our study for the first time demonstrated that miR-485-5p represses HCC invasive and metastatic capacities by targeting EMMPRIN expression. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Mitochondrial Respiration in Human Colorectal and Breast Cancer Clinical Material Is Regulated Differently

PubMed Central

Koit, Andre; Ounpuu, Lyudmila; Klepinin, Aleksandr; Chekulayev, Vladimir; Timohhina, Natalja; Tepp, Kersti; Puurand, Marju; Truu, Laura; Heck, Karoliina; Valvere, Vahur; Guzun, Rita

2017-01-01

We conducted quantitative cellular respiration analysis on samples taken from human breast cancer (HBC) and human colorectal cancer (HCC) patients. Respiratory capacity is not lost as a result of tumor formation and even though, functionally, complex I in HCC was found to be suppressed, it was not evident on the protein level. Additionally, metabolic control analysis was used to quantify the role of components of mitochondrial interactosome. The main rate-controlling steps in HBC are complex IV and adenine nucleotide transporter, but in HCC, complexes I and III. Our kinetic measurements confirmed previous studies that respiratory chain complexes I and III in HBC and HCC can be assembled into supercomplexes with a possible partial addition from the complex IV pool. Therefore, the kinetic method can be a useful addition in studying supercomplexes in cell lines or human samples. In addition, when results from culture cells were compared to those from clinical samples, clear differences were present, but we also detected two different types of mitochondria within clinical HBC samples, possibly linked to two-compartment metabolism. Taken together, our data show that mitochondrial respiration and regulation of mitochondrial membrane permeability have substantial differences between these two cancer types when compared to each other to their adjacent healthy tissue or to respective cell cultures. PMID:28781720

Clinical role and biological function of CDK5 in hepatocellular carcinoma: A study based on immunohistochemistry, RNA-seq and in vitro investigation.

PubMed

Zhang, Rui; Lin, Peng; Yang, Hong; He, Yun; Dang, Yi-Wu; Feng, Zhen-Bo; Chen, Gang

2017-12-12

To investigate the clinical role and biological function of cyclin-dependent kinase 5 (CDK5) in hepatocellular carcinoma (HCC), 412 surgically resected tissue samples (HCC, n=171; non-HCC=241) were obtained and analyzed with immunohistochemistry. The diagnostic and prognostic values of CDK5 expression levels in HCC were clarified. Moreover, RNA-seq data or microarray datasets from The Cancer Genome Atlas (TCGA) (HCC, n=374; normal, n=50) or other public databases (HCC, n=1864; non-tumor=1995) regarding CDK5 in HCC were extracted and examined. Several bioinformatic methods were performed to identify CDK5-regulated pathways. In vitro experiments were adopted to measure proliferation and apoptosis in HCC cells after CDK5 mRNA was inhibited in the HCC cell lines HepG2 and HepB3. Based on immunohistochemistry, CDK5 expression levels were notably increased in HCC tissues (n=171) compared with normal (n=33, P <0.001), cirrhosis (n=37, P <0.001), and adjacent non-cancerous liver (n=171, P <0.001) tissues. The up-regulation of CDK5 was associated with higher differentiation ( P <0.001), metastasis ( P <0.001), advanced clinical TNM stages ( P <0.001), portal vein tumor embolus ( P =0.003) and vascular invasion ( P =0.004). Additionally, TCGA data analysis also revealed significantly increased CDK5 expression in HCC compared with non-cancerous hepatic tissues ( P <0.001). The pooled standard mean deviation (SMD) based on 36 included datasets (HCC, n=2238; non-cancerous, n=2045) indicated that CDK5 was up-regulated in HCC (SMD=1.23, 95% CI: 1.00-1.45, P <0.001). The area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve was 0.88. Furthermore, CDK5 knock-down inhibited proliferation and promoted apoptosis. In conclusion, CDK5 plays an essential role in the initiation and progression of HCC, most likely via accelerating proliferation and suppressing apoptosis in HCC cells by regulating the cell cycle and DNA replication pathways.

Use of KW-2189, a DNA minor groove-binding agent, in patients with hepatocellular carcinoma: a north central cancer treatment group (NCCTG) phase II clinical trial.

PubMed

Alberts, Steven R; Suman, Vera J; Pitot, Henry C; Camoriano, John K; Rubin, Joseph

2007-01-01

Hepatocellular carcinoma (HCC) is a common cancer in certain portions of the world. Currently no effective therapies exist for patients with advanced or metastatic HCC. KW-2189, a DNA minor groove-binding agent, has shown promising activity against HCC in preclinical evaluations. A phase II study was conducted to evaluate the activity of KW-2189 in patients with histologic or cytologic confirmed advanced or metastatic HCC who had no prior systemic therapy. Patients received KW-2189 at a dose of 0.5 mg/m2 administered on day 1 of a 6-week cycle. The primary endpoint of the trial was objective regression. Other endpoints included toxicity, disease-free survival, and overall survival. Due to hematologic toxicity the dose of KW-2189 was reduced to 0.375 mg/m2 after 11 patients had been enrolled into the trial. Due to continued significant hematologic toxicity in the next five patients enrolled at the lower dose the trial was closed to accrual. Two responses were seen in patients enrolled at the higher dose, including one sustained CR. KW-2189 showed evidence of anti-tumor activity in HCC. However, because of significant and prolonged hematologic toxicity, when given as a single dose every 6 weeks, further development of this drug in HCC is not possible. Further exploration of DNA minor groove-binding agents in the treatment of HCC appears warranted.

Computational Discovery of Niclosamide Ethanolamine, a Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells In Vitro and in Mice by Inhibiting Cell Division Cycle 37 Signaling.

PubMed

Chen, Bin; Wei, Wei; Ma, Li; Yang, Bin; Gill, Ryan M; Chua, Mei-Sze; Butte, Atul J; So, Samuel

2017-06-01

Drug repositioning offers a shorter approval process than new drug development. We therefore searched large public datasets of drug-induced gene expression signatures to identify agents that might be effective against hepatocellular carcinoma (HCC). We searched public databases of messenger RNA expression patterns reported from HCC specimens from patients, HCC cell lines, and cells exposed to various drugs. We identified drugs that might specifically increase expression of genes that are down-regulated in HCCs and reduce expression of genes up-regulated in HCCs using a nonparametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov statistic. We evaluated the anti-tumor activity of niclosamide and its ethanolamine salt (NEN) in HCC cell lines (HepG2, Huh7, Hep3B, Hep40, and PLC/PRF/5), primary human hepatocytes, and 2 mouse models of HCC. In one model of HCC, liver tumor development was induced by hydrodynamic delivery of a sleeping beauty transposon expressing an activated form of Ras (v12) and truncated β-catenin (N90). In another mouse model, patient-derived xenografts were established by implanting HCC cells from patients into livers of immunocompromised mice. Tumor growth was monitored by bioluminescence imaging. Tumor-bearing mice were fed a regular chow diet or a chow diet containing niclosamide or NEN. In a separate experiment using patient-derived xenografts, tumor-bearing mice were given sorafenib (the standard of care for patients with advanced HCC), NEN, or niclosamide alone; a combination of sorafenib and NEN; or a combination sorafenib and niclosamide in their drinking water, or regular water (control), and tumor growth was monitored. Based on gene expression signatures, we identified 3 anthelmintics that significantly altered the expression of genes that are up- or down-regulated in HCCs. Niclosamide and NEN specifically reduced the viability of HCC cells: the agents were at least 7-fold more cytotoxic to HCCs than primary hepatocytes. Oral administration of NEN to mice significantly slowed growth of genetically induced liver tumors and patient-derived xenografts, whereas niclosamide did not, coinciding with the observed greater bioavailability of NEN compared with niclosamide. The combination of NEN and sorafenib was more effective at slowing growth of patient-derived xenografts than either agent alone. In HepG2 cells and in patient-derived xenografts, administration of niclosamide or NEN increased expression of 20 genes down-regulated in HCC and reduced expression of 29 genes up-regulated in the 274-gene HCC signature. Administration of NEN to mice with patient-derived xenografts reduced expression of proteins in the Wnt-β-catenin, signal transducer and activator of transcription 3, AKT-mechanistic target of rapamycin, epidermal growth factor receptor-Ras-Raf signaling pathways. Using immunoprecipitation assays, we found NEN to bind cell division cycle 37 protein and disrupt its interaction with heat shock protein 90. In a bioinformatics search for agents that alter the HCC-specific gene expression pattern, we identified the anthelmintic niclosamide as a potential anti-tumor agent. Its ethanolamine salt, with greater bioavailability, was more effective than niclosamide at slowing the growth of genetically induced liver tumors and patient-derived xenografts in mice. Both agents disrupted interaction between cell division cycle 37 and heat shock protein 90 in HCC cells, with concomitant inhibition of their downstream signaling pathways. NEN might be effective for treatment of patients with HCC. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Development of Biomarkers for Screening Hepatocellular Carcinoma Using Global Data Mining and Multiple Reaction Monitoring

PubMed Central

Yu, Su Jong; Jang, Eun Sun; Yu, Jiyoung; Cho, Geunhee; Yoon, Jung-Hwan; Kim, Youngsoo

2013-01-01

Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers and is associated with a poor survival rate. Clinically, the level of alpha-fetoprotein (AFP) has been used as a biomarker for the diagnosis of HCC. The discovery of useful biomarkers for HCC, focused solely on the proteome, has been difficult; thus, wide-ranging global data mining of genomic and proteomic databases from previous reports would be valuable in screening biomarker candidates. Further, multiple reaction monitoring (MRM), based on triple quadrupole mass spectrometry, has been effective with regard to high-throughput verification, complementing antibody-based verification pipelines. In this study, global data mining was performed using 5 types of HCC data to screen for candidate biomarker proteins: cDNA microarray, copy number variation, somatic mutation, epigenetic, and quantitative proteomics data. Next, we applied MRM to verify HCC candidate biomarkers in individual serum samples from 3 groups: a healthy control group, patients who have been diagnosed with HCC (Before HCC treatment group), and HCC patients who underwent locoregional therapy (After HCC treatment group). After determining the relative quantities of the candidate proteins by MRM, we compared their expression levels between the 3 groups, identifying 4 potential biomarkers: the actin-binding protein anillin (ANLN), filamin-B (FLNB), complementary C4-A (C4A), and AFP. The combination of 2 markers (ANLN, FLNB) improved the discrimination of the before HCC treatment group from the healthy control group compared with AFP. We conclude that the combination of global data mining and MRM verification enhances the screening and verification of potential HCC biomarkers. This efficacious integrative strategy is applicable to the development of markers for cancer and other diseases. PMID:23717429

Stress-related and basic determinants of hair cortisol in humans: A meta-analysis.

PubMed

Stalder, Tobias; Steudte-Schmiedgen, Susann; Alexander, Nina; Klucken, Tim; Vater, Annika; Wichmann, Susann; Kirschbaum, Clemens; Miller, Robert

2017-03-01

The analysis of hair cortisol concentrations (HCC) is a relatively new strategy to measure long-term cumulative cortisol levels, which is increasingly used in psychoneuroendocrinological research. Here, we conduct a first comprehensive meta-analysis of HCC research based on aggregated data from a total of 124 (sub)samples (66 independent studies; total N=10,289). We seek to answer two central questions: (i) Which covariates and basic features of HCC need to be considered in future research? (ii) What are the main determinants of HCC in terms of chronic stress exposure and mental health? Concerning basic characteristics, our findings identify several covariates to be considered (age, sex, hair washing frequency, hair treatment, oral contraceptive use), confirm a decline of HCC from the first to the second proximal 3cm hair segment, and show positive associations between HCC and short-term salivary cortisol measures. Regarding chronic stress, we show that stress-exposed groups on a whole exhibit 22% increased HCC. This long-term cortisol hypersecretion emerges particularly when stress is still ongoing at the time of study (+43% HCC) but is not present in conditions of past/absent stress (-9% HCC, n.s.). We also report evidence for 17%-reduced HCC in anxiety disorders, such as PTSD. Interestingly, no consistent associations with mood disorders and self-reports of perceived stress, depressiveness or social support are found. However, our findings reveal positive associations of HCC with stress-related anthropometric (body mass index, waist-to-hip ratio) and hemodynamic measures (systolic blood pressure). These meta-analytic results are discussed in the light of their practical implications and important areas for future inquiry are outlined. Copyright © 2017 Elsevier Ltd. All rights reserved.

Proteomic Characterization of Annexin l (ANX1) and Heat Shock Protein 27 (HSP27) as Biomarkers for Invasive Hepatocellular Carcinoma Cells.

PubMed

Wang, Ruo-Chiau; Huang, Chien-Yu; Pan, Tai-Long; Chen, Wei-Yu; Ho, Chun-Te; Liu, Tsan-Zon; Chang, Yu-Jia

2015-01-01

To search for reliable biomarkers and drug targets for management of hepatocellular carcinoma (HCC), we performed a global proteomic analysis of a pair of HCC cell lines with distinct differentiation statuses using 2-DE coupled with MALDI-TOF MS. In total, 106 and 55 proteins were successfully identified from the total cell lysate and the cytosolic, nuclear and membrane fractions in well-differentiated (HepG2) and poorly differentiated (SK-Hep-1) HCC clonal variants, respectively. Among these proteins, nine spots corresponding to proteins differentially expressed between HCC cell types were selected and confirmed by immunofluorescence staining and western blotting. Notably, Annexin 1 (ANX1), ANX-2, vimentin and stress-associated proteins, such as GRP78, HSP75, HSC-70, protein disulfide isomerase (PDI), and heat shock protein-27 (HSP27), were exclusively up-regulated in SK-Hep-1 cells. Elevated levels of ANX-4 and antioxidant/metabolic enzymes, such as MnSOD, peroxiredoxin, NADP-dependent isocitrate dehydrogenase, α-enolase and UDP-glucose dehydrogenase, were observed in HepG2 cells. We functionally demonstrated that ANX1 and HSP27 were abundantly overexpressed only in highly invasive types of HCC cells, such as Mahlavu and SK-Hep-1. Knockdown of ANX1 or HSP27 in HCC cells resulted in a severe reduction in cell migration. The in-vitro observations of ANX1 and HSP27 expressions in HCC sample was demonstrated by immunohistochemical stains performed on HCC tissue microarrays. Poorly differentiated HCC tended to have stronger ANX1 and HSP27 expressions than well-differentiated or moderately differentiated HCC. Collectively, our findings suggest that ANX1 and HSP27 are two novel biomarkers for predicting invasive HCC phenotypes and could serve as potential treatment targets.

Development of biomarkers for screening hepatocellular carcinoma using global data mining and multiple reaction monitoring.

PubMed

Kim, Hyunsoo; Kim, Kyunggon; Yu, Su Jong; Jang, Eun Sun; Yu, Jiyoung; Cho, Geunhee; Yoon, Jung-Hwan; Kim, Youngsoo

2013-01-01

Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers and is associated with a poor survival rate. Clinically, the level of alpha-fetoprotein (AFP) has been used as a biomarker for the diagnosis of HCC. The discovery of useful biomarkers for HCC, focused solely on the proteome, has been difficult; thus, wide-ranging global data mining of genomic and proteomic databases from previous reports would be valuable in screening biomarker candidates. Further, multiple reaction monitoring (MRM), based on triple quadrupole mass spectrometry, has been effective with regard to high-throughput verification, complementing antibody-based verification pipelines. In this study, global data mining was performed using 5 types of HCC data to screen for candidate biomarker proteins: cDNA microarray, copy number variation, somatic mutation, epigenetic, and quantitative proteomics data. Next, we applied MRM to verify HCC candidate biomarkers in individual serum samples from 3 groups: a healthy control group, patients who have been diagnosed with HCC (Before HCC treatment group), and HCC patients who underwent locoregional therapy (After HCC treatment group). After determining the relative quantities of the candidate proteins by MRM, we compared their expression levels between the 3 groups, identifying 4 potential biomarkers: the actin-binding protein anillin (ANLN), filamin-B (FLNB), complementary C4-A (C4A), and AFP. The combination of 2 markers (ANLN, FLNB) improved the discrimination of the before HCC treatment group from the healthy control group compared with AFP. We conclude that the combination of global data mining and MRM verification enhances the screening and verification of potential HCC biomarkers. This efficacious integrative strategy is applicable to the development of markers for cancer and other diseases.

Recognition of infection, status of outpatient treatment, and treatment history before carcinogenesis in patients with viral hepatitis-associated liver cancer.

PubMed

Shibata, Michihiko; Minami, Sota; Oe, Shinji; Miyagawa, Koichiro; Honma, Yuichi; Onitsuka, Ryo; Senju, Michio; Hiura, Masaaki; Harada, Riko; Abe, Shintaro; Tabaru, Akinari; Harada, Masaru

2016-01-01

We conducted a survey on the recognition of infection, status of outpatient treatment, and treatment history in hepatitis virus-associated hepatocellular carcinoma patients admitted to our department between 2005 and 2014. We compared these parameters in 75 patients with primary hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and 307 patients with hepatitis C virus-associated hepatocellular carcinoma (HCV-HCC). Based on the presence or absence of outpatient treatment in medical institutions at the time of HCC diagnosis, the patients were divided into an outpatient treatment-free group or an outpatient treated group. In addition, the latter group was divided into three subgroups depending on the department consulted:the Department of Internal Medicine group, the Department of Gastroenterology group, and a hepatologist-treated group. Patients in the outpatient treatment-free group accounted for 40.0% of patients with HBV-HCC. In the outpatient treated group (60.0%), 21.3% were treated in the Department of Internal Medicine, 22.7% in the Department of Gastroenterology, and 16.0% were treated by a hepatologist. The percentage of HBV-HCC patients in the outpatient treatment-free group was 1.9 times higher than that in the HCV-HCC group and 0.6-fold higher in the hepatologist-treated group. Of the HBV-HCC patients, non-recognizers who were not diagnosed with a viral infection accounted for 21.3%, and non-outpatients who had not consulted a hospital despite the recognition of infection accounted for 33.3%. These percentages were approximately 2 times higher than in HCV-HCC patients. Of the HBV-HCC patients, 66.7% in the hepatologist-treated group had received nucleic acid analogue preparations. On the other hand, one patient in each of the Department of Internal Medicine and Department of Gastroenterology groups (approximately 6.0%) had received a nucleic acid analogue, lamivudine, despite the appearance of a resistant strain. In the HBV-HCC patients, the proportions of "non-recognizers" and "non-outpatients" were higher than in the HCV-HCC patients, suggesting a lack of appropriate treatment.

Palliative Care for People With Hepatocellular Carcinoma, and Specific Benefits for Older Adults.

PubMed

Woodrell, Christopher D; Hansen, Lissi; Schiano, Thomas D; Goldstein, Nathan E

2018-04-01

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, has a rapidly rising prevalence in the United States and a very poor overall rate of survival. This epidemic is driven by the cohort of aging Baby Boomers with hepatitis C viral infection and the increasing prevalence of cirrhosis as a result of nonalcoholic steatohepatitis. Because curative options are limited, the disease course creates, in patients and their families, distressing uncertainty around prognosis and treatment decisions. Older adults are disproportionately affected by HCC and have more comorbidities, adding to the complexity of the disease. This population would benefit from increased access to palliative care services, which can potentially complement the treatments throughout the disease trajectory. The purpose of this review was to use existing evidence to propose a new model of palliative care integration in patients with HCC. Thus, we focus on the HCC stage and the treatment algorithm, the ways that palliative care can offer support in this population at each stage, as well as elements that can enhance patient and family support throughout the entire disease trajectory, with an emphasis on the care of older adults with HCC. This is a narrative review in which we identify evidence-based ways that palliative care can help younger and older adults with HCC and their families, at each stage of HCC and throughout the disease trajectory. We propose ways to integrate HCC and palliative care based on the existing evidence in both fields. Palliative care offers support in symptom management, advanced care planning, and decision making in ways that are specific to each stage of HCC. We also discuss the evidence that illustrates the palliative care needs of patients with HCC that span the entire course of illness, including coping with the stigmatization of liver disease, addressing informational needs at different stages, and discussing quality of life longitudinally. Integrating palliative care into the treatment of patients with HCC has the potential to improve outcomes, although more research is needed to build this evidence base. Published by Elsevier Inc.

Aerobic biodegradation kinetics of solid organic wastes on earth and for applications in space

NASA Astrophysics Data System (ADS)

Ramirez Perez, Javier Christian

Aerobic biodegradation plays an important role in recycling organic matter and nutrients on earth. It is also a candidate technology for waste processing and resource recovery in Advanced Life Support (ALS) systems, such as a proposed planetary base on Mars. Important questions are how long should wastes be treated, and what is the quality (stability/maturity) of the product. To address these questions two aerobic composting systems were evaluated. One treated (252 days) horse manure and cranberry fruit in duplicate open windrows (HCC) as a reference earth application. The other was a pilot-scale (330 L) enclosed, in-vessel system treating (162 days) inedible biomass collected from plant growth systems at NASA, amended with food and human wastes simulant for potential space application (ALSC). Samples were taken from both systems over time and product quality assessed with a range of physical, chemical, biological, toxicological, respirometry and plant growth analyses that were developed and standardized. Because plant growth analyses take so long, a hypothesis was that some parameters could be used to predict compost quality and suitability for growing plants. Maximum temperatures in the thermophilic range were maintained for both systems (HCC > 60°C for >129 days, ALSC > 55°C for >40 days. Fecal streptococci were reduced by 4.8 log-units for HCC and 7.8 for ALSC. Volume/mass reductions achieved were 63%/62% for HCC and 79%/67% for ALSC. Phytotoxicity tests performed on aqueous extracts to recover plant nutrients found decreasing sensitivity: arabidopsis > lettuce > tomato > wheat > cucumber, corresponding with seed size and food reserve capacity. The germination index (GI) of HCC increased over composting time indicating decreasing phytotoxicity. However, GIs for ALSC leachate decreased or fluctuated over composting time. Selected samples of HCC at 31, 157 and 252 days alone and combined with promix (1:1), and of ALSC at 7, 14, 21, 28, 40 and 84 days, or fresh (FL) or dried and leached (DL), alone and combined with promix or "Martian" regolith simulant (1:1) were assessed as plant growth media. For HCC, plants were tallest and heaviest HCC-252 > HCC-157 > HCC-31 days for HCC and FL-ALSC:promix > DL-ALSC > ALSC:regolith > ALSC:promix > ALSC. Whereas phytotoxicity decreased for HCC over composting time, for ALSC it increased. A hypothesis that increasingly high free ammonia concentration in ALSC may have been the cause of toxicity was confirmed on promix adjusted to different NH4+-N concentrations and pHs. Very good, consistent correlations for selected HCC parameters with plant growth were found. However, poor and inconsistent correlations were found for ALSC due to ammonia toxicity. Maximum oxygen uptake rate (new parameter) and GI are recommended as the best indicators of compost stability/maturity and suitability for plant growth.

Adult Primary Liver Cancer Treatment (PDQ®)—Health Professional Version

Cancer.gov

Adult primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma. Treatments include surveillance, surgery, liver transplant, ablation therapy, embolization therapy, targeted therapy, and radiation therapy. Get comprehensive information about liver cancer and treatment in this clinician summary.

The scent fingerprint of hepatocarcinoma: in-vitro metastasis prediction with volatile organic compounds (VOCs)

PubMed Central

Amal, Haitham; Ding, Lu; Liu, Bin-bin; Tisch, Ulrike; Xu, Zhen-qin; Shi, Da-you; Zhao, Yan; Chen, Jie; Sun, Rui-xia; Liu, Hu; Ye, Sheng-Long; Tang, Zhao-you; Haick, Hossam

2012-01-01

Background: Hepatocellular carcinoma (HCC) is a common and aggressive form of cancer. Due to a high rate of postoperative recurrence, the prognosis for HCC is poor. Subclinical metastasis is the major cause of tumor recurrence and patient mortality. Currently, there is no reliable prognostic method of invasion. Aim: To investigate the feasibility of fingerprints of volatile organic compounds (VOCs) for the in-vitro prediction of metastasis. Methods: Headspace gases were collected from 36 cell cultures (HCC with high and low metastatic potential and normal cells) and analyzed using nanomaterial-based sensors. Predictive models were built by employing discriminant factor analysis pattern recognition, and the classification success was determined using leave-one-out cross-validation. The chemical composition of each headspace sample was studied using gas chromatography coupled with mass spectrometry (GC-MS). Results: Excellent discrimination was achieved using the nanomaterial-based sensors between (i) all HCC and normal controls; (ii) low metastatic HCC and normal controls; (iii) high metastatic HCC and normal controls; and (iv) high and low HCC. Several HCC-related VOCs that could be associated with biochemical cellular processes were identified through GC-MS analysis. Conclusion: The presented results constitute a proof-of-concept for the in-vitro prediction of the metastatic potential of HCC from VOC fingerprints using nanotechnology. Further studies on a larger number of more diverse cell cultures are needed to evaluate the robustness of the VOC patterns. These findings could benefit the development of a fast and potentially inexpensive laboratory test for subclinical HCC metastasis. PMID:22888249

Long noncoding RNA ZNFX1-AS1 suppresses growth of hepatocellular carcinoma cells by regulating the methylation of miR-9.

PubMed

Wang, Tao; Ma, Sicong; Qi, Xingxing; Tang, Xiaoyin; Cui, Dan; Wang, Zhi; Chi, Jiachang; Li, Ping; Zhai, Bo

2016-01-01

Many long noncoding RNAs have been reported to play pivotal roles in cancer biology. Among them, the long noncoding RNA ZNFX1-AS1 has been confirmed to function in breast cancer progression, but the role of ZNFX1-AS1 in hepatocellular carcinoma (HCC) growth and the related molecular mechanisms still remains unknown. In the present study, we first identified the expression of ZNFX1-AS1 in HCC patients' specimens and HCC cell lines through quantitative reverse transcription polymerase chain reaction. Next, the effects of ZNFX1-AS1 on HCC cell growth and apoptosis were analyzed. MTT assay was used to measure the cell numbers, and fluorescence-activated cell sorting analysis was performed to evaluate cell apoptosis. Finally, the relationship between ZNFX1-AS1 and miR-9 in HCC was studied. Our results suggest that ZNFX1-AS1 was markedly downregulated in HCC samples and cell lines. Overexpression of ZNFX1-AS1 inhibited the cell proliferation and colony formation in HCC cell lines and also induced HCC cell apoptosis. Additionally, miR-9 was lowly expressed in HCC tissues and positively correlated with ZNFX1-AS1 expression. Meanwhile, significant upregulation of miR-9 and downregulation of the methylation of miR-9 promoter CpG island were observed when ZNFX1-AS1 was overexpressed. In summary, our results indicate that ZNFX1-AS1 plays a vital role in HCC progression via regulating the methylation of miR-9 and may be a potential tumor suppressor.

Up-regulation of miR-95-3p in hepatocellular carcinoma promotes tumorigenesis by targeting p21 expression

PubMed Central

Ye, Jian; Yao, Yufeng; Song, Qixue; Li, Sisi; Hu, Zhenkun; Yu, Yubing; Hu, Changqing; Da, Xingwen; Li, Hui; Chen, Qiuyun; Wang, Qing K.

2016-01-01

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers. To elucidate new regulatory mechanisms for heptocarcinogenesis, we investigated the regulation of p21, a cyclin-dependent kinase (CDK) inhibitor encoded by CDKN1A, in HCC. The expression level of p21 is decreased with the progression of HCC. Luciferase assays with a luciferase-p21-3′ UTR reporter and its serial deletions identified a 15-bp repressor element at the 3′-UTR of CDKN1A, which contains a binding site for miR-95-3p. Mutation of the binding site eliminated the regulatory effect of miR-95-3p on p21 expression. Posttranscriptional regulation of p21 expression by miR-95-3p is mainly on the protein level (suppression of translation). Overexpression of miR-95-3p in two different HCC cell lines, HepG2 and SMMC7721, significantly promoted cell proliferation, cell cycle progression and cell migration, whereas a miR-95-3p specific inhibitor decreased cell proliferation, cell cycle progression and cell migration. The effects of miR-95-3p on cellular functions were rescued by overexpression of p21. Overexpression of miR-95-3p promoted cell proliferation and tumor growth in HCC xenograft mouse models. Expression of miR-95-3p was significantly higher in HCC samples than in adjacent non-cancerous samples. These results demonstrate that miR-95-3p is a potential new marker for HCC and regulates hepatocarcinogenesis by directly targeting CDKN1A/p21 expression. PMID:27698442

Identification of cyclin B1 and Sec62 as biomarkers for recurrence in patients with HBV-related hepatocellular carcinoma after surgical resection.

PubMed

Weng, Li; Du, Juan; Zhou, Qinghui; Cheng, Binbin; Li, Jun; Zhang, Denghai; Ling, Changquan

2012-06-08

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Frequent tumor recurrence after surgery is related to its poor prognosis. Although gene expression signatures have been associated with outcome, the molecular basis of HCC recurrence is not fully understood, and there is no method to predict recurrence using peripheral blood mononuclear cells (PBMCs), which can be easily obtained for recurrence prediction in the clinical setting. According to the microarray analysis results, we constructed a co-expression network using the k-core algorithm to determine which genes play pivotal roles in the recurrence of HCC associated with the hepatitis B virus (HBV) infection. Furthermore, we evaluated the mRNA and protein expressions in the PBMCs from 80 patients with or without recurrence and 30 healthy subjects. The stability of the signatures was determined in HCC tissues from the same 80 patients. Data analysis included ROC analysis, correlation analysis, log-lank tests, and Cox modeling to identify independent predictors of tumor recurrence. The tumor-associated proteins cyclin B1, Sec62, and Birc3 were highly expressed in a subset of samples of recurrent HCC; cyclin B1, Sec62, and Birc3 positivity was observed in 80%, 65.7%, and 54.2% of the samples, respectively. The Kaplan-Meier analysis revealed that high expression levels of these proteins was associated with significantly reduced recurrence-free survival. Cox proportional hazards model analysis revealed that cyclin B1 (hazard ratio [HR], 4.762; p = 0.002) and Sec62 (HR, 2.674; p = 0.018) were independent predictors of HCC recurrence. These results revealed that cyclin B1 and Sec62 may be candidate biomarkers and potential therapeutic targets for HBV-related HCC recurrence after surgery.

Ambient ultraviolet radiation exposure and hepatocellular carcinoma incidence in the United States.

PubMed

VoPham, Trang; Bertrand, Kimberly A; Yuan, Jian-Min; Tamimi, Rulla M; Hart, Jaime E; Laden, Francine

2017-08-18

Hepatocellular carcinoma (HCC), the most commonly occurring type of primary liver cancer, has been increasing in incidence worldwide. Vitamin D, acquired from sunlight exposure, diet, and dietary supplements, has been hypothesized to impact hepatocarcinogenesis. However, previous epidemiologic studies examining the associations between dietary and serum vitamin D reported mixed results. The purpose of this study was to examine the association between ambient ultraviolet (UV) radiation exposure and HCC risk in the U.S. The Surveillance, Epidemiology, and End Results (SEER) database provided information on HCC cases diagnosed between 2000 and 2014 from 16 population-based cancer registries across the U.S. Ambient UV exposure was estimated by linking the SEER county with a spatiotemporal UV exposure model using a geographic information system. Poisson regression with robust variance estimation was used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between ambient UV exposure per interquartile range (IQR) increase (32.4 mW/m 2 ) and HCC risk adjusting for age at diagnosis, sex, race, year of diagnosis, SEER registry, and county-level information on prevalence of health conditions, lifestyle, socioeconomic, and environmental factors. Higher levels of ambient UV exposure were associated with statistically significant lower HCC risk (n = 56,245 cases; adjusted IRR per IQR increase: 0.83, 95% CI 0.77, 0.90; p < 0.01). A statistically significant inverse association between ambient UV and HCC risk was observed among males (p for interaction = 0.01) and whites (p for interaction = 0.01). Higher ambient UV exposure was associated with a decreased risk of HCC in the U.S. UV exposure may be a potential modifiable risk factor for HCC that should be explored in future research.

miR-370 regulates ISG15 expression and influences IFN-α sensitivity in hepatocellular carcinoma cells.

PubMed

Liu, Zhuo; Ma, Min; Yan, Lei; Chen, Shilin; Li, Sha; Yang, Darong; Wang, Xiaohong; Xiao, Hua; Deng, Hongyu; Zhu, Haizhen; Zuo, Chaohui; Xia, Man

2018-05-05

Interferon-α (IFN-α) is an adjuvant to chemotherapy and radiotherapy for hepatocellular carcinoma (HCC), but some HCC patients do not respond to treatment with IFN-α. We performed loss-of-function and gain-of-function experiments to examine the role of ISG15 in the IFN-α sensitivity of LH86, HLCZ01, SMMC7721, and Huh7 cell lines and tumor samples. The overexpression of ISG15 reduced apoptosis in Huh7 and LH86 cells in the presence of IFN-α, whereas the shRNA-mediated knock down of ISG15 expression increased apoptosis in both Huh7 and LH86 cells. We identified a putative miR-370 target site in the 3'-UTR in the ISG15 mRNA, and the level of miR-370 expression in HCC cell lines reflected the level of IFN-α-induced apoptosis exhibited by each. Both HCC cell lines and tumor samples had significantly lower levels of miR-370 than the control cells and tissues (P< 0.05). The overexpression of miR-370 in IFN-α-treated LH86 and Huh7 cells increased apoptosis and reduced the volume of LH86- and Huh7-derived xenograft tumors in mice treated with IFN-α compared with the control tumors. Our findings suggest that miR-370 functions as an HCC tumor suppressor and regulator of IFN-α sensitivity and that miR-370 might be a useful prognostic marker for HCC patients.

Association between aflatoxin B1 occupational airway exposure and risk of hepatocellular carcinoma: a case-control study.

PubMed

Lai, Hao; Mo, Xianwei; Yang, Yang; He, Ke; Xiao, Jun; Liu, Chao; Chen, Jiansi; Lin, Yuan

2014-10-01

The aim of this study was to determine the airway exposure of sugar and papermaking factory workers to aflatoxin B1 (AFB1) and to explore the potential association between AFB1 airway exposure and the risk of hepatocellular carcinoma (HCC) in a case-control study. Dust samples were collected from the sugarcane bagasse warehouse, and presser and paper production workshops. Blood samples were collected from 181 workshop employees and 203 controls who worked outside the workshop. AFB1 albumin adducts were detected using a double antibody sandwich enzyme-linked immunosorbent assay (ELISA). To explore the association between AFB1 airway exposure and the risk of HCC, the medical records of 68 HCC patients who worked in a sugar and papermaking factory between January 1994 and December 2013 were analyzed. A questionnaire was used to collect information from 150 healthy controls who worked for the same company and lived near the factory. AFB1 was detected in the dust samples, but could not be detected in any of the rice samples. An analysis of serum samples revealed serum AFB1 albumin adducts in 102 (56.35 %) of the study participants. However, in the control group, only 12 (5.9 %) individuals had detectable levels of AFB1 albumin adducts. Those with airway exposure to Aspergillus flavus-contaminated dust had an elevated risk of HCC compared to those without exposure (odds ratio, 5.24; 95 % confidence interval, 2.77-9.88; P = 0.00). The findings of this study indicate that occupational AFB1 airway exposure might be associated with the risk of AFB1-related HCC among the population that was used in this study. Intervention programs aimed at reducing exposure to inhalational AFB1 are needed urgently. Additional suitably designed, multicenter, prospective studies using large samples are needed to further confirm the results.

Methylation analysis of p16, SLIT2, SCARA5, and Runx3 genes in hepatocellular carcinoma

PubMed Central

Sun, Gaofeng; Zhang, Chen; Feng, Min; Liu, Wensheng; Xie, Huifang; Qin, Qin; Zhao, E.; Wan, Li

2017-01-01

Abstract This study is to investigate the methylation status of multiple tumor suppressor 1 (p16), secreted glycoprotein 2 (SLIT2), scavenger receptor class A, member 5 putative (SCARA5), and human runt-related transcription factor 3 (Runx3) genes in the peripheral blood of hepatocellular carcinoma (HCC). This is a case–control study. The peripheral blood samples were collected from 25 HCC patients, 25 patients with high risk of HCC (defined as “internal control group”), and 25 healthy individuals (defined as “external control group”), respectively. Then the methylation status of p16, SLIT2, SCARA5, and Runx3 genes in the blood samples were analyzed by pyrosequencing. The relationship between the methylation and the clinical features of HCC patients were evaluated. The methylation levels in the 7 CpG loci of p16 gene in HCC patients were low and without statistically significant difference (P > .05) compared to the control groups. Although the methylation levels of CpG3 and CpG4 in SLIT2 gene loci were higher than those of the control groups, there was no statistically significant difference (P > .05). However, the methylation rate of CpG2 locus in SCARA5 gene in HCC patients was significantly higher (P < .05). And the methylation rates of CpG1, CpG2, CpG3, CpG4, CpG5, and CpG8 in Runx3 gene in HCC patients were significantly different to that of control groups (P < .05). We also have analyzed the correlations between the CpG islands methylation of Runx3 or SCARA5 genes and the age, gender, hepatitis B, liver cirrhosis, alpha fetal protein, or hepatitis B surface antigen (HBsAg) of the HCC patients, which all showed no significant correlations (P > .05). The methylation status of SCARA5 and Runx3 genes are abnormal in HCC patients, which may further be used as molecular markers for early auxiliary diagnosis of liver cancer. PMID:29019900

The role of aflatoxins and hepatitis viruses in the etiopathogenesis of hepatocellular carcinoma: A basis for primary prevention in Guinea-Conakry, West Africa.

PubMed

Turner, Paul C; Sylla, Abdoulaye; Diallo, Mamadou S; Castegnaro, Jean-Jacques; Hall, Andrew J; Wild, Christopher P

2002-12-01

Aflatoxins and hepatitis B virus (HBV) are major risk factors for hepatocellular carcinoma (HCC) in South-east Asia and Africa, parts of the world where this cancer is most prevalent. Exposure to both factors is endemic, occurring from early in life. There is evidence from both epidemiological studies and animal models that the two factors can act synergistically to increase the risk of HCC, but the underlying cellular and molecular mechanisms of interaction are as yet undefined. One possibility suggested by studies in HBV transgenic mice is that chronic liver injury alters the expression of carcinogen metabolizing enzymes, thus modulating the level of binding of aflatoxin to DNA. Primary prevention of HCC in high incidence areas of the world should primarily be focused on provision of the safe, effective vaccine against HBV. However, measures to reduce the high levels of aflatoxin exposure, where chronic HBV infection is currently epidemic, would also significantly contribute to reducing HCC incidence. In Guinea-Conakry, West Africa, surveys of HBV infection and aflatoxin exposure have established baseline data for the implementation of a community-based intervention study. This study will evaluate the effectiveness of improving the post-harvest processing and storage of the groundnut crop, a major source of aflatoxins, using aflatoxin-albumin adducts as the outcome measurement. Copyright 2002 Blackwell Publishing Asia Pty Ltd

Downregulation of P-cadherin expression in hepatocellular carcinoma induces tumorigenicity

PubMed Central

Bauer, Richard; Valletta, Daniela; Bauer, Karin; Thasler, Wolfgang E; Hartmann, Arndt; Müller, Martina; Reichert, Torsten E; Hellerbrand, Claus

2014-01-01

P-cadherin is a major contributor to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes and in maintaining tissue integrity and homeostasis. Alterations of P-cadherin expression have been observed during the progression of several carcinomas where it appears to act as tumor suppressive or oncogenic in a context-dependent manner. Here, we found a significant downregulation of P-cadherin in hepatocellular carcinoma (HCC) cell lines and tissues compared to primary human hepatocytes and non-malignant liver tissues. Combined immunohistochemical analysis of a tissue microarray containing matched pairs of HCC tissue and corresponding non-tumorous liver tissue of 69 patients confirmed reduced P-cadherin expression in more than half of the cases. In 35 human HCC tissues, the P-cadherin immunosignal was completely lost which correlated with tumor staging and proliferation. Also in vitro, P-cadherin suppression in HCC cells via siRNA induced proliferation compared to cells transfected with control-siRNA. In summary, downregulation of P-cadherin expression appears to induce tumorigenicity in HCC. Therefore, P-cadherin expression may serve as a prognostic marker and therapeutic target of this highly aggressive tumor. PMID:25337260

Downregulation of P-cadherin expression in hepatocellular carcinoma induces tumorigenicity.

PubMed

Bauer, Richard; Valletta, Daniela; Bauer, Karin; Thasler, Wolfgang E; Hartmann, Arndt; Müller, Martina; Reichert, Torsten E; Hellerbrand, Claus

2014-01-01

P-cadherin is a major contributor to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes and in maintaining tissue integrity and homeostasis. Alterations of P-cadherin expression have been observed during the progression of several carcinomas where it appears to act as tumor suppressive or oncogenic in a context-dependent manner. Here, we found a significant downregulation of P-cadherin in hepatocellular carcinoma (HCC) cell lines and tissues compared to primary human hepatocytes and non-malignant liver tissues. Combined immunohistochemical analysis of a tissue microarray containing matched pairs of HCC tissue and corresponding non-tumorous liver tissue of 69 patients confirmed reduced P-cadherin expression in more than half of the cases. In 35 human HCC tissues, the P-cadherin immunosignal was completely lost which correlated with tumor staging and proliferation. Also in vitro, P-cadherin suppression in HCC cells via siRNA induced proliferation compared to cells transfected with control-siRNA. In summary, downregulation of P-cadherin expression appears to induce tumorigenicity in HCC. Therefore, P-cadherin expression may serve as a prognostic marker and therapeutic target of this highly aggressive tumor.

Gene profiling, biomarkers and pathways characterizing HCV-related hepatocellular carcinoma

PubMed Central

De Giorgi, Valeria; Monaco, Alessandro; Worchech, Andrea; Tornesello, MariaLina; Izzo, Francesco; Buonaguro, Luigi; Marincola, Francesco M; Wang, Ena; Buonaguro, Franco M

2009-01-01

Background Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The molecular mechanisms of HCV-induced hepatocarcinogenesis are not yet fully elucidated. Besides indirect effects as tissue inflammation and regeneration, a more direct oncogenic activity of HCV can be postulated leading to an altered expression of cellular genes by early HCV viral proteins. In the present study, a comparison of gene expression patterns has been performed by microarray analysis on liver biopsies from HCV-positive HCC patients and HCV-negative controls. Methods Gene expression profiling of liver tissues has been performed using a high-density microarray containing 36'000 oligos, representing 90% of the human genes. Samples were obtained from 14 patients affected by HCV-related HCC and 7 HCV-negative non-liver-cancer patients, enrolled at INT in Naples. Transcriptional profiles identified in liver biopsies from HCC nodules and paired non-adjacent non-HCC liver tissue of the same HCV-positive patients were compared to those from HCV-negative controls by the Cluster program. The pathway analysis was performed using the BRB-Array- Tools based on the "Ingenuity System Database". Significance threshold of t-test was set at 0.001. Results Significant differences were found between the expression patterns of several genes falling into different metabolic and inflammation/immunity pathways in HCV-related HCC tissues as well as the non-HCC counterpart compared to normal liver tissues. Only few genes were found differentially expressed between HCV-related HCC tissues and paired non-HCC counterpart. Conclusion In this study, informative data on the global gene expression pattern of HCV-related HCC and non-HCC counterpart, as well as on their difference with the one observed in normal liver tissues have been obtained. These results may lead to the identification of specific biomarkers relevant to develop tools for detection, diagnosis, and classification of HCV-related HCC. PMID:19821982

O-GlcNAcylation of RACK1 promotes hepatocellular carcinogenesis.

PubMed

Duan, Fangfang; Wu, Hao; Jia, Dongwei; Wu, Weicheng; Ren, Shifang; Wang, Lan; Song, Shushu; Guo, Xinying; Liu, Fenglin; Ruan, Yuanyuan; Gu, Jianxin

2018-06-01

Aberrant oncogenic mRNA translation and protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) are general features during tumorigenesis. Nevertheless, whether and how these two pathways are interlinked remain unknown. Our previous study indicated that ribosomal receptor for activated C-kinase 1 (RACK1) promoted chemoresistance and growth in hepatocellular carcinoma (HCC). The aim of this study is to examine the role of RACK1 O-GlcNAcylation in oncogene translation and HCC carcinogenesis. The site(s) of RACK1 for O-GlcNAcylation was mapped by mass spectrometry analysis. HCC cell lines were employed to examine the effects of RACK1 O-GlcNAcylation on the translation of oncogenic factors and behaviors of tumor cells in vitro. Transgenic knock-in mice were used to detect the role of RACK1 O-GlcNAcylation in modulating HCC tumorigenesis in vivo. The correlation of RACK1 O-GlcNAcylation with tumor progression and relapse were analyzed in clinical HCC samples. We found that ribosomal RACK1 was highly modified by O-GlcNAc at Ser122. O-GlcNAcylation of RACK1 enhanced its protein stability, ribosome binding and interaction with PKCβII (PRKCB), leading to increased eukaryotic translation initiation factor 4E phosphorylation and translation of potent oncogenes in HCC cells. Genetic ablation of RACK1 O-GlcNAcylation at Ser122 dramatically suppressed tumorigenesis, angiogenesis, and metastasis in vitro and in diethylnitrosamine (DEN)-induced HCC mouse model. Increased RACK1 O-GlcNAcylation was also observed in HCC patient samples and correlated with tumor development and recurrence after chemotherapy. These findings demonstrate that RACK1 acts as key mediator linking O-GlcNAc metabolism to cap-dependent translation during HCC tumorigenesis. Targeting RACK1 O-GlcNAcylation provides promising options for HCC treatment. O-GlcNAcylation of ribosomal receptor for activated C-kinase 1 at the amino acid serine122 promotes its stability, ribosome localization and interaction with the protein kinase, PKCβII, thus driving the translation of oncogenes and tumorigenesis of hepatocellular carcinoma. Increased O-GlcNAcylation of ribosomal receptor for activated C-kinase 1 is positively correlated with tumor growth, metastasis and recurrence in patients with hepatocellular carcinoma. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Neural network ensemble based CAD system for focal liver lesions from B-mode ultrasound.

PubMed

Virmani, Jitendra; Kumar, Vinod; Kalra, Naveen; Khandelwal, Niranjan

2014-08-01

A neural network ensemble (NNE) based computer-aided diagnostic (CAD) system to assist radiologists in differential diagnosis between focal liver lesions (FLLs), including (1) typical and atypical cases of Cyst, hemangioma (HEM) and metastatic carcinoma (MET) lesions, (2) small and large hepatocellular carcinoma (HCC) lesions, along with (3) normal (NOR) liver tissue is proposed in the present work. Expert radiologists, visualize the textural characteristics of regions inside and outside the lesions to differentiate between different FLLs, accordingly texture features computed from inside lesion regions of interest (IROIs) and texture ratio features computed from IROIs and surrounding lesion regions of interests (SROIs) are taken as input. Principal component analysis (PCA) is used for reducing the dimensionality of the feature space before classifier design. The first step of classification module consists of a five class PCA-NN based primary classifier which yields probability outputs for five liver image classes. The second step of classification module consists of ten binary PCA-NN based secondary classifiers for NOR/Cyst, NOR/HEM, NOR/HCC, NOR/MET, Cyst/HEM, Cyst/HCC, Cyst/MET, HEM/HCC, HEM/MET and HCC/MET classes. The probability outputs of five class PCA-NN based primary classifier is used to determine the first two most probable classes for a test instance, based on which it is directed to the corresponding binary PCA-NN based secondary classifier for crisp classification between two classes. By including the second step of the classification module, classification accuracy increases from 88.7 % to 95 %. The promising results obtained by the proposed system indicate its usefulness to assist radiologists in differential diagnosis of FLLs.

Heparanase mRNA expression and point mutation in hepatocellular carcinoma

PubMed Central

Chen, Xiao-Peng; Liu, Yin-Bib; Rui, Jing; Peng, Shu-You; Peng, Cheng-Hong; Zhou, Zi-Yan; Shi, Liang-Hui; Shen, Hong-Wei; Xu, Bin

2004-01-01

AIM: To explore the expression of heparanase mRNA and point mutation in hepatocellular carcinoma (HCC). METHODS: Reverse transcription polymerase chain reaction was used to measure the expression of heparanase mRNA in the primary tumor tissues and surrounding liver tissues of 33 HCC patients. T-A cloning and sequencing were used to detect whether there was any mutation in the amplified PCR products. RESULTS: The expression of heparanase mRNA was positive in 16 primary tumor tissues of HCC, and the positive rate was 48.5%, which was significantly higher than that in the surrounding liver parenchyma (P < 0.01). The positive rate for heparanase gene in high-tendency to metastatic recurrence group (71.4%, 10/14) was obviously higher than that in low-tendency to metastatic recurrence group (31.6%, 6/19) (P = 0.023). The positive rate for heparanase gene in patients with metastatic recurrence during postoperative follow-up (78.6%, 11/14) was also significantly higher than that in those without metastatic recurrence (21.4%, 3/14) (P = 0.003). Sequence analysis of the HPA PCR products was made in 7 patients, and 2-point mutations were found in 4 patients, one of which was sense mutation, neither base insertion nor deletion was detected. The mutation rate was 57.1% (4/7). CONCLUSION: The expression rate of heparanase mRNA increases in HCC, and HPA mRNA may be one of the reliable markers for the metastatic activity gained by the liver tumor cells and could be used clinically in predicting metastatic recurrence of HCC. Point mutation may be one of the causes for enhanced heparanase mRNA expression. PMID:15334672

A Nonrandomized, Phase II Study of Sequential Irinotecan and Flavopiridol in Patients With Advanced Hepatocellular Carcinoma

PubMed Central

Ang, Celina; O'Reilly, Eileen M.; Carvajal, Richard D.; Capanu, Marinela; Gonen, Mithat; Doyle, Laurence; Ghossein, Ronald; Schwartz, Lawrence; Jacobs, Gria; Ma, Jennifer; Schwartz, Gary K.

2012-01-01

ABSTRACT BACKGROUND: Flavopiridol, a Cdk inhibitor, potentiates irinotecan-induced apoptosis. In a phase I trial of sequential irinotecan and flavopiridol, 2 patients with advanced hepatocellular carcinoma (HCC) had stable disease (SD) for ≥14 months. We thus studied the sequential combination of irinotecan and flavopiridol in patients with HCC. METHODS: Patients with advanced HCC naïve to systemic therapy, Child-Pugh ≤B8, and Karnofsky performance score (KPS) ≥70% received 100 mg/m2 irinotecan followed 7 hours later by flavopiridol 60 mg/m2 weekly for 4 of 6 weeks. The primary end point was an improvement in progression-free survival at 4 months (PFS-4) from 33% to 54%, using a Simon's two-stage design. Tumors were stained for p53. RESULTS: Only 16 patients in the first stage were enrolled: median age, 64 years; median KPS, 80%; Child-Pugh A, 87.5%; and stage III/IV, 25%/75%. The primary end point was not met; PFS-4 was 20%, leading to early termination of the study. Ten patients were evaluable for response: 1 had SD >1 year and 9 had disease progression. Grade 3 fatigue, dehydration, diarrhea, neutropenia with or without fever, lymphopenia, anemia, hyperbilirubinemia, and transaminitis occurred in ≥10% of the patients. Of the 9 patients who progressed, 5 had mutant p53 and 4 had wild-type p53. The patient with stable disease had wild-type p53. CONCLUSION: Sequential irinotecan and flavopiridol are ineffective and poorly tolerated in patients with advanced HCC. Despite our limited assessments, it is possible that the presence of wild-type p53 is necessary but not sufficient to predict response in HCC. PMID:23293699

Genomic and epigenomic heterogeneity of hepatocellular carcinoma

PubMed Central

Lin, De-Chen; Mayakonda, Anand; Dinh, Huy Q.; Huang, Pinbo; Lin, Lehang; Liu, Xiaoping; Ding, Ling-wen; Wang, Jie; Berman, Benjamin P.; Song, Er-Wei; Yin, Dong; Koeffler, H. Phillip

2017-01-01

Understanding the intratumoral heterogeneity of hepatocellular carcinoma (HCC) is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diversity was found in all 11 HCC cases, with 29% of driver mutations being heterogeneous, including TERT, ARID1A, NOTCH2, and STAG2. Similar with other cancer types, TP53 mutations were always shared between all tumor regions i.e. located on the “trunk” of the evolutionary tree. In addition, we found that variants within several drug targets such as KIT, SYK and PIK3CA were mutated in a fully clonal manner, indicating their therapeutic potentials for HCC. Temporal dissection of mutational signatures suggested that mutagenic processes associated with exposure to aristolochic acid and aflatoxin might play a more important role in early, as opposed to late, stages of HCC development. Moreover, we observed extensive intratumoral epigenetic heterogeneity in HCC based on multiple independent analytical methods and showed that intratumoral methylation heterogeneity might play important roles in the biology of HCC cells. Our results also demonstrated prominent heterogeneity of intratumoral methylation even in a stable HCC genome. Together, these findings highlight widespread intratumoral heterogeneity at both the genomic and epigenomic levels in HCC and provide an important molecular foundation for better understanding the pathogenesis of this malignancy. PMID:28302680

TCP10L acts as a tumor suppressor by inhibiting cell proliferation in hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zuo, Jie; Cai, Hao; Wu, Yanhua

2014-03-28

Highlights: • TCP10L was down-regulated in clinical hepatocellular carcinoma (HCC). • Expression of TCP10L correlated significantly with tumor size and Milan criteria. • Overexpression of TCP10L attenuated growth of HCC cells both in vitro and in vivo. • Knocking down TCP10L promoted cell proliferation and tumorigenesis of HCC cells. - Abstract: TCP10L (T-complex 10 (mouse)-like) has been identified as a liver and testis-specific gene. Although a potential transcriptional suppression function of TCP10L has been reported previously, biological function of this gene still remains largely elusive. In this study, we reported for the first time that TCP10L was significantly down-regulated inmore » clinical hepatocellular carcinoma (HCC) samples when compared to the corresponding non-tumorous liver tissues. Furthermore, TCP10L expression was highly correlated with advanced cases exceeding the Milan criteria. Overexpression of TCP10L in HCC cells suppressed colony formation, inhibited cell cycle progression through G0/G1 phase, and attenuated cell growth in vivo. Consistently, silencing of TCP10L promoted cell cycle progression and cell growth. Therefore, our study has revealed a novel suppressor role of TCP10L in HCC, by inhibiting proliferation of HCC cells, which may facilitate the diagnosis and molecular therapy in HCC.« less

Expression of cytoskeleton regulatory protein Mena in human hepatocellular carcinoma and its prognostic significance.

PubMed

Hu, Kunpeng; Wang, Jiani; Yao, Zhicheng; Liu, Bo; Lin, Yuan; Liu, Lei; Xu, Lihua

2014-05-01

The molecular mechanisms of the development and progression of hepatocellular carcinoma (HCC) are poorly understood. The main objective of this study was to analyze the expression of Enabled [mammalian Ena (Mena)] protein and its clinical significance in human HCC. The Mena expression was examined at mRNA and protein levels by real-time quantitative polymerase chain reaction and Western blotting analysis in ten paired HCC tissues and the adjacent normal tissues. The expression of Mena protein in 81 specimens of HCC tissues was determined by immunohistochemistry. Associations of Mena expression with the clinicopathological features were analyzed, and prognosis of HCC patients was evaluated. The result shows the expression of Mena mRNA and protein was higher in HCC than in the adjacent normal tissues in ten paired samples. Mena was mainly accumulated in the cytoplasm of tumor cells and over-expressed in 40.74% (33/81) patients by immunohistochemical staining. Over-expression of Mena was significantly associated with poor cellular differentiation (P = 0.025), advanced tumor stage (P = 0.003) and worse disease-free survival (DFS, P < 0.001). In addition, Mena is an independent prognostic factor for DFS in multivariate analysis (HR 2.309, 95% CI 1.104-4.828; P = 0.026). Mena is up-regulated in HCC and associated with tumor differentiation and clinical stage. Mena may be an independent prognostic marker for DFS of HCC patients.

Zinc finger protein 267 is up-regulated in hepatocellular carcinoma and promotes tumor cell proliferation and migration.

PubMed

Schnabl, Bernd; Valletta, Daniela; Kirovski, Georgi; Hellerbrand, Claus

2011-12-01

Zinc finger protein 267 (ZNF267) belongs to the family of Kruppel-like transcription factors, which regulates diverse biological processes that include development, proliferation, and differentiation. We have previously demonstrated that ZNF267 mRNA is up-regulated in liver cirrhosis, which is the main risk factor for hepatocellular carcinoma (HCC). Here, we analyzed the expression of ZNF267 in human HCC cells and tissue specimens and found a significant up-regulation compared to primary human hepatocytes and corresponding non-tumorous liver tissue. Over-expression of the transcription factor Ets-1 further enhanced ZNF267 expression, and reporter gene assays revealed that mutation of the Ets-1 binding site to the ZNF267 promotor markedly inhibited ZNF267 promotor activity. Hypoxic conditions induced Ets-1 in HCC cells via HIF1alpha activation, and hypoxia induced ZNF267 expression while HIF1alpha inhibition significantly reduced both hypoxia-induced as well as basal ZNF267 expression in HCC cells. It is known that hypoxic conditions in tumorous tissues induce the formation of reactive oxygen species (ROS), and ROS have been identified as important factor in the regulation of Ets-1 expression in tumor cells. Here, we found that ROS induction induced and ROS scavenging reduced ZNF267 expression in HCC cells, respectively. Loss and gain of function analysis applying siRNA directed against ZNF267 or transient transfection revealed that ZNF267 promotes proliferation and migration of HCC cells in vitro. These findings indicate Ets-1 and HIF1alpha as critical regulators of basal and hypoxia- or ROS-induced ZNF267 expression in HCC, and further suggest that the pro-tumorigenic effect of these factors is at least in part mediated via increased ZNF267 expression in HCC. Since ZNF267 is already elevated in cirrhosis, ZNF267 appears as promising target for both prevention as well as treatment of HCC in patients with chronic liver disease. Copyright © 2011 Elsevier Inc. All rights reserved.

Zinc finger protein 267 is up-regulated in hepatocellular carcinoma and promotes tumor cell proliferation and migration

PubMed Central

Schnabl, Bernd; Valletta, Daniela; Kirovski, Georgi; Hellerbrand, Claus

2012-01-01

Zinc finger protein 267 (ZNF267) belongs to the family of Kruppel-like transcription factors, which regulates diverse biological processes that include development, proliferation, and differentiation. We have previously demonstrated that ZNF267 mRNA is up-regulated in liver cirrhosis, which is the main risk factor for hepatocellular carcinoma (HCC). Here, we analyzed the expression of ZNF267 in human HCC cells and tissue specimens and found a significant up-regulation compared to primary human hepatocytes and corresponding non-tumorous liver tissue. Over-expression of the transcription factor Ets-1 further enhanced ZNF267 expression, and reporter gene assays revealed that mutation of the Ets-1 binding site to the ZNF267 promotor markedly inhibited ZNF267 promotor activity. Hypoxic conditions induced Ets-1 in HCC cells via HIF1alpha activation, and hypoxia induced ZNF267 expression while HIF1alpha inhibition significantly reduced both hypoxia-induced as well as basal ZNF267 expression in HCC cells. It is known that hypoxic conditions in tumorous tissues induce the formation of reactive oxygen species (ROS), and ROS have been identified as important factor in the regulation of Ets-1 expression in tumor cells. Here, we found that ROS induction induced and ROS scavenging reduced ZNF267 expression in HCC cells, respectively. Loss and gain of function analysis applying siRNA directed against ZNF267 or transient transfection revealed that ZNF267 promotes proliferation and migration of HCC cells in vitro. These findings indicate Ets-1 and HIF1alpha as critical regulators of basal and hypoxia- or ROS-induced ZNF267 expression in HCC, and further suggest that the pro-tumorigenic effect of these factors is at least in part mediated via increased ZNF267 expression in HCC. Since ZNF267 is already elevated in cirrhosis, ZNF267 appears as promising target for both prevention as well as treatment of HCC in patients with chronic liver disease. PMID:21840307

Zebrafish as a disease model for studying human hepatocellular carcinoma.

PubMed

Lu, Jeng-Wei; Ho, Yi-Jung; Yang, Yi-Ju; Liao, Heng-An; Ciou, Shih-Ci; Lin, Liang-In; Ou, Da-Liang

2015-11-14

Liver cancer is one of the world's most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma (HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel small-molecule inhibitors. This review will focus on illustrative examples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts, drug discovery, and drug-induced toxic liver injury.

Zebrafish as a disease model for studying human hepatocellular carcinoma

PubMed Central

Lu, Jeng-Wei; Ho, Yi-Jung; Yang, Yi-Ju; Liao, Heng-An; Ciou, Shih-Ci; Lin, Liang-In; Ou, Da-Liang

2015-01-01

Liver cancer is one of the world’s most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma (HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel small-molecule inhibitors. This review will focus on illustrative examples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts, drug discovery, and drug-induced toxic liver injury. PMID:26576090

Gamma-glutamyltranspeptidase to platelet ratio and albumin to gamma-glutamyltranspeptidase between degrees of the Barcelona clinic liver cancer on hepatocellular carcinoma patients in Haji Adam Malik general hospital Medan during 2015-2016

NASA Astrophysics Data System (ADS)

Siregar, G. A.; Siregar, R. H.

2018-03-01

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and occurs predominantly in apatient with underlying chronic liver disease and cirrhosis. HCC presented at an advancedstage with right-upper-quadrant pain, weight loss, and signs of decompensated liver disease; it is now increasingly recognized atmuch measurements of the biomarker. Some of them are Gamma-glutamyltranspeptidase to platelet ratio (GPR) and Albumin to Gamma- glutamyltranspeptidase (AGR). This study aimed to know the difference between GPR and AGR between degrees of the Barcelona Clinic Liver cancer (BCLC) on HCC patients. A retrospective study was carried out in 166 outpatient and inpatient HCC in Haji Adam Malik General Hospital from January 2015–December2016.Kruskal-Wallis test showed that there is no significant differentiation of GPR between degrees of BCLC (p=0.23), but there is a considerable differentiation of AGR between degrees of BCLC (p=0.032).

Do People with Disabilities Have Difficulty Finding a Family Physician?

PubMed Central

McColl, Mary Ann; Aiken, Alice; Schaub, Michael

2015-01-01

Primary care has been ideally characterized as the medical home for all citizens, and yet recent data shows that approximately 6% do not have a family physician, and only 17.5% of family practices are open to new patients. Given acknowledged shortages of family physicians, this research asks the question: Do people with disabilities have particular difficulty finding a family physician? Health Care Connect (HCC) is a government-funded agency in Ontario Canada, designed to “help Ontarians who are without a family health care provider to find one”. Using data from HCC, supplemented by interviews with HCC staff, the study explores the average wait time for patients with disabilities to be linked with a primary care physician, and the challenges faced by agency staff in doing so. The study found that disabled registrants with the program are only slightly disadvantaged in terms of wait times to find a family physician, and success rates are ultimately comparable; however, agency staff report that there are a number of significant challenges associated with placing disabled patients. PMID:25927477

Two-color immunostaining of liver fine needle aspiration biopsies with CD34 and carcinoembryonic antigen. Potential utilization in the diagnosis of primary hepatocellular carcinoma vs. metastatic tumor.

PubMed

Yoder, Michael; Zimmerman, Robert L; Bibbo, Marluce

2004-04-01

To examine immunohistochemical staining of cell block material with antibodies against vascular marker CD34 and polyclonal carcinoembryonic antigen (pCEA) for their clinical utility as part of a 2-color staining protocol in fine needle aspiration (FNA) biopsy of liver masses to distinguish metastases from primary hepatocellular carcinoma (HCC). The authors obtained cell block material from 96 liver FNAs and performed simultaneous (i.e., "dual-color") immunohistochemical staining utilizing antibodies against vascular marker CD34 and pCEA. Cases were blinded and evaluated by the authors for staining pattern and intensity. A consensus was obtained, the results were unblinded, and the diagnoses were correlated. After staining, 89 cases had sufficient tissue for evaluation. Of the 19 HCC cases, 16 (84%) showed peripheral staining with CD34, and 13 (68%) showed a canalicular or mixed canalicular-cytoplasmic staining pattern for pCEA. Thirteen cases (68%) showed staining for both antigens. All HCC exhibited immunostaining for at least 1 antibody in an appropriate staining pattern. Of the 67 cases of metastatic malignancy, 5 (7%) showed a predominantly transgressing pattern of CD34 staining, 43 (64%) showed a predominantly cytoplasmic or mixed cytoplasmic-canalicular pattern of pCEA staining, and 2 cases (3%) showed staining for both antigens in a transgressing CD34 pattern and cytoplasmic pCEA pattern. None of the 3 normal liver tissue blocks showed staining with either antigen. Two-color immunohistochemical staining of liver cell block material obtained by FNA with antibodies to CD34 and pCEA can be helpful in differentiating metastatic tumors vs. primary HCC.

Transport and Metabolism of Radiolabeled Choline in Hepatocellular Carcinoma

PubMed Central

Kuang, Yu; Salem, Nicolas; Corn, David J.; Erowku, Bernadette; Tian, Haibin; Wang, Fangjing; Lee, Zhenghong

2010-01-01

Objectives Altered choline (Cho) metabolism in cancerous cells can be used as a basis for molecular imaging with PET using radiolabeled Cho. In this study, the metabolism of tracer Cho was investigated in a woodchuck hepatocellular carcinoma (HCC) cell line (WCH17) and in freshly-derived rat hepatocytes. The transporter responsible for [11C]-Cho uptake in HCC was also characterized in WCH17 cells. The study helped to define the specific mechanisms responsible for radio-Cho uptake seen on the PET images of primary liver cancer such as HCC. Methods Cells were pulsed with [14C]-Cho for 5 min and chased for varying durations in cold media to simulate the rapid circulation and clearance of [11C]-Cho. Radioactive metabolites were extracted and analyzed by radio-HPLC and radio-TLC. The Cho transporter (ChoT) was characterized in WCH17 cells. Results WCH17 cells showed higher 14C uptake than rat primary hepatocytes. [14C]-Phosphocholine (PC) was the major metabolite in WCH17. In contrast, the intracellular Cho in primary hepatocytes was found to be oxidized to betaine (partially released into media) and to a less degree, phosphorylated to PC. [14C]-Cho uptake by WCH17 cells was found to have both facilitative transport and non-facilitative diffusion components. The facilitative transport was characterized by Na+ dependence and low affinity (Km = 28.59 ± 6.75 μM) with partial energy dependence. In contrast, ChoT in primary hepatocytes is Na+ independent and low affinity. Conclusions Our data suggest that transport and phosphorylation of Cho are responsible for the tracer accumulation during [11C]-Cho PET imaging of HCC. WCH17 cells incorporate [14C]-Cho preferentially into PC. Conversion of [14C]-PC into phosphatidylcholine occurred slowly in vitro. Basal oxidation and phosphorylation activities in surrounding hepatic tissue contribute to the background seen in [11C]-Cho PET images. PMID:20698576

INFLUENCE OF HEPATOCELLULAR CARCINOMA ETIOLOGY IN THE SURVIVAL AFTER RESECTION.

PubMed

Lopes, Felipe de Lucena Moreira; Coelho, Fabricio Ferreira; Kruger, Jaime Arthur Pirolla; Fonseca, Gilton Marques; Araujo, Raphael Leonardo Cunha de; Jeismann, Vagner Birk; Herman, Paulo

2016-01-01

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and its incidence is increasing around the world in the last decades, making it the third cause of death by cancer in the world. Hepatic resection is one of the most effective treatments for HCC with five-year survival rates from 50-70%, especially for patients with a single nodule and preserved liver function. Some studies have shown a worse prognosis for HCC patients whose etiology is viral. That brings us to the question about the existence of a difference between the various causes of HCC and its prognosis. To compare the prognosis (overall and disease-free survival at five years) of patients undergoing hepatectomy for the treatment of HCC with respect to various causes of liver disease. Was performed a review of medical records of patients undergoing hepatectomy between 2000 and 2014 for the treatment of HCC. They were divided into groups according to the cause of liver disease, followed by overall and disease-free survival analysis for comparison. There was no statistically significant difference in the outcomes of the groups of patients divided according to the etiology of HCC. Overall and disease-free survival at five years of the patients in this sample were 49.9% and 40.7%, respectively. From the data of this sample, was verified that there was no prognostic differences among the groups of HCC patients of the various etiologies. O carcinoma hepatocelular (CHC) é o mais frequente tipo de câncer primário do fígado e a sua incidência vem aumentando nas últimas décadas, tornando-o hoje a terceira causa de morte por câncer no mundo. A ressecção hepática é um dos tratamentos mais eficazes para ele com taxas de sobrevida em cinco anos de 50-70%, especialmente para pacientes com nódulo único e função hepática preservada. Alguns estudos mostraram pior prognóstico para os pacientes com CHC cuja causa é a infecção por vírus B ou C. Isso leva à questão sobre a existência de possível diferença entre as diversas causas e o prognóstico. Comparar o prognóstico (sobrevida global e livre de doença em cinco anos) de pacientes submetidos à hepatectomia para o tratamento do CHC com relação às diversas causas da hepatopatia. Foi realizado levantamento de prontuários dos pacientes submetidos à hepatectomia entre 2000 e 2014 para tratamento de CHC. Eles foram divididos em grupos de acordo com a causa da hepatopatia, sendo feita análise de sobrevida para comparação. Não houve diferença estatisticamente significante de prognóstico entre os grupos de pacientes divididos conforme a causa do CHC. A sobrevida global e livre de doença em cinco anos foi de 49.9% e 40.7%, respectivamente. Pôde-se constatar que não houve diferença em relação ao prognóstico entre os grupos de pacientes das diversas causas de CHC.

PKCα promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Jiajun; Shao, Miaomiao; Liu, Min

2015-08-07

Hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related death worldwide, and elevated rates of reactive oxygen species (ROS) have long been considered as a hallmark of almost all types of cancer including HCC. Protein kinase C alpha (PKCα), a serine/threonine kinase among conventional PKC family, is recognized as a major player in signal transduction and tumor progression. Overexpression of PKCα is commonly observed in human HCC and associated with its poor prognosis. However, how PKCα is involved in hepatocellular carcinogenesis remains not fully understood. In this study, we found that among the members of conventional PKC family, PKCα,more » but not PKCβI or βII, promoted ROS production in HCC cells. PKCα stimulated generation of ROS by up-regulating DUOX2 at post-transcriptional level. Depletion of DUOX2 abrogated PKCα-induced activation of AKT/MAPK pathways as well as cell proliferation, migration and invasion in HCC cells. Moreover, the expression of DUOX2 and PKCα was well positively correlated in both HCC cell lines and patient samples. Collectively, our findings demonstrate that PKCα plays a critical role in HCC development by inducing DUOX2 expression and ROS generation, and propose a strategy to target PKCα/DUOX2 as a potential adjuvant therapy for HCC treatment. - Highlights: • PKCα promotes the generation of ROS in hepatocellular carcinoma. • PKCα induces ROS production by up-regulating DUOX2 at post-transcriptional level. • DUOX2 is required for PKCα-induced AKT/MAPK activation and tumor progression in HCC. • The expression of PKCα is positively correlated with DUOX2 in HCC.« less

Feasibility of α-fetoprotein as a diagnostic tool for hepatocellular carcinoma in Korea

PubMed Central

Ahn, Dae Geon; Kim, Hyung Joon; Kang, Hyun; Lee, Hyun Woong; Bae, Si Hyun; Lee, Joon Hyoek; Paik, Yong Han; Lee, June Sung

2016-01-01

Background/Aims: The aim of this study was to evaluate the feasibility of α-fetoprotein (AFP) as a diagnostic tool for hepatocellular carcinoma (HCC) in Korean patients. Methods: We retrospectively reviewed the medical records of HCC and cirrhosis patients at three hospitals. For each HCC patient, a cirrhosis patient matched for age, sex, etiology, and Child-Pugh classification was selected by simple random sampling. The performance of AFP in the diagnosis of HCC was determined using receiver operating characteristic curve analysis. Results: A total of 732 patients with HCC or cirrhosis were selected for each case and the control groups. The mean age was 54 years, and 72.4% of patients were male. The mean serum AFP levels in the HCC group and cirrhosis group were 3,315.6 and 117.2 ng/mL, respectively (p < 0.001). The area under the receiver operating characteristic curve for all HCC patients was 0.757. The sensitivity, specificity, and positive predictive value of AFP was 50.55%, 87.70%, and 80.43%, respectively, at a cut-off of 20 ng/mL; 37.70%, 95.90%, and 90.20%, respectively, at a cut-off of 100 ng/mL, and 30.05%, 97.27%, and 91.67%, respectively, at a cut-off of 200 ng/mL. A cut-off of 100 ng/mL was more sensitive than one of 200 ng/mL with equivalent specificity and positive predictive value. Conclusions: The cut-off AFP value for early-stage HCC was 17.4 ng/mL. Our study cautiously suggests that AFP has a role in the diagnosis of HCC, and that the appropriate value of AFP for the diagnosis of HCC may be 100 ng/mL rather than 200 ng/mL. PMID:26767857

Feasibility of α-fetoprotein as a diagnostic tool for hepatocellular carcinoma in Korea.

PubMed

Ahn, Dae Geon; Kim, Hyung Joon; Kang, Hyun; Lee, Hyun Woong; Bae, Si Hyun; Lee, Joon Hyoek; Paik, Yong Han; Lee, June Sung

2016-01-01

The aim of this study was to evaluate the feasibility of α-fetoprotein (AFP) as a diagnostic tool for hepatocellular carcinoma (HCC) in Korean patients. We retrospectively reviewed the medical records of HCC and cirrhosis patients at three hospitals. For each HCC patient, a cirrhosis patient matched for age, sex, etiology, and Child-Pugh classification was selected by simple random sampling. The performance of AFP in the diagnosis of HCC was determined using receiver operating characteristic curve analysis. A total of 732 patients with HCC or cirrhosis were selected for each case and the control groups. The mean age was 54 years, and 72.4% of patients were male. The mean serum AFP levels in the HCC group and cirrhosis group were 3,315.6 and 117.2 ng/mL, respectively (p < 0.001). The area under the receiver operating characteristic curve for all HCC patients was 0.757. The sensitivity, specificity, and positive predictive value of AFP was 50.55%, 87.70%, and 80.43%, respectively, at a cut-off of 20 ng/mL; 37.70%, 95.90%, and 90.20%, respectively, at a cut-off of 100 ng/mL, and 30.05%, 97.27%, and 91.67%, respectively, at a cut-off of 200 ng/mL. A cut-off of 100 ng/mL was more sensitive than one of 200 ng/mL with equivalent specificity and positive predictive value. The cut-off AFP value for early-stage HCC was 17.4 ng/mL. Our study cautiously suggests that AFP has a role in the diagnosis of HCC, and that the appropriate value of AFP for the diagnosis of HCC may be 100 ng/mL rather than 200 ng/mL.

GABA stimulates human hepatocellular carcinoma growth through overexpressed GABAA receptor theta subunit

PubMed Central

Li, Yue-Hui; Liu, Yan; Li, Yan-Dong; Liu, Yan-Hong; Li, Feng; Ju, Qiang; Xie, Ping-Li; Li, Guan-Cheng

2012-01-01

AIM: To investigate the function of gamma-aminobutyric acid (GABA) and gamma-aminobutyric acid A receptor θ subunit (GABRQ) in hepatocellular carcinoma (HCC). METHODS: Semiquantitative polymerase chain reaction was used for detecting the expression of GABRQ receptor among HCC cell line HepG2, normal liver cell line L-02, non-malignant Chang’s liver cells, 8 samples of HCC tissues and paired non-cancerous tissues. HepG2 cells were treated with GABA at serial concentrations (0, 1, 10, 20, 40 and 60 μmol/L), and their proliferating abilities were analyzed with the methyl thiazolyl tetrazolium assay, cell cycle analysis and tumor implanted in nude mice. Small interfering RNA was used for knocking down the endogenous GABRQ in HepG2. Proliferating abilities of these cells treated with or without GABA were analyzed. RESULTS: We identified the overexpression of GABRQ in HCC cell lines and half of the tested HCC tissues. Knockdown of endogenous GABRQ expression in HepG2 attenuated HCC cell growth, suggesting its role in HCC cell viability. We studied the effect of GABA in the proliferation of GABRQ-positive cell lines in vitro and in vivo, and found that GABA increased HCC growth in a dose-dependent manner. Notably, the addition of GABA into the cell culture medium promoted the proliferation of GABRQ-expressing HepG2 cells, but not GABRQ-knockdown HepG2 cells, which means that GABA stimulates HepG2 cell growth through GABRQ. CONCLUSION: GABRQ play important roles in HCC development and progression and could be a promising molecular target for the development of new diagnostic and therapeutic strategies of HCC. PMID:22690081

Contrast-enhanced US with Perfluorobutane(Sonazoid) used as a surveillance test for Hepatocellular Carcinoma (HCC) in Cirrhosis (SCAN): an exploratory cross-sectional study for a diagnostic trial.

PubMed

Park, Ji Hoon; Park, Mi-Suk; Lee, So Jung; Jeong, Woo Kyoung; Lee, Jae Young; Park, Min Jung; Han, Kyunghwa; Nam, Chung Mo; Park, Seong Ho; Lee, Kyoung Ho

2017-04-18

Ultrasonography (US) is widely used as a standard surveillance tool for patients who are at a high risk of having hepatocellular carcinoma (HCC); however, conventional B-mode US appears to be insufficient in order to ensure the early detection of HCC. Perfluorobutane allows very stable Kupffer phase imaging for at least 60 min, which is tolerable for examinations of the entire liver. The purpose of our study is to evaluate the added value of contrast-enhanced US using perfluorobutane to that of conventional B-mode US as an HCC surveillance tool for patients with liver cirrhosis. SCAN (Sonazoid-US for surveillance of hepatoCellulArcarciNoma) is a prospective, multi-institutional, diagnostic trial using an intra-individual comparison design in a single arm of patients. This study was approved by our five institutional review board and informed consent was obtained from all participating. We obtained consent for publication of these data (contrast enhanced US images, CT or MRI images, laboratory findings, age, sex) from all participating patients. All patients will undergo conventional B-mode US immediately followed by contrast-enhanced US. The standardized case report forms will be completed by operating radiologists after B-mode US and contrast-enhanced US, respectively. If any lesion(s) is detected, the likelihood of HCC will be recorded. The primary endpoints are a detection rate of early-stage HCC and a false referral rate of HCC. Intra-individual comparison using Mcnemar's test will be performed between B-mode US and contrast-enhanced US. The study will include 523 patients under HCC surveillance in five medical institutions in Korea. SCAN is the first study to investigate the efficacy of contrast-enhanced US in surveillance using two reciprocal endpoints specialized for the evaluation of a surveillance test. SCAN will provide evidence regarding whether patients can truly benefit from contrast-enhanced US in terms of the detection of early stage HCC while avoiding additional unnecessary examinations. In addition to the study protocol, we elaborate on potentially debatable components of SCAN, including the design of an intra-individual comparison study, study endpoints, composite reference standards, and indefinite imaging criteria regarding the likelihood of HCC. The date of trial registration (ClincalTrials.gov: NCT02188901 ) in this study is July 3, 2014. The last patient enrolled in August 30, 2016 and follow up to see the primary end point is still ongoing. All authors have no other relationships/conditions/circumstances that present a potential conflict of interest of relationships. Our study protocol has undergone peer-review by the funding body (GE Healthcare). No other relationships/conditions/circumstances that present a potential conflict of interest. Also, we clearly stated in the 'competing interests' section of my manuscript.

A Gene Expression Signature Associated with Overall Survival in Patients with Hepatocellular Carcinoma Suggests a New Treatment Strategy.

PubMed

Gillet, Jean-Pierre; Andersen, Jesper B; Madigan, James P; Varma, Sudhir; Bagni, Rachel K; Powell, Katie; Burgan, William E; Wu, Chung-Pu; Calcagno, Anna Maria; Ambudkar, Suresh V; Thorgeirsson, Snorri S; Gottesman, Michael M

2016-02-01

Despite improvements in the management of liver cancer, the survival rate for patients with hepatocellular carcinoma (HCC) remains dismal. The survival benefit of systemic chemotherapy for the treatment of liver cancer is only marginal. Although the reasons for treatment failure are multifactorial, intrinsic resistance to chemotherapy plays a primary role. Here, we analyzed the expression of 377 multidrug resistance (MDR)-associated genes in two independent cohorts of patients with advanced HCC, with the aim of finding ways to improve survival in this poor-prognosis cancer. Taqman-based quantitative polymerase chain reaction revealed a 45-gene signature that predicts overall survival (OS) in patients with HCC. Using the Connectivity Map Tool, we were able to identify drugs that converted the gene expression profiles of HCC cell lines from ones matching patients with poor OS to profiles associated with good OS. We found three compounds that convert the gene expression profiles of three HCC cell lines to gene expression profiles associated with good OS. These compounds increase histone acetylation, which correlates with the synergistic sensitization of those MDR tumor cells to conventional chemotherapeutic agents, including cisplatin, sorafenib, and 5-fluorouracil. Our results indicate that it is possible to modulate gene expression profiles in HCC cell lines to those associated with better outcome. This approach also increases sensitization of HCC cells toward conventional chemotherapeutic agents. This work suggests new treatment strategies for a disease for which few therapeutic options exist. U.S. Government work not protected by U.S. copyright.

Survival and prognostic factors for hepatocellular carcinoma: an Egyptian multidisciplinary clinic experience.

PubMed

Abdelaziz, Ashraf Omar; Elbaz, Tamer Mahmoud; Shousha, Hend Ibrahim; Ibrahim, Mostafa Mohamed; Rahman El-Shazli, Mostafa Abdel; Abdelmaksoud, Ahmed Hosni; Aziz, Omar Abdel; Zaki, Hisham Atef; Elattar, Inas Anwar; Nabeel, Mohamed Mahmoud

2014-01-01

Hepatocellular carcinoma (HCC) is a dismal tumor with a high incidence, prevalence and poor prognosis and survival. Management of HCC necessitates multidisciplinary clinics due to the wide heterogeneity in its presentation, different therapeutic options, variable biologic behavior and background presence of chronic liver disease. We studied the different prognostic factors that affected survival of our patients to improve future HCC management and patient survival. This study is performed in a specialized multidisciplinary clinic for HCC in Kasr El Eini Hospital, Cairo University, Egypt. We retrospectively analyzed the different patient and tumor characteristics and the primary mode of management applied to our patients. Further analysis was performed using univariate and multivariate statistics. During the period February 2009 till February 2013, 290 HCC patients presented to our multidisciplinary clinic. They were predominantly males and the mean age was 56.5 ± 7.7 years. All cases developed HCC on top of cirrhosis that was mainly due to HCV (71%). Most of our patients were Child-Pugh A (50%) or B (36.9%) and commonly presented with small single lesions. Transarterial chemoembolization was the most common line of treatment used (32.4%). The overall survival was 79.9% at 6 months, 54.5% at 1 year and 22.4% at 2 years. Serum bilirubin, site of the tumor and type of treatment were the significant independent prognostic factors for survival. Our main prognostic variables are the bilirubin level, the bilobar hepatic affection and the application of specific treatment (either curative or palliative). Multidisciplinary clinics enhance better HCC management.

Sorafenib prescribed by gastroenterologists and hepatologists for hepatocellular carcinoma

PubMed Central

Kaplan, David E.; Mehta, Rajni; D’Addeo, Kathryn; Valderrama, Adriana; Taddei, Tamar H.

2018-01-01

Abstract Sorafenib is the only Food and Drug Administration (FDA)-approved first-line therapy shown to have survival benefit for patients with advanced hepatocellular carcinoma (HCC). Patients with advanced HCC are often but not exclusively transferred from non-oncologists to oncologists to initiate systemic therapy. The objective of this study was to assess whether sorafenib prescribing by non-oncologists has any impact on utilization, adverse effects, cost or outcome. This was a retrospective cohort study utilizing data from patients prescribed sorafenib for HCC within Veterans Health Administration hospitals with 100% chart abstraction to confirm HCC diagnosis, identify prescribing provider specialty (oncology versus gastroenterology/hepatology), and obtain data required for cancer staging by the Barcelona Clinic Liver Cancer (BCLC) system. The primary outcome was overall survival from the time of sorafenib prescription. A total of 4903 patients who prescribed sorafenib for HCC were identified, for whom 340 patients (6.9%) were prescribed drug by a non-oncologist (Onc). BCLC Stage, age, Child–Turcotte–Pugh score, and comorbidity indices were similar between patients prescribed sorafenib by oncologists and non-oncologists. Oncologists more often discontinued sorafenib due to progression, whereas non-oncologists were more likely to continue sorafenib until death resulting in greater pill utilization and cost. Overall survival in both unadjusted and multivariable models showed no significant impact of prescriber type on survival (222 vs 217 days, P = .96), confirmed with propensity-matched subcohorts. Similar survival outcomes were observed for patients with HCC prescribed sorafenib by non-oncologists and oncologists, suggesting that non-oncologists with expertise in the management of HCC can safely and effectively administer sorafenib. PMID:29369224

GPX4 and GPX7 Over-Expression in Human Hepatocellular Carcinoma Tissues

PubMed Central

Guerriero, E.; Capone, F.; Accardo, M.; Sorice, A.; Costantini, M.; Colonna, G.; Castello, G.

2015-01-01

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is still one of the most fatal cancers. Hence, it needs to identify always new putative markers to improve its diagnosis and prognosis. The selenium is an essential trace mineral implicated as a key factor in the early stage of cancer and exerts its biological function through the selenoproteins. In the last years our group has been studying the involvement of some selenoproteins in HCC. However, no many data are reported in literature about the correlation between HCC and the glutathione peroxidases (GPXs), both selenium and non selenium-containing GPXs. In this paper we have evaluated the GPX4 and GPX7 expression in some paraffin-embedded tissues from liver biopsy of patients with hepatitis C virus (HCV)-related cirrhosis and HCC by immunohistochemistry and RT-qPCR analysis. Our results evidenced that i) GPX4 and GPX7 had a statistically significant over-expression in HCC tissues compared to cirrhotic counterparts used as non tumor tissues, and ii) their expression was higher in grade III HCC tissues with respect to grade I-II samples. Therefore, we propose to use GPX4 and GPX7 as possible markers for improving HCC diagnosis/prognosis. PMID:26708178

The Silencing of RECK Gene is Associated with Promoter Hypermethylation and Poor Survival in Hepatocellular Carcinoma

PubMed Central

Zhang, Changsong; Ling, Yang; Zhang, Chenghui; Xu, Yun; Gao, Lu; Li, Rong; Zhu, Jing; Fan, Lieying; Wei, Lixin

2012-01-01

Background: To evaluate the promoter methylation status of RECK gene and mRNA expression in patients with hepatocellular carcinoma (HCC). Methods: We analyzed RECK methylation by MSP, and RECK mRNA by real-time PCR in 74 HCC. The liver cell lines (7721, Chang and Hep-G2) were treated with 5-Aza-CdR and TSA. Results: RECK mRNA were lower in HCC tissues (Mean -∆Ct = -3.29) than that in Non-Hcc tissues (Mean -∆Ct = -2.42). Expression of RECK was elevated in only 24 (32.43%) of the 74 HCC patients but decreased (-∆∆Ct<0) in 50 (67.57%) of the patients. RECK promoter was hypermethylated in 55.4% (41/74) of HCCs, and in only 17.6% (13/74) of Non-Hcc samples. RECK mRNA were lower in HCC patients with hypermethylation (∆MI>=0.5) (Mean -∆∆Ct = -1.75) than those with demethylation (∆MI<0.5) (Mean -∆∆Ct = 0.05), and there is a decreased tendency for RECK mRNA in HCC patients with promoter hypermethylation (p = 0.002). There was a significantly correlation found between RECK mRNA and poor survival after surgery. After treated by 5-Aza-CdR and TSA, we found that RECK mRNA induced different changes in 7721, Chang and Hep-G2 cells. And RECK demethylation also induced by epigenetic inhibitors. Conclusion: The results suggested that the hypermethylation may lead to promoter silencing of RECK mRNA and associated with poor survival in HCC. PMID:22419890

Thalidomide combined with transcatheter artierial chemoembolzation for primary hepatocellular carcinoma: a systematic review and meta-analysis

PubMed Central

Cao, De-Dong; Xu, Hui-Lin; Liu, Liang; Zheng, Yong-Fa; Gao, Si-Fa; Xu, Xi-Ming; Ge, Wei

2017-01-01

Objective Transcatheter arterial chemoembolization (TACE) and thalidomide have been used for treating primary hepatocellular carcinoma(HCC). This study aims to evaluate the clinical efficacy and safety of thalidomide and TACE in primary HCC. Methods Randomized controlled trials(RCTs) about efficacy and safety of thalidomide combined with TACE for primary HCC were identified from the Cochrane Library, Pubmed, Embase, CNKI, and Wan Fang until August, 2016. The retrieved trials were reviewed and the data were extracted by two reviewers, independently. Combined analyses of survival rates, overall response rate(ORR), disease control rate(DCR), changes of KPS, parameters of cellular immunity and vascular endothelial growth factor(VEGF), and adverse events were performed using RevMan 5.3 software. Results A total of 23 RCTs involving 1836 patients were included. The results showed that thalidomide plus TACE was significantly superior in increasing 6-month survival rate(OR=1.79, 95% CI:1.02-3.15, P=0.04), 1-year survival rate(OR=1.76, 95% CI:1.38-2.24, P<0.0001), 1.5-year survival rate(OR=4.72, 95% CI:2.64-8.43, P<0.001), 2-year survival rate(OR=1.78, 95% CI:1.37-2.30, P<0.001), ORR(OR=1.89, 95% CI:1.48-2.42, P<0.0001), DCR(OR=2.62, 95% CI:1.90-3.63, P<0.001), improvement in cellular immunity(MD=0.63, 95% CI:0.45-0.80, P<0.0001), and reduction of VEGF(MD=-119.71, 95% CI:-135.75—103.68, P<0.0001), when compared with TACE group. The incidences of gastrointestinal reactions, myelosuppression, and liver dysfunction were similar between combination group and TACE group(P>0.05). However, compared to TACE, the combination of thalidomide and TACE had a higher incidence of drug rash(OR=6.35, 95% CI:2.75-14.68, P<0.0001). Conclusion Our findings suggest that thalidomide combined with TACE shows better clinical efficacy and tolerable adverse events in patients with primary HCC when compared with TACE alone. PMID:28402958

Preoperative galactose elimination capacity predicts complications and survival after hepatic resection.

PubMed

Redaelli, Claudio A; Dufour, Jean-François; Wagner, Markus; Schilling, Martin; Hüsler, Jürg; Krähenbühl, Lukas; Büchler, Markus W; Reichen, Jürg

2002-01-01

To analyze a single center's 6-year experience with 258 consecutive patients undergoing major hepatic resection for primary or secondary malignancy of the liver, and to examine the predictive value of preoperative liver function assessment. Despite the substantial improvements in diagnostic and surgical techniques that have made liver surgery a safer procedure, careful patient selection remains mandatory to achieve good results in patients with hepatic tumors. In this prospective study, 258 patients undergoing hepatic resection were enrolled: 111 for metastases, 78 for hepatocellular carcinoma (HCC), 21 for cholangiocellular carcinoma, and 48 for other primary hepatic tumors. One hundred fifty-eight patients underwent segment-oriented liver resection, including hemihepatectomies, and 100 had subsegmental resections. Thirty-two clinical and biochemical parameters were analyzed, including liver function assessment by the galactose elimination capacity (GEC) test, a measure of hepatic functional reserve, to predict postoperative (60-day) rates of death and complications and long-term survival. All variables were determined within 5 days before surgery. Data were subjected to univariate and multivariate analysis for two patient subgroups (HCC and non-HCC). The cutoffs for GEC in both groups were predefined. Long-term survival (>60 days) was subjected to Kaplan-Meier analysis and the Cox proportional hazard model. In the entire group of 258 patients, a GEC less than 6 mg/min/kg was the only preoperative biochemical parameter that predicted postoperative complications and death by univariate and stepwise regression analysis. A GEC of more than 6 mg/min/kg was also significantly associated with longer survival. This predictive value could also be shown in the subgroup of 180 patients with tumors other than HCC. In the subgroup of 78 patients with HCC, a GEC less than 4 mg/min/kg predicted postoperative complications and death by univariate and stepwise regression analysis. Further, a GEC of more than 4 mg/min/kg was also associated with longer survival. This prospective study establishes the preoperative determination of the hepatic reserve by GEC as a strong independent and valuable predictor for short- and long-term outcome in patients with primary and secondary hepatic tumors undergoing resection.

Preoperative Galactose Elimination Capacity Predicts Complications and Survival After Hepatic Resection

PubMed Central

Redaelli, Claudio A.; Dufour, Jean-François; Wagner, Markus; Schilling, Martin; Hüsler, Jürg; Krähenbühl, Lukas; Büchler, Markus W.; Reichen, Jürg

2002-01-01

Objective To analyze a single center’s 6-year experience with 258 consecutive patients undergoing major hepatic resection for primary or secondary malignancy of the liver, and to examine the predictive value of preoperative liver function assessment. Summary Background Data Despite the substantial improvements in diagnostic and surgical techniques that have made liver surgery a safer procedure, careful patient selection remains mandatory to achieve good results in patients with hepatic tumors. Methods In this prospective study, 258 patients undergoing hepatic resection were enrolled: 111 for metastases, 78 for hepatocellular carcinoma (HCC), 21 for cholangiocellular carcinoma, and 48 for other primary hepatic tumors. One hundred fifty-eight patients underwent segment-oriented liver resection, including hemihepatectomies, and 100 had subsegmental resections. Thirty-two clinical and biochemical parameters were analyzed, including liver function assessment by the galactose elimination capacity (GEC) test, a measure of hepatic functional reserve, to predict postoperative (60-day) rates of death and complications and long-term survival. All variables were determined within 5 days before surgery. Data were subjected to univariate and multivariate analysis for two patient subgroups (HCC and non-HCC). The cutoffs for GEC in both groups were predefined. Long-term survival (>60 days) was subjected to Kaplan-Meier analysis and the Cox proportional hazard model. Results In the entire group of 258 patients, a GEC less than 6 mg/min/kg was the only preoperative biochemical parameter that predicted postoperative complications and death by univariate and stepwise regression analysis. A GEC of more than 6 mg/min/kg was also significantly associated with longer survival. This predictive value could also be shown in the subgroup of 180 patients with tumors other than HCC. In the subgroup of 78 patients with HCC, a GEC less than 4 mg/min/kg predicted postoperative complications and death by univariate and stepwise regression analysis. Further, a GEC of more than 4 mg/min/kg was also associated with longer survival. Conclusions This prospective study establishes the preoperative determination of the hepatic reserve by GEC as a strong independent and valuable predictor for short- and long-term outcome in patients with primary and secondary hepatic tumors undergoing resection. PMID:11753045

[Value of R2(*) in evaluating the biological behavior of primary hepatocellular carcinoma].

PubMed

Tian, S F; Liu, A L; Liu, J H; Li, Y; Liu, X D; Huang, K; Song, Q W; Xu, M Z; Guo, W Y

2016-04-19

To investigate the correlation between R2(*) value of enhanced T2 star-weighted angiography (ESWAN) sequence and primary hepatocellular carcinoma infiltration and tumor thrombus, and investigate the biological behavior of HCC. A total of 221 cases of patients' imaging data with MRI examination(including ESWAN sequence) diagnosed as primary HCC were retrospectively analyzed.All the patients were collected from January 2014 to September 2015 in the First Affiliated Hospital of Dalian Medical University.The differences of R2(*) values in different MR types of HCC were analyzed.All patients were divided into infiltration group and non-infiltration group, tumor thrombus group and non-tumor thrombus group, the R2(*) values of the paired groups were compared.The diagnostic efficiency of R2(*) in HCC infiltration and tumor thrombus were evaluated by ROC curve, and to find out the threshold values. The MR types of 221 patients included 90 cases of nodular type, 62 cases of massive type, 69 cases of diffuse type.70 patients had tumor thrombus.The R2(*) values of different MR types were (21.82±8.52), (24.17±8.84)and (34.45±11.73) Hz, respectively.There was no statistically significant difference between the nodular and the massive types (P=0.144), while the difference between the nodular and diffuse type, the massive and diffuse types were statistically significant(P=0.000). The R2(*) values of infiltration group and non-infiltration group were (34.45±11.73) and (22.78±8.70) Hz , the R2(*) values of tumor thrombus group and non-tumor thrombus group were (31.20±12.17) and (24.21±9.90) Hz, the difference also had statistically significant(t=7.397 and 4.534, P=0.000 and 0.000). The AUC of R2(*) values for infiltration and tumor thrombus were 0.804, 0.681. R2(*) ≥24.68 Hz was the threshold value to diagnose the infiltration and tumor thrombus. R2(*) value can be used as a MR non-enhancement quantitative index to evaluate the biological behavior of HCC.

Detection of doublecortin domain-containing 2 (DCDC2), a new candidate tumor suppressor gene of hepatocellular carcinoma, by triple combination array analysis

PubMed Central

2013-01-01

Background To detect genes correlated with hepatocellular carcinoma (HCC), we developed a triple combination array consisting of methylation array, gene expression array and single nucleotide polymorphism (SNP) array analysis. Methods A surgical specimen obtained from a 68-year-old female HCC patient was analyzed by triple combination array, which identified doublecortin domain-containing 2 (DCDC2) as a candidate tumor suppressor gene of HCC. Subsequently, samples from 48 HCC patients were evaluated for their DCDC2 methylation and expression status using methylation specific PCR (MSP) and semi-quantitative reverse transcriptase (RT) PCR, respectively. Then, we investigated the relationship between clinicopathological factors and methylation status of DCDC2. Results DCDC2 was revealed to be hypermethylated (methylation value 0.846, range 0–1.0) in cancer tissue, compared with adjacent normal tissue (0.212) by methylation array in the 68-year-old female patient. Expression array showed decreased expression of DCDC2 in cancerous tissue. SNP array showed that the copy number of chromosome 6p22.1, in which DCDC2 resides, was normal. MSP revealed hypermethylation of the promoter region of DCDC2 in 41 of the tumor samples. DCDC2 expression was significantly decreased in the cases with methylation (P = 0.048). Furthermore, the methylated cases revealed worse prognosis for overall survival than unmethylated cases (P = 0.048). Conclusions The present study indicates that triple combination array is an effective method to detect novel genes related to HCC. We propose that DCDC2 is a tumor suppressor gene of HCC. PMID:24034596

Caregivers' hair cortisol: a possible biomarker of chronic stress is associated with obesity measures among children with disabilities.

PubMed

Chen, Xiaoli; Gelaye, Bizu; Velez, Juan Carlos; Barbosa, Clarita; Pepper, Micah; Andrade, Asterio; Gao, Wei; Kirschbaum, Clemens; Williams, Michelle A

2015-02-15

The stress of caring for a loved one with chronic illness has been associated with childhood obesity. Hair cortisol has been proposed as a novel biomarker of chronic psychological stress. This study aimed to evaluate the associations between caregivers' chronic stress evaluated by hair cortisol concentrations (HCC) and obesity measures among children with disabilities such as autism. Eighty-five dyads of children with disabilities and their primary caregivers participated in the study between April and July 2013 in the Patagonia Region, Chile. Trained research staff conducted anthropometric measurements of children and caregivers. Cortisol concentrations, extracted from hair samples with methanol, were quantified using liquid chromatography tandem mass spectrometry. Pearson's correlation coefficients and linear regression models were used to examine the associations between caregiver HCC (log-transformed) and child obesity measures with adjustment for covariates. Caregiver HCC were positively and significantly correlated with child weight (child age- and sex-adjusted r =0.23, P = 0.036), body mass index (BMI) (r = 0.23, P = 0.035), circumferences of neck (r = 0.30, P = 0.006), waist (r = 0.27, P = 0.014), and hip (r = 0.22, P = 0.044). After adjustment for children's age and sex, caregiver HCC were significantly related to child weight (kg) (beta = 4.47, standard error (SE) = 2.09), BMI (kg/m(2)) (beta = 1.52, SE = 0.71), neck circumference (cm) (beta = 1.20, SE = 0.43), waist circumference (cm) (beta = 3.75, SE = 1.50), and hip circumference (cm) (beta = 3.02, SE = 1.48). Caregiver HCC were also positively but not statistically significantly associated with child waist-to-hip ratio (beta = 0.01, SE = 0.01; P = 0.191) or body fat percentage (%) (beta = 2.11, SE = 1.28; P = 0.104). Further adjustment for other covariates including child disability diagnosis and caregiver age, sex, education, current smoking, perceived stress, and caregiver BMI did not change the results substantially. Chronic stress of caregivers, evaluated by increased cortisol concentrations in hair, was positively associated with obesity measures among children with disabilities.

Clinical values of AFP, GPC3 mRNA in peripheral blood for prediction of hepatocellular carcinoma recurrence following OLT: AFP, GPC3 mRNA for prediction of HCC.

PubMed

Wang, Yuliang; Shen, Zhongyang; Zhu, Zhijun; Han, Ruifa; Huai, Mingsheng

2011-03-01

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Annually, about 200,000 patients died of HCC in China. Liver transplantation (LT) holds great theoretical appeal in treating HCC. However, the high recurrence rate after transplantation is the most important limiting factor for long-term survival. To assess the value of alpha-fetoprotein (AFP) messenger RNA (mRNA), Glypican-3 (GPC3) mRNA-expressing cells in the peripheral blood (PB) for prediction of HCC recurrence following orthotopic liver transplantation (OLT). 29 patients with HCC who underwent OLT with a minimum clinical follow-up of 12 months were included in this retrospective study. We detected AFP mRNA, GPC3 mRNA-expressing cells in the PB by TaqMan real-time reverse transcriptase-polymerase chain reaction (RT-PCR), pre-, intra- and post-operatively. The early recurrence of patients was evaluated. 8 (28%), 15 (52%), and 9 (31%) patients had AFP mRNA detected pre-, intra-, and post-operatively, respectively. With 12 months of follow-up, HCC recurred in 7 (24%) patients. Univariate analysis revealed that positive pre- and post-operative AFP mRNA, TNM stage as well as vascular invasion were significant predictors for the HCC recurrence. Multivariate analysis revealed that being positive for AFP mRNA pre-operatively remained a significant risk factor for HCC recurrence after OLT. GPC3 mRNA was expressed in all PB samples. There was no significant difference in the expression levels of GPC3 mRNA between the HCC and control groups. There were no significant differences in GPC3 mRNA expression values between those patients with and without tumor recurrence. The pre-operative detection of circulating AFP mRNA-expressing cells could be a useful predictor for HCC recurrence following OLT. GPC3 mRNA-expressing cells in PB seem to have no diagnostic value.

Quasispecies variant of pre-S/S gene in HBV-related hepatocellular carcinoma with HBs antigen positive and occult infection.

PubMed

Hatazawa, Yuri; Yano, Yoshihiko; Okada, Rina; Tanahashi, Toshihito; Hayashi, Hiroki; Hirano, Hirotaka; Minami, Akihiro; Kawano, Yuki; Tanaka, Motofumi; Fukumoto, Takumi; Murakami, Yoshiki; Yoshida, Masaru; Hayashi, Yoshitake

2018-01-01

Hepatocellular carcinoma (HCC) can develop in patients who are negative for the hepatitis B surface antigen (HBsAg) in serum but positive for hepatitis B virus (HBV) DNA in the liver, referred to as occult HBV infection (OBI). Previous reports showed that HBV variants in OBI-related HCC are different from those in HBsAg-positive HCC. In the present study, HBV quasispecies based on the pre-S/S gene in OBI-related HCC patients were examined by high throughput sequencing and compared with those in HBsAg-positive HCC. Nineteen tissue samples (9 OBI-related and 10 HBsAg-positive non-cancerous tissues) were collected at the time of surgery at Kobe University Hospital. The quasispecies with more than 1% variation in the pre-S/S region were isolated and analysed by ultra-deep sequencing. There were no significant differences in the major HBV populations, which exhibit more than 20% variation within the entire pre-S/S region, between OBI-related HCC and HBsAg-positive HCC. However, the prevalences of major populations with pre-S2 region mutations and of minor populations with polymerized human serum albumin-binding domain mutations were significantly higher in OBI-related HCC than in HBsAg-positive HCC. Moreover, the major variant populations associated with the B-cell epitope, located within the pre-S1 region, and the a determinant domain, located in the S region, were detected frequently in HBsAg-positive HCC. The minor populations of variants harbouring the W4R, L30S, Q118R/Stop, N123D and S124F/P mutations in the pre-S region and the L21F/S and L42F/S mutations in the S region were detected more frequently in OBI-related HCC than in HBsAg-positive HCC. Ultra-deep sequencing revealed that the B-cell epitope domain in the pre-S1 region and alpha determinant domain in the S region were variable in HBsAg-positive HCC, although the quasispecies associated with the pre-S2 region were highly prevalent in OBI-related HCC. Ref: R000034382/UMIN000030113; Retrospectively registered 25 November 2017.

Reduced expression of ASS is closely related to clinicopathological features and post-resectional survival of hepatocellular carcinoma.

PubMed

Yang, Hua; Lin, Ming; Xiong, Fu Xia; Yang, Yu; Nie, Xiu; Zhou, Rou Li

2010-01-01

Argininosuccinate synthetase (ASS) has previously been proven to be reductively expressed in hepatocellular carcinoma (HCC) and various types of HCC cell lines. Arginine, the product of ASS, has been used as a target in HCC by recombinant human arginase or arginine deiminase, which is now in the phase II clinical trial stage. This study aimed to present the levels of ASS expression in HCCs and its correlation with clinicopathological features and prognosis of HCC patients. Immunohistochemical detection of ASS was performed on samples from 71 patients with HCC. Positive staining was found in 21 HCCs, with a score of 2, as well as in normal liver tissues. Reduced ASS staining was found in 70.4% (50/71) of HCC tissues, including 21 with a score of 0 and 29 with a score of 1. The staining score in cancer tissues was significantly associated with gender, background liver, histopathological differentiation, recurrence, TNM staging and portal vein invasion (P<0.05), but not with age, viral status, tumor size and serum α-fetoprotein level. Patients with a high ASS expression had significantly poorer overall and disease-free survival (P<0.001 and P<0.001, respectively). These data showed that ASS was reductively or negatively expressed in a large portion of HCC, and that ASS levels in HCCs correlated inversely with prognosis. In conclusion, a high expression of ASS may be a novel marker of poor prognosis of patients presenting with HCC.

Understanding adherence to therapeutic guidelines: a multilevel analysis of statin prescription in the Skaraborg Primary Care Database.

PubMed

Hjerpe, Per; Ohlsson, Henrik; Lindblad, Ulf; Boström, Kristina Bengtsson; Merlo, Juan

2011-04-01

In Skaraborg, Sweden, the economic responsibility for tax-financed prescription drug costs was transferred from the regional administrative level to the local level (health care centre; HCC) in 2003. The aim of this study was to investigate the impact of this decentralization of economic responsibility on adherence to guidelines for prescribing lipid-lowering drugs. Data from all 24 public HCCs in Skaraborg on prescriptions for lipid-lowering drugs during 2003 and 2005 were extracted from the Skaraborg Primary Care Database (SPCD). Multilevel regression analysis (MLRA) was used to disentangle the variances at different levels of data (patient, physician, HCC). The outcome variable on the patient level was the prescription of the recommended statin (yes/no). Sex and age of the patients and sex, age and occupational status of the physician were included as fixed effects. The variance was expressed as the median odds ratio (MOR). The prevalence of adherence to guidelines for the prescription of statins increased from 77% in 2003 to 84% in 2005. The MLRA showed that in 2003 the variance was equally distributed between the HCC and physician levels (MOR(HCC2003)=1.89 vs. MOR(PHYSICIAN2003)=1.88). The variance between physicians and between HCCs decreased considerably between 2003 and 2005. The inclusion of individual and physician characteristics did not explain any of the remaining variance. The decentralized budget appears to have increased adherence to guidelines and reduced inefficient variation in prescribing.

[False positive serum des-gamma-carboxy prothrombin after resection of hepatocellular carcinoma].

PubMed

Hiramatsu, Kumiko; Tanaka, Yasuhito; Takagi, Kazumi; Iida, Takayasu; Takasaka, Yoshimitsu; Mizokami, Masashi

2007-04-01

Measurements of serum concentrations of des-gamma-carboxy-prothrombin (PIVKA-II) are widely used for diagnosing hepatocellular carcinoma (HCC). Recently, when we evaluated the correlation of PIVKA-II between two commercially available PIVKA-II immunoassay kits (Lumipulse f vs. Picolumi) to introduce it in our hospital, false high values of PIVKA-II were observed in Lumipulse assay. Four(4%) of 100 serum samples showed false high values, and all of them were obtained from patients less than 2 month after curative resection of HCC. Examining additional 7 patients with HCC resection, serum samples from the 5 patients had the same trend. To elucidate the non-specific reaction by Lumipulse assay which utilized alkaline phosphatase (ALP) enzymatic reaction, inhibition assays by various absorbents such as inactive ALP and IgM antibodies were performed. Excess of inactive ALP reduced the high values of PIVKA-II. Note that anti-bleeding sheets (fibrinogen combined drug), which included bovine thrombin, were directly attached on liver of all patients with HCC resection in this study. As the sheets also contaminate ALP and probably produce IgM antibodies to ALP, the IgM may cross-react with anti-PIVKA-II antibodies directly. Taken together, it was suggested that produced antibodies against ALP derived from anti-bleeding sheets led false high values of PIVKA-II in the patients with HCC resection.

SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma.

PubMed

Tai, Wei-Tien; Hung, Man-Hsin; Chu, Pei-Yi; Chen, Yao-Li; Chen, Li-Ju; Tsai, Ming-Hsien; Chen, Min-Husan; Shiau, Chung-Wai; Boo, Yin-Pin; Chen, Kuen-Feng

2016-04-19

Pyruvate kinase M2 (PKM2) is known to promote tumourigenesis through dimer formation of p-PKM2Y105. Here, we investigated whether SH2-containing protein tyrosine phosphatase 1 (SHP-1) decreases p-PKM2Y105 expression and, thus, determines the sensitivity of sorafenib through inhibiting the nuclear-related function of PKM2. Immunoprecipitation and immunoblot confirmed the effect of SHP-1 on PKM2Y105 dephosphorylation. Lactate production was assayed in cells and tumor samples to determine whether sorafenib reversed the Warburg effect. Clinical hepatocellular carcinoma (HCC) tumor samples were assessed for PKM2 expression. SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated HCC cells. PKM2 was also found to determine the sensitivity of targeted drugs, such as sorafenib, brivanib, and sunitinib, by SHP-1 activation. Significant sphere-forming activity was found in HCC cells stably expressing PKM2. Clinical findings suggest that PKM2 acts as a predicting factor of early recurrence in patients with HCC, particularly those without known risk factors (63.6%). SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs. Targeting PKM2 by SHP-1 might provide new therapeutic insights for patients with HCC.

DNA Methylation Suppresses Expression of the Urea Cycle Enzyme Carbamoyl Phosphate Synthetase 1 (CPS1) in Human Hepatocellular Carcinoma

PubMed Central

Liu, Hongyan; Dong, Huijia; Robertson, Keith; Liu, Chen

2011-01-01

Carbamoyl phosphate synthetase 1 (CPS1) is a liver-specific, intramitochondrial, rate-limiting enzyme in the urea cycle. A previous study showed that CPS1 is the antigen for hepatocyte paraffin 1 antibody, a commonly used antibody in surgical pathology practice; and CPS1 expression appears to be down-regulated in liver cancer tissue and cell lines. The aim of this study is to understand how the CPS1 gene is regulated in liver carcinogenesis. In this report, we show that human hepatocellular carcinoma (HCC) cells do not express CPS1, whereas cultured human primary hepatocytes express abundant levels. In addition, CPS1 was silenced or down-regulated in liver tumor tissues compared with the matched noncancerous tissues. The expression of CPS1 in HCC cells was restored with a demethylation agent, 5-azacytidine. We show that two CpG dinucleotides, located near the transcription start site, and a CpG-rich region in the first intron were hypermethylated in HCC cells. The hypermethylation of the two CpG dinucleotides was also detected in HCC tumor tissues compared with noncancerous tissues. Further molecular analysis with mutagenesis indicated that the two CpG dinucleotides play a role in promoter activity of the CPS1 gene. In conclusion, our study demonstrates that DNA methylation is a key mechanism of silencing CPS1 expression in human HCC cells, and CPS1 gene hypermethylation of the two CpG dinucleotides is a potential biomarker for HCC. PMID:21281797

A laboratory marker, FIB-4 index, as a predictor for long-term outcomes of hepatocellular carcinoma patients after curative hepatic resection.

PubMed

Toyoda, Hidenori; Kumada, Takashi; Tada, Toshifumi; Kaneoka, Yuji; Maeda, Atsuyuki

2015-04-01

Liver fibrosis is associated with the prognosis of patients with hepatocellular carcinoma (HCC) after treatment. The laboratory marker for liver fibrosis, the FIB-4 index, is reportedly correlated with the degree of liver fibrosis. We evaluated the predictive value of FIB-4 index on the recurrence and survival of HCC patients who underwent curative hepatectomy. A total of 431 consecutive patients who underwent hepatectomy for primary, nonrecurrent HCC were analyzed. The FIB-4 index was calculated from the patient's age, serum alanine aminotransferase and aspartate aminotransferase levels, and platelet count at the time of HCC diagnosis. Postoperative recurrence and survival rates were compared according to tumor characteristics, tumor markers, Child-Pugh class, and the FIB-4 index. The pretreatment FIB-4 index was associated with recurrence and survival rates, independent of HCC progression or tumor marker levels in a multivariate analysis. Recurrence rates after hepatectomy were higher in patients with a FIB-4 index >3.25 versus ≤3.25 (5-year recurrence rates 69.6% vs 54.8%; P = .0049). Survival was also worse in patients with a FIB-4 index >3.25 than those with a FIB-4 index ≤3.25 (5-year survival rates 67.1% vs 72.2%; P = .0030). The FIB-4 index is a predictive marker for long-term outcomes in patients with HCC treated with curative hepatic resection. Copyright © 2015 Elsevier Inc. All rights reserved.

Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma

PubMed Central

Li, Min; Zhang, Chao; Liu, Li-Li; Fu, Jia; Jin, Jie-Tian; Luo, Rong-Zhen; Zhang, Chris Zhiyi; Yun, Jing-Ping

2015-01-01

Pyruvate kinase M2 (PKM2) contributes to the Warburg effect, a hallmark of cancer. We showed that PKM2 levels were correlated with overall survival (hazard ration = 1.675, 95% confidence interval: 1.389–2.019, P < 0.001) and disease-free survival (hazard ration = 1.573, 95% confidence interval: 1.214–2.038, P < 0.001) in a cohort of 490 patients with HCC. The correlations were further validated in an independent cohort of 148 HCC patients. Multivariate analyses revealed that PKM2 was an independent indicator of poor outcome in HCC. The knockdown of PKM2 in HCC cells inhibited cell proliferation and induced apoptosis in vitro and in vivo. Bim siRNA markedly abolished the PKM2-depletion-induced apoptosis. PKM2 depletion decreased the degradation of Bim. In clinical samples, PKM2 expression was reversely correlated with Bim expression. Combination of PKM2 and Bim levels had the best prognostic significance. We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim. PMID:25788265

MicroRNAs dysregulation in hepatocellular carcinoma: Insights in genomic medicine

PubMed Central

Lyra-González, Iván; Flores-Fong, Laura E; González-García, Ignacio; Medina-Preciado, David; Armendáriz-Borunda, Juan

2015-01-01

Hepatocellular carcinoma (HCC) is the leading primary liver cancer and its clinical outcome is still poor. MicroRNAs (miRNAs) have demonstrated an interesting potential to regulate gene expression at post-transcriptional level. Current findings suggest that miRNAs deregulation in cancer is caused by genetic and/or epigenetic, transcriptional and post-transcriptional modifications resulting in abnormal expression and hallmarks of malignant transformation: aberrant cell growth, cell death, differentiation, angiogenesis, invasion and metástasis. The important role of miRNAs in the development and progression of HCC has increased the efforts to understand and develop mechanisms of control overt this single-stranded RNAs. Several studies have analyzed tumoral response to the regulation and control of deregulated miRNAs with good results in vitro and in vivo, proving that targeting aberrant expression of miRNAs is a powerful anticancer therapeutic. Identification of up and/or down regulated miRNAs related to HCC has led to the discovery of new potential application for detection of their presence in the affected organism. MiRNAs represent a relevant new target for diagnosis, prognosis and treatment in a wide variety of pathologic entities, including HCC. This manuscript intends to summarize current knowledge regarding miRNAs and their role in HCC development. PMID:26085912

MicroRNAs dysregulation in hepatocellular carcinoma: Insights in genomic medicine.

PubMed

Lyra-González, Iván; Flores-Fong, Laura E; González-García, Ignacio; Medina-Preciado, David; Armendáriz-Borunda, Juan

2015-06-18

Hepatocellular carcinoma (HCC) is the leading primary liver cancer and its clinical outcome is still poor. MicroRNAs (miRNAs) have demonstrated an interesting potential to regulate gene expression at post-transcriptional level. Current findings suggest that miRNAs deregulation in cancer is caused by genetic and/or epigenetic, transcriptional and post-transcriptional modifications resulting in abnormal expression and hallmarks of malignant transformation: aberrant cell growth, cell death, differentiation, angiogenesis, invasion and metástasis. The important role of miRNAs in the development and progression of HCC has increased the efforts to understand and develop mechanisms of control overt this single-stranded RNAs. Several studies have analyzed tumoral response to the regulation and control of deregulated miRNAs with good results in vitro and in vivo, proving that targeting aberrant expression of miRNAs is a powerful anticancer therapeutic. Identification of up and/or down regulated miRNAs related to HCC has led to the discovery of new potential application for detection of their presence in the affected organism. MiRNAs represent a relevant new target for diagnosis, prognosis and treatment in a wide variety of pathologic entities, including HCC. This manuscript intends to summarize current knowledge regarding miRNAs and their role in HCC development.

NOTCH2 signaling confers immature morphology and aggressiveness in human hepatocellular carcinoma cells

PubMed Central

HAYASHI, YOSHIHIRO; OSANAI, MAKOTO; LEE, GANG-HONG

2015-01-01

The NOTCH family of membranous receptors plays key roles during development and carcinogenesis. Since NOTCH2, yet not NOTCH1 has been shown essential for murine hepatogenesis, NOTCH2 rather than NOTCH1 may be more relevant to human hepatocarcinogenesis; however, no previous studies have supported this hypothesis. We therefore assessed the role of NOTCH2 in human hepatocellular carcinoma (HCC) by immunohistochemistry and cell culture. Immunohistochemically, 19% of primary HCCs showed nuclear staining for NOTCH2, indicating activated NOTCH2 signaling. NOTCH2-positive HCCs were on average in more advanced clinical stages, and exhibited more immature cellular morphology, i.e. higher nuclear-cytoplasmic ratios and nuclear densities. Such features were not evident in NOTCH1-positive HCCs. In human HCC cell lines, abundant NOTCH2 expression was associated with anaplasia, represented by loss of E-cadherin. When NOTCH2 signaling was stably downregulated in HLF cells, an anaplastic HCC cell line, the cells were attenuated in potential for in vitro invasiveness and migration, as well as in vivo tumorigenicity accompanied by histological maturation. Generally, inverse results were obtained for a differentiated HCC cell line, Huh7, manipulated to overexpress activated NOTCH2. These findings suggested that the NOTCH2 signaling may confer aggressive behavior and immature morphology in human HCC cells. PMID:26252838

NOTCH2 signaling confers immature morphology and aggressiveness in human hepatocellular carcinoma cells.

PubMed

Hayashi, Yoshihiro; Osanai, Makoto; Lee, Gang-Hong

2015-10-01

The NOTCH family of membranous receptors plays key roles during development and carcinogenesis. Since NOTCH2, yet not NOTCH1 has been shown essential for murine hepatogenesis, NOTCH2 rather than NOTCH1 may be more relevant to human hepatocarcinogenesis; however, no previous studies have supported this hypothesis. We therefore assessed the role of NOTCH2 in human hepatocellular carcinoma (HCC) by immunohistochemistry and cell culture. Immunohistochemically, 19% of primary HCCs showed nuclear staining for NOTCH2, indicating activated NOTCH2 signaling. NOTCH2-positive HCCs were on average in more advanced clinical stages, and exhibited more immature cellular morphology, i.e. higher nuclear-cytoplasmic ratios and nuclear densities. Such features were not evident in NOTCH1‑positive HCCs. In human HCC cell lines, abundant NOTCH2 expression was associated with anaplasia, represented by loss of E-cadherin. When NOTCH2 signaling was stably downregulated in HLF cells, an anaplastic HCC cell line, the cells were attenuated in potential for in vitro invasiveness and migration, as well as in vivo tumorigenicity accompanied by histological maturation. Generally, inverse results were obtained for a differentiated HCC cell line, Huh7, manipulated to overexpress activated NOTCH2. These findings suggested that the NOTCH2 signaling may confer aggressive behavior and immature morphology in human HCC cells.

Noninvasive imaging of hepatocellular carcinoma: From diagnosis to prognosis

PubMed Central

Jiang, Han-Yu; Chen, Jie; Xia, Chun-Chao; Cao, Li-Kun; Duan, Ting; Song, Bin

2018-01-01

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major public health problem worldwide. Hepatocarcinogenesis is a complex multistep process at molecular, cellular, and histologic levels with key alterations that can be revealed by noninvasive imaging modalities. Therefore, imaging techniques play pivotal roles in the detection, characterization, staging, surveillance, and prognosis evaluation of HCC. Currently, ultrasound is the first-line imaging modality for screening and surveillance purposes. While based on conclusive enhancement patterns comprising arterial phase hyperenhancement and portal venous and/or delayed phase wash-out, contrast enhanced dynamic computed tomography and magnetic resonance imaging (MRI) are the diagnostic tools for HCC without requirements for histopathologic confirmation. Functional MRI techniques, including diffusion-weighted imaging, MRI with hepatobiliary contrast agents, perfusion imaging, and magnetic resonance elastography, show promise in providing further important information regarding tumor biological behaviors. In addition, evaluation of tumor imaging characteristics, including nodule size, margin, number, vascular invasion, and growth patterns, allows preoperative prediction of tumor microvascular invasion and patient prognosis. Therefore, the aim of this article is to review the current state-of-the-art and recent advances in the comprehensive noninvasive imaging evaluation of HCC. We also provide the basic key concepts of HCC development and an overview of the current practice guidelines. PMID:29904242

Rifaximin treatment is associated with reduced risk of cirrhotic complications and prolonged overall survival in patients experiencing hepatic encephalopathy.

PubMed

Kang, S H; Lee, Y B; Lee, J-H; Nam, J Y; Chang, Y; Cho, H; Yoo, J-J; Cho, Y Y; Cho, E J; Yu, S J; Kim, M Y; Kim, Y J; Baik, S K; Yoon, J-H

2017-11-01

Rifaximin might decrease the risk of portal hypertension-related complications by controlling small intestinal bacterial overgrowth. To evaluate whether rifaximin was associated with the risk of death and cirrhotic complications. We conducted a retrospective study that included 1042 patients experiencing hepatic encephalopathy (HE): 421 patients without hepatocellular carcinoma (HCC; the non-HCC cohort) and 621 patients with HCC (the HCC cohort). The primary endpoint was overall survival and secondary endpoints were recurrence of HE and the development of spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS) and variceal bleeding. In the non-HCC cohort, 145 patients received rifaximin plus lactulose (the rifaximin group) and 276 patients received lactulose alone (the control group). The multivariate analysis revealed that rifaximin was significantly associated with lower risk of death (adjusted hazard ratio [aHR], 0.697; P = .024) and reduced the risk of recurrent HE (aHR, 0.452; P < .001), SBP (aHR, 0.210; P < .001) and variceal bleeding (aHR, 0.425; P = .011) but not HRS (aHR, 0.598; P = .08). In the HCC cohort, 173 patients received rifaximin plus lactulose and 448 patients received lactulose. Rifaximin was not associated with the risk of death (aHR, 1.177; P = .121). Rifaximin was associated with lower risk of SBP (aHR, 0.323; P < .001) but not with variceal bleeding (aHR, 0.660; P = .104) or recurrent HE (aHR, 0.689; P = .057). The risk of Clostridium difficile-associated diarrhoea was not different between the groups (aHR, 0.028; P = .338). In patients without HCC, rifaximin treatment was significantly associated with prolonged overall survival and reduced risks of spontaneous bacterial peritonitis, variceal bleeding and recurrent hepatic encephalopathy. © 2017 John Wiley & Sons Ltd.

Expression of β-catenin protein in hepatocellular carcinoma and its relationship with alpha-fetoprotein.

PubMed

Ren, Ya-Jun; Huang, Tao; Yu, Hong-Lu; Zhang, Li; He, Qian-Jin; Xiong, Zhi-Fan; Peng, Hua

2016-12-01

This study aimed to investigate the expression of β-catenin in hepatocellular carcinoma (HCC) tissues and its relationship with α-fetoprotein (AFP) in HCC. Immunohistochemistry was used to determine the expression of β-catenin in normal liver tissues (n=10), liver cirrhosis tissues (n=20), and primary HCC tissues (n=60). The relationship between β-catenin expression and clinical parameters of HCC was investigated. Real-time PCR and Western blotting were used to detect the mRNA and protein expression levels of β-catenin in the liver cancer cell line SMMC-7721 transfected with a plasmid encoding AFP, and also the mRNA and protein expression levels of β-catenin were measured in the liver cancer cell line Huh7 before and after the transfection with AFP shRNA plasmids. The results showed that β-catenin was only expressed on the cell membrane in normal liver tissues. Its localization to the cytoplasm and nucleus of cells was observed in a small proportion of cirrhotic tissues or adjacent HCC tissues, and such ectopic expression of β-catenin was predominant in HCC tissues. The abnormal expression of β-catenin was correlated with serum AFP levels, cancer cell differentiation and vascular invasion (P<0.05). Additionally, the increased expression of AFP resulted in the upregulation of β-catenin mRNA and protein levels, while knockdown of AFP with AFP shRNA led to significantly decreased β-catenin mRNA and protein levels (P<0.05). It was suggested that the abnormal expression of β-catenin is implicated in hepatic carcinogenesis and development. AFP can lead to increased expression of β-catenin, which may account for the poor prognosis of AFP-associated HCC patients.

Surveillance for Hepatocellular Carcinoma Reduces Mortality: an Inverse Probability of Treatment Weighted Analysis.

PubMed

Chaiteerakij, Roongruedee; Chattieng, Piyanat; Choi, Jonggi; Pinchareon, Nutcha; Thanapirom, Kessirin; Geratikornsupuk, Nopavut

Evidence supporting benefit of hepatocellular carcinoma (HCC) surveillance in reducing mortality is not well-established. The effect of HCC surveillance in reducing mortality was assessed by an inverse probability of treatment weighting (IPTW)-based analysis controlled for inherent bias and confounders in observational studies. This retrospective cohort study was conducted on 446 patients diagnosed with HCC between 2007 and 2013 at a major referral center. Surveillance was defined as having at least 1 ultrasound test within a year before HCC diagnosis. Primary outcome was survival estimated using the Kaplan-Meier method with lead-time bias adjustment and compared using the log-rank test. Hazard ratio (HR) and 95% confidence interval (CI) were computed using conventional Cox and weighted Cox proportional hazards analysis with IPTW adjustment. Of the 446 patients, 103 (23.1%) were diagnosed with HCC through surveillance. The surveillance group had more patients with the Barcelona-Clinic Liver Cancer stage A (80.6% vs. 33.8%, P < 0.0001), more patients eligible for potentially curative treatment (73.8% vs. 44.9%, P < 0.0001), and longer median survival (49.6 vs. 15.9 months, P < 0.0001). By conventional multivariate Cox analysis, HR (95% CI) of surveillance was 0.63 (0.45-0.87), P = 0.005. The estimated effect of surveillance remained similar in the IPTW-adjusted Cox analysis (HR: 0.57; 95% CI: 0.43-0.76, P < 0.001). HCC surveillance by ultrasound is associated with a 37% reduction in mortality. Even though surveillance is recommended in all guidelines, but in practice, it is underutilized. Interventions are needed to increase surveillance rate for improving HCC outcome.

Non-hypervascular hypointense nodules detected by Gd-EOB-DTPA-enhanced MRI are a risk factor for recurrence of HCC after hepatectomy.

PubMed

Toyoda, Hidenori; Kumada, Takashi; Tada, Toshifumi; Niinomi, Takuro; Ito, Takanori; Sone, Yasuhiro; Kaneoka, Yuji; Maeda, Atsuyuki

2013-06-01

The gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) often depicts non-hypervascular hypointense hepatic nodules during the hepatobiliary phase in patients with hepatocellular carcinoma (HCC). It is unclear whether the presence of these nodules is associated with HCC recurrence after hepatectomy. We conducted a prospective observational study to investigate the impact of the presence of non-hypervascular hypointense hepatic nodules on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI on the recurrence of HCC after hepatectomy. A total of 77 patients who underwent hepatectomy for primary, non-recurrent, hypervascular HCC were prospectively followed up after hepatectomy. Post-operative recurrence rates were compared according to the presence of non-hypervascular hypointense nodules on preoperative Gd-EOB-DTPA-enhanced MRI. Recurrence rates after hepatectomy were higher in patients with non-hypervascular hypointense nodules (risk ratio 1.9396 [1.3615-2.7222]) and the presence of non-hypervascular hypointense nodules was an independent factor associated with postoperative recurrence (risk ratio 2.1767 [1.5089-3.1105]) along with HCC differentiation and portal vein invasion. While no differences were found in the rate of intrahepatic metastasis recurrence based on the preoperative presence of non-hypervascular hypointense hepatic nodules, the rate of multicentric recurrence was significantly higher in patients with preoperative non-hypervascular hypointense hepatic nodules. Patients with preoperative non-hypervascular hypointense hepatic nodules detected during the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI are at higher risk of HCC recurrence after hepatectomy, mainly due to multicentric recurrence. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Function of oval cells in hepatocellular carcinoma in rats.

PubMed

Fang, Chi-Hua; Gong, Jia-Qing; Zhang, Wei

2004-09-01

To study oval cells' pathological characteristics and relationship with the occurrence of hepatocellular carcinoma (HCC); to observe the form and structural characteristics of oval cells; to explore the expression characteristics of C-kit, PCNA mRNA and c-myc gene during the occurrence and development of HCC and the effect of ulinastatin (UTI) on C-kit and PCNA expression. One hundred and twenty-five SD rats fed on 3,3'-diaminobenzidine (DAB) to construct HCC models were divided into control group, cancer-inducing group and UTI intervention group. In each group, rat liver samples were collected at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24 respectively to study pathological distribution characteristics of oval cells in the process of carcinogenesis under optical microscope. Oval cells were separated by the methods of improved density gradient centrifugation and their structural characteristics were observed under optical microscope and electronic microscope respectively; the oval cells expressing C-kit and PCNA in the collected samples were observed by the methods of immunohistochemistry and image analysis and the expression of c-myc mRNA was also detected by reverse transcription polymerase chain reaction (RT-PCR). Oval cells proliferated firstly in the portal area then gradually migrated into hepatic parenchyma in the inducing group and intervention group. The oval cells distributed inside and outside the carcinoma nodes. The oval cells presented the characteristics of undifferentiated cells: a high ratio of nucleolus and cellular plasm and obvious nucleoli, rare organelle in plasm. Only a few mitochondria and endoplasmic reticulum and some villus-like apophysis on surface of cells could be seen. Cells stained with C-kit and PCNA antibody were mainly oval cells distributed in the portal area. The expression of c-myc mRNA increased with the progression of HCC. However, in the intervention group, UTI could retard its increase. Oval cells work throughout the development of HCC, and might play important roles in this process. c-myc gene may be a kind of promoter gene of HCC, and play a key role in hepatic injury and development of HCC. UTI could retard the occurrence of HCC. Copyright 2004 The WJG Press ISSN

Function of oval cells in hepatocellular carcinoma in rats

PubMed Central

Fang, Chi-Hua; Gong, Jia-Qing; Zhang, Wei

2004-01-01

AIM: To study oval cells pathological characteristics and relationship with the occurrence of hepatocellular carcinoma (HCC); to observe the form and structural characteristics of oval cells; to explore the expression characteristics of C-kit, PCNA mRNA and c-myc gene during the occurrence and development of HCC and the effect of ulinastatin (UTI) on C-kit and PCNA expression. METHODS: One hundred and twenty-five SD rats fed on 3,3'-diaminobenzidine (DAB) to construct HCC models were divided into control group, cancer-inducing group and UTI intervention group. In each group, rat liver samples were collected at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24 respectively to study pathological distribution characteristics of oval cells in the process of carcinogenesis under optical microscope. Oval cells were separated by the methods of improved density gradient centrifugation and their structural characteristics were observed under optical microscope and electronic microscope respectively; the oval cells expressing C-kit and PCNA in the collected samples were observed by the methods of immunohistochemistry and image analysis and the expression of c-myc mRNA was also detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Oval cells proliferated firstly in the portal area then gradually migrated into hepatic parenchyma in the inducing group and intervention group. The oval cells distributed inside and outside the carcinoma nodes. The oval cells presented the characteristics of undifferentiated cells: a high ratio of nucleolus and cellular plasm and obvious nucleoli, rare organelle in plasm. Only a few mitochondria and endoplasmic reticulum and some villus-like apophysis on surface of cells could be seen. Cells stained with C-kit and PCNA antibody were mainly oval cells distributed in the portal area. The expression of c-myc mRNA increased with the progression of HCC. However, in the intervention group, UTI could retard its increase. CONCLUSION: Oval cells work throughout the development of HCC, and might play important roles in this process. c-myc gene may be a kind of promoter gene of HCC, and play a key role in hepatic injury and development of HCC. UTI could retard the occurrence of HCC. PMID:15300889

Scalp hair cortisol for diagnosis of Cushing's syndrome.

PubMed

Wester, Vincent L; Reincke, Martin; Koper, Jan W; van den Akker, Erica L T; Manenschijn, Laura; Berr, Christina M; Fazel, Julia; de Rijke, Yolanda B; Feelders, Richard A; van Rossum, Elisabeth F C

2017-06-01

Current first-line screening tests for Cushing's syndrome (CS) only measure time-point or short-term cortisol. Hair cortisol content (HCC) offers a non-invasive way to measure long-term cortisol exposure over several months of time. We aimed to evaluate HCC as a screening tool for CS. Case-control study in two academic referral centers for CS. Between 2009 and 2016, we collected scalp hair from patients suspected of CS and healthy controls. HCC was measured using ELISA. HCC was available in 43 confirmed CS patients, 35 patients in whom the diagnosis CS was rejected during diagnostic work-up and follow-up (patient controls), and 174 healthy controls. Additionally, we created HCC timelines in two patients with ectopic CS. CS patients had higher HCC than patient controls and healthy controls (geometric mean 106.9 vs 12.7 and 8.4 pg/mg respectively, P  < 0.001). At a cut-off of 31.1 pg/mg, HCC could differentiate between CS patients and healthy controls with a sensitivity of 93% and a specificity of 90%. With patient controls as a reference, specificity remained the same (91%). Within CS patients, HCC correlated significantly with urinary free cortisol ( r  = 0.691, P  < 0.001). In two ectopic CS patients, HCC timelines indicated that cortisol was increased 3 and 6 months before CS became clinically apparent. Analysis of cortisol in a single scalp hair sample offers diagnostic accuracy for CS similar to currently used first-line tests, and can be used to investigate cortisol exposure in CS patients months to years back in time, enabling the estimation of disease onset. © 2017 European Society of Endocrinology.

Neurotensin expression and release in human colon cancers.

PubMed Central

Evers, B M; Ishizuka, J; Chung, D H; Townsend, C M; Thompson, J C

1992-01-01

Neurotensin (NT), a distal gut peptide released by intraluminal fats, is trophic for normal small bowel and colonic mucosa. In addition, NT stimulates growth of certain colon cancers; the mechanism for this effect is not known. The purpose of this study was to determine whether human colon cancers (HCC) (1) express the mRNA for NT/neuromedin N (N), (2) produce NT peptide, and (3) express the mRNA for a functional NT receptor (NTR). RNA was extracted from four HCC cell lines in culture, nine HCC lines established in athymic nude mice, and from six HCC and adjacent normal mucosa from freshly resected operative specimens; the RNA was analyzed for NT/N mRNA by Northern hybridization with a complementary DNA probe. Neurotensin peptide content, NTR expression, and intracellular Ca++ ([Ca++]i) mobilization in response to NT were evaluated in three HCC cell lines (LoVo, HT29, HCT116). Neurotensin/N mRNA transcripts were identified in all four of the HCC cell lines and in one of nine HCC in nude mice. Neurotensin expression was found in two of six freshly resected HCC and in none of the six corresponding samples of normal mucosa. Neurotensin peptide was identified by RIA in LoVo, HT29, and HCT116. In addition, NTR mRNA was found in HT29 and HCT116. Neurotensin stimulated [Ca++]i mobilization in HCT116 (without serum) and in LoVo (with 0.25% serum). These findings demonstrate the presence of NT/N mRNA and NT peptide and the presence of a functional NTR in certain HCC. Neurotensin, a potent trophic factor for normal gut mucosa, may function as an autocrine growth factor in certain human colon cancers. Images FIG. 1. FIG. 4. PMID:1329682

Association of twelve polymorphisms in three onco-lncRNA genes with hepatocellular cancer risk and prognosis: A case-control study

PubMed Central

Wang, Ben-Gang; Xu, Qian; Lv, Zhi; Fang, Xin-Xin; Ding, Han-Xi; Wen, Jing; Yuan, Yuan

2018-01-01

AIM To evaluate the association of 12 tag single nucleotide polymorphisms (tagSNPs) in three onco-long non-coding RNA (lncRNA) genes (HOTTIP, CCAT2, MALAT1) with the risk and prognosis of hepatocellular cancer (HCC). METHODS Twelve tagSNPs covering the three onco-lncRNAs were genotyped by the KASP method in a total of 1338 samples, including 521 HCC patients and frequency-matched 817 controls. The samples were obtained from an unrelated Chinese population at the First Hospital of China Medical University from 2012-2015. The expression quantitative trait loci (eQTL) analyses were conducted to explore further the potential function of the promising SNPs. RESULTS Three SNPs in HOTTIP, one promoter SNP in MALAT1, and one haplotype of HOTTIP were associated with HCC risk. The HOTTIP rs17501292, rs2067087, and rs17427960 SNPs were increased to 1.55-, 1.20-, and 1.18-fold HCC risk under allelic models (P = 0.012, 0.017 and 0.049, respectively). MALAT1 rs4102217 SNP was increased to a 1.32-fold HCC risk under dominant models (P = 0.028). In addition, the two-way interaction of HOTTIP rs17501292-MALAT1 rs619586 polymorphisms showed a decreased effect on HCC risk (Pinteraction = 0.028, OR = 0.30) and epistasis with each other. HOTTIP rs3807598 variant genotype showed significantly longer survival time in HBV negative subgroup (P = 0.049, HR = 0.12), and MALAT1 rs591291 showed significantly better prognosis in female and HBV negative subgroups (P = 0.022, HR = 0.37; P = 0.042, HR = 0.25, respectively). In the study, no significant effect was observed in eQTL analysis. CONCLUSION Specific lncRNA (HOTTIP and MALAT1) SNPs have potential to be biomarkers for HCC risk and prognosis. PMID:29930469

Hair as a long-term retrospective cortisol calendar in orang-utans (Pongo spp.): new perspectives for stress monitoring in captive management and conservation.

PubMed

Carlitz, Esther H D; Kirschbaum, Clemens; Stalder, Tobias; van Schaik, Carolus P

2014-01-01

This study examined whether the method of hair cortisol analysis is applicable to orang-utans (Pongo spp.) and can help to advance the objective monitoring of stress in non-human primates. Specifically, we examined whether fundamental prerequisites for hair cortisol analysis are given in orang-utans and, subsequently, whether segmental hair analysis may provide a retrospective calendar of long-term cortisol levels. For this, hair samples were examined from 71 zoo-living orang-utans (38 males, mean age=22.5years; 33 females, mean age=24years) for which detailed records of past living conditions were available. Hair samples were cut from defined body regions and were analyzed either in full length or in segments. Results showed that hair cortisol concentrations (HCC) were unrelated to age or sex of the individual animal. HCC were found to be higher in orang-utans, with perceived long-term stressful periods (mean HCC=43.6±26.5pg/mg, n=13) compared to animals without perceived stressful periods (19.3±5.5pg/mg, n=55, P<0.001). In non-stressed animals, segmental hair analyses revealed that HCC was stable along the hair shaft even when hair reached >40cm. The possibility of obtaining a retrospective calendar of stress-related cortisol changes through hair analysis was further supported by data of three case studies showing close correspondence between the segmental HCC results and keeper reports of stress exposure during the respective time periods. Finally, low within-animal variation in HCC from different body regions (CV%: 14.3) suggested that this method may also be applicable to naturally shed hair, e.g., as found in nests of wild orang-utans and other great apes. Therefore, using HCC may provide an ideal non-invasive tool for both captive management as well as conservation in orang-utans and potentially other great apes. Copyright © 2013 Elsevier Inc. All rights reserved.

The anti-hepatocellular carcinoma cell activity by a novel mTOR kinase inhibitor CZ415

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Wei; Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People’s Hospital of Hangzhou medical College, Hangzhou; Chen, Bingyu

Dysregulation of mammalian target of rapamycin (mTOR) in hepatocellular carcinoma (HCC) represents a valuable treatment target. Recent studies have developed a highly-selective and potent mTOR kinase inhibitor, CZ415. Here, we showed that nM concentrations of CZ415 efficiently inhibited survival and induced apoptosis in HCC cell lines (HepG2 and Huh-7) and primary-cultured human HCC cells. Meanwhile, CZ415 inhibited proliferation of HCC cells, more potently than mTORC1 inhibitors (rapamycin and RAD001). CZ415 was yet non-cytotoxic to the L02 human hepatocytes. Mechanistic studies showed that CZ415 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in HepG2 cells. Meanwhile, activation of mTORC1 (p-S6K1)more » and mTORC2 (p-AKT, Ser-473) was almost blocked by CZ415. In vivo studies revealed that oral administration of CZ415 significantly suppressed HepG2 xenograft tumor growth in severe combined immuno-deficient (SCID) mice. Activation of mTORC1/2 was also largely inhibited in CZ415-treated HepG2 tumor tissue. Together, these results show that CZ415 blocks mTORC1/2 activation and efficiently inhibits HCC cell growth in vitro and in vivo. - Highlights: • CZ415 is anti-survival and pro-apoptotic to hepatocellular carcinoma (HCC) cells. • CZ415 inhibits HCC cell proliferation, more efficiently than mTORC1 inhibitors. • CZ415 blocks assembly and activation of both mTORC1 and mTORC2 in HCC cells. • CZ415 oral administration inhibits HepG2 tumor growth in SCID mice. • mTORC1/2 activation in HepG2 tumor is inhibited with CZ415 administration.« less

Effects of body region and time on hair cortisol concentrations in chimpanzees (Pan troglodytes).

PubMed

Carlitz, Esther H D; Kirschbaum, Clemens; Miller, Robert; Rukundo, Joshua; van Schaik, Carel P

2015-11-01

Hair cortisol concentrations (HCC) are increasingly recognized as an integrated measure of the systemic cortisol secretion. Yet, we still know very little about confounding effects on HCC in animals. The present study therefore used hair from semi-wild and zoo living chimpanzees to investigate (1) intra-individual variability of HCC (body-region effect), and (2) the stability of HCC along the hair shaft (traditionally called the washout effect). Our results indicate that absolute HCC varied substantially between certain body regions, but a factor analysis revealed that these HCC differences were mainly attributable to one common source of variance. Thus, hair from all body regions provides similar biological signals and can be mixed, albeit at the cost of a lower signal-to-noise ratio. With regard to potential underlying mechanisms, we studied skin blood flow, as observed through thermal images from one chimpanzee. We found the general HCC pattern was reflected in differences in surface body temperature observed in this individual in three out of four body regions. In a separate set of samples, we found first evidence to suggest that the systematic cortisol decrease along the hair shaft, as observed in humans, is also present in chimpanzee hair. The effect was more pronounced in semi-wild than in zoo chimpanzees presumably due to more exposure to ambient weather conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

Recent negative life events increase hair cortisol concentrations in patients with bipolar disorder.

PubMed

Staufenbiel, Sabine M; Koenders, Manja A; Giltay, Erik J; Elzinga, Bernet M; Manenschijn, Laura; Hoencamp, Erik; van Rossum, Elisabeth F C; Spijker, Anne T

2014-12-01

Life events induce stress, which is considered to negatively impact the course of disease in patients with bipolar disorder (BD), its effects being predominantly mediated by cortisol. Cortisol in scalp hair has been identified as a biomarker for assessing long-term cortisol levels, and allows clarifying the relation between life events, hair cortisol concentrations (HCC), and clinical course over time. In 71 BD patients, we analyzed the proximal 3 cm of hair, reflecting 3 months of cortisol production, and investigated the association between HCC, the number of life events, the amount of social support, and mood in the 3 months prior to the hair assessment and between HCC and mood in the subsequent 3 months. Although the total number of life events was not associated with HCC (p > 0.05), the number of negative life events was associated with increased HCC (r(2)( )= 0.04, p = 0.02). Social support showed an inverse association with HCC in patients reporting negative life events (r(2)( )= 0.07, p = 0.03). HCC and mood were not associated in the 3 months prior to hair sampling or in the subsequent 3 months. This study indicates that patients who experienced recent negative life events have increased hair cortisol levels, which seem to be attenuated by social support.

Combined use of nuclear phosphoprotein c-Myc and cellular phosphoprotein p53 for hepatocellular carcinoma detection in high-risk chronic hepatitis C patients.

PubMed

Attallah, A M; El-Far, M; Abdelrazek, M A; Omran, M M; Attallah, A A; Elkhouly, A A; Elkenawy, H M; Farid, K

2017-10-01

Hepatocellular carcinoma (HCC) is a multistage process resulting from various genetic changes. We aimed to determine nuclear phosphoprotein c-Myc and cellular phosphoprotein p53 expression and to evaluate their importance in HCC diagnosis. One hundred and twenty chronic hepatitis C (CHC) patients (60 non-HCC CHC patients and 60 HCC patients who had a single small (<5 cm) tumour) were recruited. The gene products of c-Myc and p53 were identified in liver tissues and serum samples using immunostaining, western blot and ELISA. Immunohistochemical detection of c-Myc and p53 with monospecific antibodies revealed intense and diffuse cytoplasmic staining patterns. Accumulated mutant proteins, released from tumour cells into the extracellular serum, were detected at 62 KDa, for c-Myc, and 53 KDa, for p53, using western blotting. In contrast to alpha feto-protein, there was a significant increase (p < 0.0001) in the positivity rate of c-Myc (86.7% vs. 6.7%) and p53 (78.3% vs. 8.3%) in the malignant vs. non-malignant patients. The parallel combination of c-Myc and p53 reach the absolute sensitivity (100%), for more accurate and reliable HCC detection (specificity was 87%). c-Myc and p53 are potential HCC diagnostic biomarkers, and convenient combinations of them could improve diagnostic accuracy of HCC.

Verbal and physical client aggression - A longitudinal analysis of professional caregivers' psychophysiological stress response and burnout.

PubMed

Kind, Nina; Eckert, Anne; Steinlin, Célia; Fegert, Jörg M; Schmid, Marc

2018-08-01

We investigated the impact of verbal and physical client aggression on risk of developing high hair cortisol concentration (HCC) as an indicator of chronic stress exposure and burnout in a Swiss population of professional caregivers working in youth residential care. Participants (n = 121; 62.0% women) reported on client aggression and burnout symptoms and provided hair samples at four annual sampling points. HCC was determined in the first 1.5 cm hair segment. Sociodemographic variables, private stressors, burnout symptoms, and HCC were compared between participants reporting either 'no aggression', 'verbal' aggression, or 'verbal + physical' aggression. Cox proportional hazards regressions were calculated to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between client aggression and risk of high HCC or burnout over the course of three years. Professional caregivers reporting 'verbal + physical' aggression had higher HCC, more cognitive burnout symptoms, and greater burden in interpersonal domains. Both 'verbal' and 'verbal + physical' aggression were positively associated with burnout risk (verbal: HR = 1.83; 95% CI = 1.27-2.65; verbal + physical: HR = 2.44, 95% CI = 1.56-3.84). 'Verbal + physical' aggression was positively associated with risk of high HCC (HR = 1.58; 95% CI = 1.07-2.36). This longitudinal analysis suggested that psychophysiological stress response is primarily associated with combined verbal and physical aggression. The emotional wearing-down associated with verbal aggression should however not be disregarded. Our exploratory findings could have implications for youth welfare policy, clinical child psychiatry, and future research. Copyright © 2018. Published by Elsevier Ltd.

Hair cortisol and progesterone detection in dairy cattle: interrelation with physiological status and milk production.

PubMed

Tallo-Parra, O; Carbajal, A; Monclús, L; Manteca, X; Lopez-Bejar, M

2018-07-01

Hair cortisol concentrations (HCCs) and hair progesterone concentrations (HPCs) allow monitoring long-term retrospective steroid levels. However, there are still gaps in the knowledge of the mechanisms of steroid deposition in hair and its potential application in dairy cattle research. This study aimed to evaluate the potential uses of hair steroid determinations by studying the interrelations between HCC, HPC, physiological data from cows, and their milk production and quality. Cortisol and progesterone concentrations were analyzed in hair from 101 milking Holstein Friesian cows in a commercial farm. Physiological data were obtained from the 60 d prior to hair collection. Moreover, productive data from the month when hair was collected and the previous one were also obtained as well as at 124 d after hair sampling. Significant but weak correlations were found between HCC and HPC (r = 0.25, P < 0.0001) and between HPC and age (r = 0.06, P = 0.0133). High HCC were associated with low milk yields from the 2 previous months to hair sampling (P = 0.0396) and during the whole lactation (P < 0.0001). High HCC were also related to high somatic cell count (P = 0.0241). No effect of HCC on fat or protein content was detected. No significant correlations were detected between hair steroid concentrations and pregnancy status, days of gestation, parturition category (primiparous vs multiparous), number of lactations or days in milk. The relationship between physiological variables and HCC or HPC could depend on the duration of the time period over which hair accumulates hormones. Steroid concentrations in hair present high variability between individuals but are a potential tool for dairy cattle welfare and production research by providing a useful and practical tool for long-term steroid monitoring. Copyright © 2018 Elsevier Inc. All rights reserved.

Quantitative analysis of aberrant protein glycosylation in liver cancer plasma by AAL-enrichment and MRM mass spectrometry.

PubMed

Ahn, Yeong Hee; Shin, Park Min; Kim, Yong-Sam; Oh, Na Ree; Ji, Eun Sun; Kim, Kwang Hoe; Lee, Yeon Jung; Kim, Sung Ho; Yoo, Jong Shin

2013-11-07

A lectin-coupled mass spectrometry (MS) approach was employed to quantitatively monitor aberrant protein glycosylation in liver cancer plasma. To do this, we compared the difference in the total protein abundance of a target glycoprotein between hepatocellular carcinoma (HCC) plasmas and hepatitis B virus (HBV) plasmas, as well as the difference in lectin-specific protein glycoform abundance of the target glycoprotein. Capturing the lectin-specific protein glycoforms from a plasma sample was accomplished by using a fucose-specific aleuria aurantia lectin (AAL) immobilized onto magnetic beads via a biotin-streptavidin conjugate. Following tryptic digestion of both the total plasma and its AAL-captured fraction of each HCC and HBV sample, targeted proteomic mass spectrometry was conducted quantitatively by a multiple reaction monitoring (MRM) technique. From the MRM-based analysis of the total plasmas and AAL-captured fractions, differences between HCC and HBV plasma groups in fucosylated glycoform levels of target glycoproteins were confirmed to arise from both the change in the total protein abundance of the target proteins and the change incurred by aberrant fucosylation on target glycoproteins in HCC plasma, even when no significant change occurs in the total protein abundance level. Combining the MRM-based analysis method with the lectin-capturing technique proved to be a successful means of quantitatively investigating aberrant protein glycosylation in cancer plasma samples. Additionally, it was elucidated that the differences between HCC and control groups in fucosylated biomarker candidates A1AT and FETUA mainly originated from an increase in fucosylation levels on these target glycoproteins, rather than an increase in the total protein abundance of the target glycoproteins.

Down-regulation of Transducin-Like Enhancer of Split protein 4 in hepatocellular carcinoma promotes cell proliferation and epithelial-Mesenchymal-Transition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Xiao-cai; Xiao, Cui-cui; Li, Hua

Background: Transducin-Like Enhancer of Split protein 4 (TLE4) has been reported to be involved in some subsets of acute myeloid leukemia and colorectal cancer. In the present study, we aimed to explore the role of TLE4 in tumorigenesis and cancer progression in hepatocellular carcinoma (HCC). Methods: The expression pattern of TLE4 in HCC was determined by Western-blot and qRT-PCR, gain-of-function and loss-of-function was used to explore the biological role of TLE4 in HCC cells. A xenograft model was established to confirm its effects on proliferation. Results: The protein expression levels of TLE4 were significantly down-regulated in HCC tissues compared tomore » matched adjacent normal liver tissues. In vitro, down-regulation of TLE4 in Huh7 or SMMC-7721 promoted cell proliferation and ectopical expression of TLE4 in Hep3B or Bel-7404 suppressed cell proliferation. In addition, the cell colony formation ability was enhanced after down-regulation of TLE4 expression in Huh-7 but suppressed after over-expression in Hep3B. Furthermore, down-regulation of TLE4 increased the cell invasion ability, as well as increased the expression level of Vimentin and decreased that of E-cadherin, indicating a phenotype of epithelial-mesenchymal transition (EMT) in HCC cells. On the contrary, ectopical expression of TLE4 in HCC cells decreased the cell invasion ability and inhibited EMT. In vivo, compared to control group, xenograft tumor volumes were significantly decreased in TLE4 overexpression group. Conclusions: These results demonstrated that TLE4 might play important regulatory roles in cellular proliferation and EMT process in HCC. - Highlights: • TLE4 is significantly down-regulated in HCC samples. • Down regulated of TLE4 in HCC cells promotes cell proliferation. • Down regulated of TLE4 in HCC cells promotes epithelial-to-mesenchymal transition.« less

Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors.

PubMed

Chiyonobu, Norimichi; Shimada, Shu; Akiyama, Yoshimitsu; Mogushi, Kaoru; Itoh, Michiko; Akahoshi, Keiichi; Matsumura, Satoshi; Ogawa, Kosuke; Ono, Hiroaki; Mitsunori, Yusuke; Ban, Daisuke; Kudo, Atsushi; Arii, Shigeki; Suganami, Takayoshi; Yamaoka, Shoji; Ogawa, Yoshihiro; Tanabe, Minoru; Tanaka, Shinji

2018-05-01

Metabolic syndrome is a newly identified risk factor for hepatocellular carcinoma (HCC); however, tumor-specific biomarkers still remain unclear. We performed cross-species analysis to compare gene signatures of HCC from human patients and melanocortin 4 receptor-knockout mice, which develop HCC with obesity, insulin resistance, and dyslipidemia. Unsupervised hierarchical clustering and principle component analysis of 746 differentially expressed orthologous genes classified HCC of 152 human patients and melanocortin 4 receptor-knockout mice into two distinct subgroups, one of which included mouse HCC and was causatively associated with metabolic risk factors. Nine genes commonly overexpressed in human and mouse metabolic disease-associated HCC were identified; fatty acid binding protein 4 (FABP4) was remarkably enriched in intratumoral activated hepatic stellate cells (HSCs). Subclones constitutively expressing FABP4 were established from a human HSC cell line in which expression levels of inflammatory chemokines, including IL-1A and IL-6, were up-regulated through NF-κB nuclear translocation, resulting in recruitment of macrophages. An immunohistochemical validation study of 106 additional human HCC samples indicated that FABP4-positive HSCs were distributed in tumors of 38 cases, and the FABP4-high group consisted of patients with nonviral and nonalcoholic HCC (P = 0.027) and with multiple metabolic risk factors (P < 0.001) compared with the FABP4-low group. Thus, FABP4 overexpression in HSCs may contribute to hepatocarcinogenesis in patients with metabolic risk factors by modulation of inflammatory pathways. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Pesticide exposure and hepatocellular carcinoma risk: A case-control study using a geographic information system (GIS) to link SEER-Medicare and California pesticide data.

PubMed

VoPham, Trang; Brooks, Maria M; Yuan, Jian-Min; Talbott, Evelyn O; Ruddell, Darren; Hart, Jaime E; Chang, Chung-Chou H; Weissfeld, Joel L

2015-11-01

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is associated with low survival. U.S. studies examining self-reported pesticide exposure in relation to HCC have demonstrated inconclusive results. We aimed to clarify the association between pesticide exposure and HCC by implementing a novel data linkage between Surveillance, Epidemiology, and End Results (SEER)-Medicare and California Pesticide Use Report (PUR) data using a geographic information system (GIS). Controls were frequency-matched to HCC cases diagnosed between 2000 and 2009 in California by year, age, race, sex, and duration of residence in California. Potential confounders were extracted from Medicare claims. From 1974 to 2008, pounds (1 pound represents 0.45 kg) of applied organophosphate, organochlorine, and carbamate pesticides provided in PURs were aggregated to the ZIP Code level using area weighting in a GIS. ZIP Code exposure estimates were linked to subjects using Medicare-provided ZIP Codes to calculate pesticide exposure. Agricultural residents were defined as living in ZIP Codes with a majority area intersecting agricultural land cover according to the 1992, 2001, and 2006 National Land Cover Database (NLCD) rasters. Multivariable conditional logistic regression was used to estimate the association between pesticide exposure and HCC. Among California residents of agriculturally intensive areas, previous annual ZIP Code-level exposure to over 14.53 kg/km(2) of organochlorine pesticides (75(th) percentile among controls) was associated with an increased risk of HCC after adjusting for liver disease and diabetes (adjusted odds ratio [OR] 1.87, 95% confidence interval [CI] 1.17, 2.99; p=0.0085). ZIP Code-level organochlorines were significantly associated with an increased risk of HCC among males (adjusted OR 2.76, 95% CI 1.58, 4.82; p=0.0004), but not associated with HCC among females (adjusted OR 0.83, 95% CI 0.35, 1.93; p=0.6600) (interaction p=0.0075). This is the first epidemiologic study to use GIS-based exposure estimates to study pesticide exposure and HCC. Our results suggest that organochlorine pesticides are associated with an increase in HCC risk among males but not females. Copyright © 2015 Elsevier Inc. All rights reserved.

Pesticide exposure and hepatocellular carcinoma risk: a case-control study using a geographic information system (GIS) to link SEER-Medicare and California pesticide data

PubMed Central

VoPham, Trang; Brooks, Maria M.; Yuan, Jian-Min; Talbott, Evelyn O.; Ruddell, Darren; Hart, Jaime E.; Chang, Chung-Chou H.; Weissfeld, Joel L.

2015-01-01

Background Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is associated with low survival. U.S. studies examining self-reported pesticide exposure in relation to HCC have demonstrated inconclusive results. We aimed to clarify the association between pesticide exposure and HCC by implementing a novel data linkage between Surveillance, Epidemiology, and End Results (SEER)-Medicare and California Pesticide Use Report (PUR) data using a geographic information system (GIS). Methods Controls were frequency-matched to HCC cases diagnosed between 2000 and 2009 in California by year, age, race, sex, and duration of residence in California. Potential confounders were extracted from Medicare claims. From 1974 to 2008, pounds (1 pound represents 0.45 kg) of applied organophosphate, organochlorine, and carbamate pesticides provided in PURs were aggregated to the ZIP Code level using area weighting in a GIS. ZIP Code exposure estimates were linked to subjects using Medicare-provided ZIP Codes to calculate pesticide exposure. Agricultural residents were defined as living in ZIP Codes with a majority area intersecting agricultural land cover according to the 1992, 2001, and 2006 National Land Cover Database (NLCD) rasters. Multivariable conditional logistic regression was used to estimate the association between pesticide exposure and HCC. Results Among California residents of agriculturally intensive areas, previous annual ZIP Code-level exposure to over 14.53 kg/km2 of organochlorine pesticides (75th percentile among controls) was associated with an increased risk of HCC after adjusting for liver disease and diabetes (adjusted odds ratio [OR] 1.87, 95% confidence interval [CI] 1.17, 2.99; p=0.0085). ZIP Code-level organochlorines were significantly associated with an increased risk of HCC among males (adjusted OR 2.76, 95% CI 1.58, 4.82; p=0.0004), but not associated with HCC among females (adjusted OR 0.83, 95% CI 0.35, 1.93; p=0.6600) (interaction p=0.0075). Conclusions This is the first epidemiologic study to use GIS-based exposure estimates to study pesticide exposure and HCC. Our results suggest that organochlorine pesticides are associated with an increase in HCC risk among males but not females. PMID:26451881

Association between PNPLA3 gene polymorphisms and risk of hepatitis B virus-related hepatocellular carcinoma in Han population in China:a case-control study.

PubMed

Gao, Xia; Liu, Wenxuan; Yang, Lei; Zhang, Xiaolin; Ma, Ning; Wang, Liqin; Yan, Lina; Tang, Longmei; Yang, Haitao; Liu, Dianwu

2017-10-01

Several recent studies showed that the genetic polymorphisms in the PNPLA3 region (rs738408, rs738409, rs2294918, rs2294919 and rs2281135) were with related to various kinds of liver diseases. We analyzed the five single-nucleotide polymorphisms (SNPs) for major HBV outcomes in Han Chinese. A total of 2410 samples were involved and peripheral blood samples were collected in this study. The SNPs in the PNPLA3 region were genotyped by using Matrix-assisted laser desorption/ionization time of flight mass spectrometry. Our study indicated the clear relationship between the PNPLA3 rs2294918, rs2294919 and HBV-related HCC after control for the effects of sex, drinking and smoking. Health subjects with the PNPLA3 rs2294919 TC genotype would have a 0.605 (95% CI: 0.413, 0.886; p = .010) times lower odds of having HCC, and those with the rs2294918 AG genotype would have a 1.872 (95% CI: 1.256, 2.792; p = .002) times higher odds of having HCC, whereas the values of sex, age, drinking and smoking were fixed. In addition, CA haplotype of the haplotype block of rs738409 and rs2281135 was also associated with HBV-related HCC. Our study suggested that PNPLA3 loci (rs2294918, rs2294919) were associated with HBV-related HCC in Han Chinese.

IGF-1 induces the epithelial-mesenchymal transition via Stat5 in hepatocellular carcinoma.

PubMed

Zhao, Chuanzong; Wang, Qian; Wang, Ben; Sun, Qi; He, Zhaobin; Hong, Jianguo; Kuehn, Florian; Liu, Enyu; Zhang, Zongli

2017-12-19

It has been reported that the epithelial-mesenchymal transition (EMT) plays an important role in hepatocellular carcinoma (HCC). However, the relationship between the insulin-like growth factor-1 (IGF-1) and EMT of HCC was not fully elucidated. In the present work, we found that the expression of N-cadherin, Vimentin, Snail1, Snail2, and Twist1 was positively associated with IGF-1R expression, while E-cadherin expression was negatively associated with IGF-1 expression in human HCC samples. Furthermore, we observed that IGF-1 up-regulated the expression of N-cadherin, Vimentin, Snail1, Snail2 and Twist1, and down-regulated the expression of E-cadherin. In addition, Stat5 was induced in IGF-1-treated HepG2 and Hep3B cells, and Stat5 inhibition or siRNA significantly affected IGF-1-induced EMT in HepG2 and Hep3B cells. In conclusion, IGF-1 induces EMT of HCC via Stat5 signaling pathway. Thus, IGF-1/Stat5 can be recommended as a potential and novel therapeutic strategy for HCC patients.

Serum Metabolomics to Identify the Liver Disease-Specific Biomarkers for the Progression of Hepatitis to Hepatocellular Carcinoma

NASA Astrophysics Data System (ADS)

Gao, Rong; Cheng, Jianhua; Fan, Chunlei; Shi, Xiaofeng; Cao, Yuan; Sun, Bo; Ding, Huiguo; Hu, Chengjin; Dong, Fangting; Yan, Xianzhong

2015-12-01

Hepatocellular carcinoma (HCC) is a common malignancy that has region specific etiologies. Unfortunately, 85% of cases of HCC are diagnosed at an advanced stage. Reliable biomarkers for the early diagnosis of HCC are urgently required to reduced mortality and therapeutic expenditure. We established a non-targeted gas chromatography-time of flight-mass spectrometry (GC-TOFMS) metabolomics method in conjunction with Random Forests (RF) analysis based on 201 serum samples from healthy controls (NC), hepatitis B virus (HBV), liver cirrhosis (LC) and HCC patients to explore the metabolic characteristics in the progression of hepatocellular carcinogenesis. Ultimately, 15 metabolites were identified intimately associated with the process. Phenylalanine, malic acid and 5-methoxytryptamine for HBV vs. NC, palmitic acid for LC vs. HBV, and asparagine and β-glutamate for HCC vs. LC were screened as the liver disease-specific potential biomarkers with an excellent discriminant performance. All the metabolic perturbations in these liver diseases are associated with pathways for energy metabolism, macromolecular synthesis, and maintaining the redox balance to protect tumor cells from oxidative stress.

Direct costs of care for hepatocellular carcinoma in patients with hepatitis C cirrhosis.

PubMed

Tapper, Elliot B; Catana, Andreea M; Sethi, Nidhi; Mansuri, Daniel; Sethi, Saurabh; Vong, Annie; Afdhal, Nezam H

2016-03-15

Hepatitis C virus (HCV) is the commonest cause of hepatocellular carcinoma (HCC) in the United States. The benefits of HCV therapy may be measured in part by the prevention of HCC and other complications of cirrhosis. The true cost of care of the HCV patient with HCC is unknown. One hundred patients were randomly selected from a cohort of all HCC patients with HCV at a US transplant center between 2003 and 2013. Patients were categorized by the primary treatment modality, Barcelona class, and ultimate transplant status. Costs included the unit costs of procedures, imaging, hospitalizations, medications, and all subsequent care of the HCC patient until either death or the end of follow-up. Associations with survival and cost were assessed in multivariate regression models. Overall costs included a median of $176,456 (interquartile range [IQR], $84,489-$292,192) per patient or $6279 (IQR, $4043-$9720) per patient-month of observation. The median costs per patient-month were $7492 (IQR, $5137-$11,057) for transplant patients and $4830 for nontransplant patients. The highest median monthly costs were for transplant patients with Barcelona A4 disease ($11,349) and patients who received chemoembolization whether they underwent transplantation ($10,244) or not ($8853). Transarterial chemoembolization and radiofrequency ablation were independently associated with a 28% increase and a 22% decrease in costs, respectively, with adjustments for the severity of liver disease and Barcelona class. These data represent real-world estimates of the cost of HCC care provided at a transplant center and should inform economic studies of HCV therapy. © 2015 American Cancer Society.

Multicenter Prospective Study of Angiogenesis Polymorphism Validation in HCC Patients Treated with Sorafenib. An INNOVATE Study Protocol.

PubMed

Casadei Gardini, Andrea; Faloppi, Luca; Aprile, Giuseppe; Brunetti, Oronzo; Caparello, Chiara; Corbelli, Jody; Chessa, Luchino; Bruno, Daniele; Ercolani, Giorgio; Leonetti, Alessandro; de Stefano, Giorgio; Farella, Nunzia; Foschi, Francesco Giuseppe; Lanzi, Arianna; Dadduzio, Vincenzo; Marisi, Giorgia; Masi, Gianluca; Negri, Francesca V; Pagan, Flavia; Santini, Daniele; Scarpi, Emanuela; Silletta, Marianna; Silvestris, Nicola; Tamburini, Emiliano; Tassinari, Davide; Vivaldi, Caterina; Gentilucci, Umberto Vespasiani; Zagonel, Vittorina; Calvetti, Lorenzo; Cascinu, Stefano; Frassineti, Giovanni Luca; Scartozzi, Mario

2017-12-01

Introduction Although sorafenib is the upfront standard of care for advanced hepatocellular carcinoma (HCC), molecular predictors of efficacy have not been identified yet. In the ALICE-1 study, rs2010963 of VEGF-A and VEGF-C proved to be independent predictive factors for progression-free survival (PFS) and overall survival (OS) in multivariate analysis. The ALICE-1 study results were confirmed in the ALICE-2 study, in which VEGF and VEGFR SNPs were analyzed. In the ePHAS study we analyzed the SNPs of eNOS. In univariate analysis, patients homozygous for an eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had significantly shorter median PFS and OS than those with other haplotypes. These data were confirmed in the validation set. Methods This nonpharmacological, interventional, prospective multicenter study aims to determine whether eNOS, HIF-1, VEGF, Ang2 and VEGFR polymorphisms play a role in predicting the objective response rate, PFS, and OS of advanced HCC patients treated with sorafenib. The study will involve 160 advanced HCC patients with Child-Pugh class A disease. The primary aim is to validate the prognostic or predictive roles of eNOS, Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to the clinical outcome (PFS) of HCC patients treated with sorafenib. Conclusions Overall, our data may suggest that polymorphism analysis of the VEGF, VEGFR-2, HIF and eNOS genes can identify HCC patients who are more likely to benefit from sorafenib.

Silymarin and hepatocellular carcinoma: a systematic, comprehensive, and critical review.

PubMed

Mastron, Jeanetta K; Siveen, Kodappully S; Sethi, Gautam; Bishayee, Anupam

2015-06-01

The blessed milk thistle (Silybum marianum L.), a flowering plant native to Mediterranean Europe, has been consumed and extensively used as a cure for various chronic liver ailments over several centuries. Milk thistle extract, known as silymarin, is a complex mixture of seven major flavonolignans and one flavonoid. The phytoconstituents of silymarin owe their therapeutic and hepatoprotective effects to their strong antioxidant and anti-inflammatory properties. Primary liver cancer, also known as hepatocellular carcinoma (HCC), occurs in a milieu of oxidative stress and inflammation. The etiology of HCC includes chronic infection with hepatitis B and C viruses, cirrhosis, and exposure to dietary and environmental hepatocarcinogens. Current therapeutic options for HCC, including surgical resection and liver transplantation, have limited benefits and are essentially ineffective. Chemoprevention, using phytochemicals with potent antioxidant and anti-inflammatory properties, represents a fascinating strategy, which has been a subject of intense investigation in the recent years. In this review, we explore the potential role of silymarin as a chemopreventive and therapeutic agent for HCC. The review systematically evaluates the preclinical in-vitro and in-vivo studies investigating the effects of silymarin and its constituents on HCC. The biochemical mechanisms involved in the anti-liver-cancer effects of silymarin have been presented. The current status of clinical studies evaluating the potential of role of silymarin in liver cancer, especially that caused by hepatitis C virus, has also been examined. Potential challenges and future directions of research involved in the 'bench-to-bedside' transition of silymarin phytoconstituents for the chemoprevention and treatment of HCC have also been discussed.

Comparison of methanol and isopropanol as wash solvents for determination of hair cortisol concentration in grizzly bears and polar bears.

PubMed

Kroshko, Thomas; Kapronczai, Luciene; Cattet, Marc R L; Macbeth, Bryan J; Stenhouse, Gordon B; Obbard, Martyn E; Janz, David M

2017-01-01

Methodological differences among laboratories are recognized as significant sources of variation in quantification of hair cortisol concentration (HCC). An important step in processing hair, particularly when collected from wildlife, is the choice of solvent used to remove or "wash" external hair shaft cortisol prior to quantification of HCC. The present study systematically compared methanol and isopropanol as wash solvents for their efficiency at removing external cortisol without extracting internal hair shaft cortisol in samples collected from free-ranging grizzly bears and polar bears. Cortisol concentrations in solvents and hair were determined in each of one to eight washes of hair with each solvent independently. •There were no significant decreases in internal hair shaft cortisol among all eight washes for either solvent, although methanol removed detectable hair surface cortisol after one wash in grizzly bear hair whereas hair surface cortisol was detected in all eight isopropanol washes.•There were no significant differences in polar bear HCC washed one to eight times with either solvent, but grizzly bear HCC was significantly greater in hair washed with isopropanol compared to methanol.•There were significant differences in HCC quantified using different commercial ELISA kits commonly used for HCC determinations.

Validation of a preclinical model of diethylnitrosamine-induced hepatic neoplasia in Yucatan miniature pigs

PubMed Central

Mitchell, Jennifer; Tinkey, Peggy T.; Avritscher, Rony; Van Pelt, Carolyn; Eskandari, Ghazaleh; George, Suraj Konnath; Xiao, Lianchun; Cressman, Erik; Morris, Jeffrey S.; Rashid, Asif; Kaseb, Ahmed O.; Amin, Hesham M.; Uthamanthil, Rajesh

2016-01-01

Objective The purpose of this study was to reduce time to tumor onset in a diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) swine model via partial liver embolization (PLE) and to characterize the model for use in translational research. Methods Eight Yucatan miniature pigs were injected intraperitoneally with either saline (n=2) or DEN (n=6) solution weekly for 12 weeks. Three of the DEN-treated pigs underwent PLE. Animals underwent periodic radiological evaluation, liver biopsy, and blood sampling, and full necropsy was performed at study termination (~29 months). Results All DEN-treated pigs developed hepatic adenoma and HCC. PLE accelerated the time to adenoma development but not to HCC development. Biomarker analysis results showed that IGF1 levels decreased in all DEN-treated pigs, as functional liver capacity decreased with progression of HCC. VEGF and IL-6 levels were positively correlated with disease progression. Immunohistochemical probing of HCC tissues demonstrated the expression of several important survival-promoting proteins. Conclusion To our knowledge, we are the first to demonstrate accelerated development of hepatic neoplasia in Yucatan miniature pigs. Our HCC swine model closely mimics the human condition (i.e., progressive disease stages and expression of relevant molecular markers) and is a viable translational model. PMID:27305144

Significance of genetic variants in DLC1 and their association with hepatocellular carcinoma

PubMed Central

XIE, CHENG-RONG; SUN, HONG-GUANG; SUN, YU; ZHAO, WEN-XIU; ZHANG, SHENG; WANG, XIAO-MIN; YIN, ZHEN-YU

2015-01-01

DLC1 has been shown to be downregulated or absent in hepatocellular carcinoma (HCC) and is associated with tumorigenesis and development. However, only a small number of studies have focused on genetic variations of DLC1. The present study performed exon sequencing for the DLC1 gene in HCC tissue samples from 105 patients to identify functional genetic variation of DLC1 and its association with HCC susceptibility, clinicopathological features and prognosis. A novel missense mutation and four non-synonymous single nucleotide polymorphisms (SNPs; rs3816748, rs11203495, rs3816747 and rs532841) were identified. A significant correlation of rs3816747 polymorphisms with HCC susceptibility was identified. Compared to individuals with the GG genotype of rs3816747, those with the GA (odds ratio (OR)=0.486; P=0.037) or GA+AA genotype (OR=0.51; P=0.039) were associated with a significantly decreased HCC risk. Furthermore, patients with the GC+CC genotype of rs3816748, the TC+CC genotype of rs11203495 or the GA+AA genotype of rs3816747 had small-sized tumors compared with those carrying the wild-type genotype. No significant association of DLC1 SNPs with the patients' prognosis was found. These results indicated that genetic variations in the DLC1 gene may confer a risk for HCC. PMID:26095787

Clinicopathological characteristics of TERT promoter mutation and telomere length in hepatocellular carcinoma.

PubMed

Lee, Hye Won; Park, Tae In; Jang, Se Young; Park, Soo Young; Park, Won-Jin; Jung, Soo-Jung; Lee, Jae-Ho

2017-02-01

Promoter mutations in telomerase reverse transcriptase (TERT) and telomere length have been studied in various tumors. In the present study, the frequency and clinical characteristics of TERT promoter mutation and telomere length were studied in hepatocellular carcinoma (HCC). TERT promoter mutation and telomere length were analyzed in 162 tumor samples of the patients with HCC by sequencing and real-time PCR, respectively. The TERT promoter mutation rate was 28.8% (46/160) in HCC and was associated with males (P = 0.027). The telomere length was not significantly different in the presence of a TERT promoter mutation but was shorter in high-grade tumor stages (P = 0.048). Survival analyses showed that poor overall survival was associated with longer telomere length (P = 0.013). However, the TERT promoter mutation did not have a prognostic value for HCC. Multivariate survival analyses demonstrated that the telomere length was an independent prognostic marker for poor overall survival (hazard ratio = 1.75, 95% confidence interval: 1.046-2.913, P = 0.033). These data demonstrated that TERT promoter mutation is a frequent event in HCC; however, telomere length, but not the presence of a TERT promoter mutation, might have potential value as a prognostic indicator of HCC.

Gain of GRHL2 is associated with early recurrence of hepatocellular carcinoma.

PubMed

Tanaka, Yasuo; Kanai, Fumihiko; Tada, Motohisa; Tateishi, Ryosuke; Sanada, Masashi; Nannya, Yasuhito; Ohta, Miki; Asaoka, Yoshinari; Seto, Motoko; Shiina, Shuichiro; Yoshida, Haruhiko; Kawabe, Takao; Yokosuka, Osamu; Ogawa, Seishi; Omata, Masao

2008-11-01

The aim of this study is to identify genomic changes that might be implicated in hepatocellular carcinoma (HCC) progression, and evaluate the associations with clinico-pathological features. The genomic DNA of 17 hepatoma cell lines was analyzed using Affymetrix GeneChip Human Mapping 50K high-density oligonucleotide arrays. We selected representative genes from recurrent amplified regions and measured the copy number of these genes in 70 HCC clinical samples. We found 10 recurrent high-grade gain regions spanning less than 3 Mb in at least two hepatoma cell lines, and selected 10 representative genes. The copy number was almost normal in non-cancerous tissue and frequently amplified in Edmondson grade II or III HCC compared to Edmondson grade I HCC. Gain of TAX1BP1 in 7p15.2-1 was associated with larger tumor size and positivity of HCV antibody, and gain of CCND1 in 11q13.2-3 was associated with larger tumor size by multivariate analysis. Furthermore, a gain of GRHL2 in 8q22.3 was associated with early recurrence of HCC, controlling for clinical parameters. Decreased GRHL2 expression by RNA interference inhibits the growth of hepatoma cells, suggesting its association with cell proliferation. A gain of GRHL2 might be a predictive marker for HCC recurrence.

Pure laparoscopic hepatectomy with augmented reality-assisted indocyanine green fluorescence versus open hepatectomy for hepatocellular carcinoma with liver cirrhosis: A propensity analysis at a single center.

PubMed

Cheung, Tan To; Ma, Ka Wing; She, Wong Hoi; Dai, Wing Chiu; Tsang, Simon Hing Yin; Chan, Albert Chi Yan; Chok, Kenneth Siu Ho; Lo, Chung Mau

2018-05-10

Laparoscopic hepatectomy is considered an acceptable treatment of choice in selected patients with primary hepatocellular carcinoma (HCC). Whether indocyanine green (ICG) immunofluorescence, a new technology, may improve surgery outcomes has yet to be tested. The aim of the present study was to investigate and compare the effect of ICG fluorescence imaging on the outcomes of pure laparoscopic hepatectomy and open hepatectomy for primary HCC with background cirrhosis. From January 2015 to June 2016, 20 patients with HCC and liver cirrhosis underwent laparoscopic hepatectomy with ICG immunofluorescence. The outcomes of pure laparoscopic hepatectomy with ICG immunofluorescence were compared with those of open hepatectomy. To avoid selection bias, patients were propensity score matched in a ratio of 1 : 6, with 20 patients in the laparoscopic group and 120 in the open group. The laparoscopic group had 20 patients, and the open group had 120 patients. The laparoscopic group had less blood loss (125 vs 450 mL, P < 0.001), a shorter operation time (200 vs 250 min, P = 0.003), and a shorter hospital stay (5 vs 6 days, P < 0.001). The complication rate was 0% in the laparoscopic group compared to 15.0% in the open group (P = 0.135). All patients in the laparoscopic group had negative margin involvement. Four patients (3.3%) in the open resection group had positive margin involvement. Two patients in the ICG immunofluorescence group had additional lesions identified and resected during operation. Pure laparoscopic hepatectomy with ICG immunofluorescence for primary HCC can be carried out safely with favorable short-term outcomes even in cirrhotic patients. Better identification of the bile duct structure and better assessment of the tumor resection margin and perfusion are advantages of this new technique. © 2018 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.

Applications of next-generation sequencing analysis for the detection of hepatocellular carcinoma-associated hepatitis B virus mutations.

PubMed

Wu, I-Chin; Liu, Wen-Chun; Chang, Ting-Tsung

2018-06-02

Next-generation sequencing (NGS) is a powerful and high-throughput method for the detection of viral mutations. This article provides a brief overview about optimization of NGS analysis for hepatocellular carcinoma (HCC)-associated hepatitis B virus (HBV) mutations, and hepatocarcinogenesis of relevant mutations. For the application of NGS analysis in the genome of HBV, four noteworthy steps were discovered in testing. First, a sample-specific reference sequence was the most effective mapping reference for NGS. Second, elongating the end of reference sequence improved mapping performance at the end of the genome. Third, resetting the origin of mapping reference sequence could probed deletion mutations and variants at a certain location with common mutations. Fourth, using a platform-specific cut-off value to distinguish authentic minority variants from technical artifacts was found to be highly effective. One hundred and sixty-seven HBV single nucleotide variants (SNVs) were found to be studied previously through a systematic literature review, and 12 SNVs were determined to be associated with HCC by meta-analysis. From comprehensive research using a HBV genome-wide NGS analysis, 60 NGS-defined HCC-associated SNVs with their pathogenic frequencies were identified, with 19 reported previously. All the 12 HCC-associated SNVs proved by meta-analysis were confirmed by NGS analysis, except for C1766T and T1768A which were mainly expressed in genotypes A and D, but including the subgroup analysis of A1762T. In the 41 novel NGS-defined HCC-associated SNVs, 31.7% (13/41) had cut-off values of SNV frequency lower than 20%. This showed that NGS could be used to detect HCC-associated SNVs with low SNV frequency. Most SNV II (the minor strains in the majority of non-HCC patients) had either low (< 20%) or high (> 80%) SNV frequencies in HCC patients, a characteristic U-shaped distribution pattern. The cut-off values of SNV frequency for HCC-associated SNVs represent their pathogenic frequencies. The pathogenic frequencies of HCC-associated SNV II also showed a U-shaped distribution. Hepatocarcinogenesis induced by HBV mutated proteins through cellular pathways was reviewed. NGS analysis is useful to discover novel HCC-associated HBV SNVs, especially those with low SNV frequency. The hepatocarcinogenetic mechanisms of novel HCC-associated HBV SNVs defined by NGS analysis deserve further investigation.

CXXC5 suppresses hepatocellular carcinoma by promoting TGF-β-induced cell cycle arrest and apoptosis.

PubMed

Yan, Xiaohua; Wu, Jingyi; Jiang, Quanlong; Cheng, Hao; Han, Jing-Dong J; Chen, Ye-Guang

2018-02-01

Evading TGF-β-mediated growth inhibition is often associated with tumorigenesis in liver, including hepatocellular carcinoma (HCC). To better understand the functions and the underlying molecular mechanisms of TGF-β in HCC initiation and progression, we carried out transcriptome sequencing (RNA-Seq) to identify the target genes of TGF-β. CXXC5, a member of the CXXC-type zinc finger domain-containing protein family, was identified as a novel TGF-β target gene in Hep3B HCC cells. Knockdown of CXXC5 attenuated the expression of a substantial portion of TGF-β target genes and ameliorated TGF-β-induced growth inhibition or apoptosis of Hep3B cells, suggesting that CXXC5 is required for TGF-β-mediated inhibition of HCC progression. Analysis of the TCGA database indicated that CXXC5 expression is reduced in the majority of HCC tissue samples in comparison to that in normal tissues. Furthermore, CXXC5 associates with the histone deacetylase HDAC1 and competes its interaction with Smad2/3, thereby abolishing the inhibitory effect of HDAC1 on TGF-β signaling. These observations together suggest that CXXC5 may act as a tumor suppressor by promoting TGF-β signaling via a positive feedback loop, and reveal a strategy for HCC to bypass TGF-β-mediated cytostasis by disrupting the positive feedback regulation. Our findings shed new light on TGF-β signaling regulation and demonstrate the function of CXXC5 in HCC development.

Definition of tumor-associated antigens in hepatocellular carcinoma.

PubMed

Stenner-Liewen, F; Luo, G; Sahin, U; Tureci, O; Koslovski, M; Kautz, I; Liewen, H; Pfreundschuh, M

2000-03-01

With an estimated annual incidence of about one million cases, hepatocellular carcinoma (HCC) is one of the most common neoplasms worldwide. Of all malignant diseases, it is the major cause of death in some regions of Africa and Asia. The pathogenic mechanisms responsible for HCC are not well defined, and therapeutic means, especially in inoperable HCCs, are still unsatisfactory and await improvement. In the quest for tumor antigens exploitable for gene therapy, we studied immune responses in the context of HCC. A cDNA library derived from a human HCC sample was screened using the SEREX approach. Nineteen distinct antigens reactive with autologous IgG were identified. Sequence analysis revealed three of the cDNA clones to code for hitherto unknown proteins and 16 known genes products. Proteins as diverse in function as LDH, albumin, and kinectin were found. Furthermore, proteins involved in the transcription/translation machinery had elicited an immune response in the autologous host. A panel of allogenic sera including sera from patients with hepatitis, liver cirrhosis, HCC, and other tumor entities, as well as sera from normal individuals, was used for frequency analysis of antibody responses. Whereas allogenic sera of HCC patients detected most antigens at a high percentage, control sera were rarely antibody-positive. The nature of the major fraction of antigens described here are linked to liver. Thus, our findings demonstrate not only the complexity of the humoral immune response against HCC, but may also offer new insight into mechanisms underlying transformation of the liver cell.

The prognostic utility of baseline alpha-fetoprotein for hepatocellular carcinoma patients.

PubMed

Silva, Jack P; Gorman, Richard A; Berger, Nicholas G; Tsai, Susan; Christians, Kathleen K; Clarke, Callisia N; Mogal, Harveshp; Gamblin, T Clark

2017-12-01

Alpha-fetoprotein (AFP) has a valuable role in postoperative surveillance for hepatocellular carcinoma (HCC) recurrence. The utility of pretreatment or baseline AFP remains controversial. The present study hypothesized that elevated baseline AFP levels are associated with worse overall survival in HCC patients. Adult HCC patients were identified using the National Cancer Database (2004-2013). Patients were stratified according to baseline AFP measurements into the following groups: Negative (<20), Borderline (20-199), Elevated (200-1999), and Highly Elevated (>2000). The primary outcome was overall survival (OS), which was analyzed by log-rank test and graphed using Kaplan-Meier method. Multivariate regression modeling was used to determine hazard ratios (HR) for OS. Of 41 107 patients identified, 15 809 (33.6%) were Negative. Median overall survival was highest in the Negative group, followed by Borderline, Elevated, and Highly Elevated (28.7 vs 18.9 vs 8.8 vs 3.2 months; P < 0.001). On multivariate analysis, overall survival hazard ratios for the Borderline, Elevated, and Highly Elevated groups were 1.18 (P = 0.267), 1.94 (P < 0.001), and 1.77 (P = 0.007), respectively (reference Negative). Baseline AFP independently predicted overall survival in HCC patients regardless of treatment plan. A baseline AFP value is a simple and effective method to assist in expected survival for HCC patients. © 2017 Wiley Periodicals, Inc.

Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer.

PubMed

Philip, Philip A; Mahoney, Michelle R; Holen, Kyle D; Northfelt, Donald W; Pitot, Henry C; Picus, Joel; Flynn, Patrick J; Erlichman, Charles

2012-05-01

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC). Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point. Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child's A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea. In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients. Copyright © 2011 American Cancer Society.

Phase 2 Study of Bevacizumab Plus Erlotinib in Patients With Advanced Hepatocellular Cancer

PubMed Central

Philip, Philip A.; Mahoney, Michelle R.; Holen, Kyle D.; Northfelt, Donald W.; Pitot, Henry C.; Picus, Joel; Flynn, Patrick J.; Erlichman, Charles

2013-01-01

BACKGROUND Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC). METHODS Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child’s Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point. RESULTS Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child’s A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea. CONCLUSIONS In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients. PMID:21953248

Quantitative proteome analysis of plasma microparticles for the characterization of HCV-induced hepatic cirrhosis and hepatocellular carcinoma.

PubMed

Taleb, Raghda Saad Zaghloul; Moez, Pacint; Younan, Doreen; Eisenacher, Martin; Tenbusch, Matthias; Sitek, Barbara; Bracht, Thilo

2017-12-01

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor and a leading cause of cancer-related deaths worldwide. Cirrhosis induced by hepatitis-C virus (HCV) infection is the most critical risk factor for HCC. However, the mechanism of HCV-induced carcinogenesis is not fully understood. Plasma microparticles (PMP) contribute to numerous physiological and pathological processes and contain proteins whose composition correlates to the respective pathophysiological conditions. We analyzed PMP from 22 HCV-induced cirrhosis patients, 16 HCV-positive HCC patients with underlying cirrhosis and 18 healthy controls. PMP were isolated using ultracentrifugation and analyzed via label-free LC-MS/MS. We identified 840 protein groups and quantified 507 proteins. 159 proteins were found differentially abundant between the three experimental groups. PMP in both disease entities displayed remarkable differences in the proteome composition compared to healthy controls. Conversely, the proteome difference between both diseases was minimal. GO analysis revealed that PMP isolated from both diseases were significantly enriched in proteins involved in complement activation, while endopeptidase activity was downregulated exclusively in HCC patients. This study reports for the first time a quantitative proteome analysis for PMP from patients with HCV-induced cirrhosis and HCC. Data are available via ProteomeXchange with identifier PXD005777. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Improved method increases sensitivity for circulating hepatocellular carcinoma cells

PubMed Central

Liu, Hui-Ying; Qian, Hai-Hua; Zhang, Xiao-Feng; Li, Jun; Yang, Xia; Sun, Bin; Ma, Jun-Yong; Chen, Lei; Yin, Zheng-Feng

2015-01-01

AIM: To improve an asialoglycoprotein receptor (ASGPR)-based enrichment method for detection of circulating tumor cells (CTCs) of hepatocellular carcinoma (HCC). METHODS: Peripheral blood samples were collected from healthy subjects, patients with HCC or various other cancers, and patients with hepatic lesions or hepatitis. CTCs were enriched from whole blood by extracting CD45-expressing leukocytes with monoclonal antibody coated-beads following density gradient centrifugation. The remaining cells were cytocentrifuged on polylysine-coated slides. Isolated cells were treated by triple immunofluorescence staining with CD45 antibody and a combination of antibodies against ASGPR and carbamoyl phosphate synthetase 1 (CPS1), used as liver-specific markers, and costained with DAPI. The cell slide was imaged and stained tumor cells that met preset criteria were counted. Recovery, sensitivity and specificity of the detection methods were determined and compared by spiking experiments with various types of cultured human tumor cell lines. Expression of ASGPR and CPS1 in cultured tumor cells and tumor tissue specimens was analyzed by flow cytometry and triple immunofluorescence staining, respectively. RESULTS: CD45 depletion of leukocytes resulted in a significantly greater recovery of multiple amounts of spiked HCC cells than the ASGPR+ selection (Ps < 0.05). The expression rates of either ASGPR or CPS1 were different in various liver cancer cell lines, ranging between 18% and 99% for ASGPR and between 9% and 98% for CPS1. In both human HCC tissues and liver cancer cell lines, there were a few HCC cells that did not stain positive for ASGPR or CPS1. The mixture of monoclonal antibodies against ASGPR and CPS1 identified more HCC cells than either antibody alone. However, these antibodies did not detect any tumor cells in blood samples spiked with the human breast cancer cell line MCF-7 and the human renal cancer cell line A498. ASGPR+ or/and CPS1+ CTCs were detected in 29/32 (91%) patients with HCC, but not in patients with any other kind of cancer or any of the other test subjects. Furthermore, the improved method detected a higher CTC count in all patients examined than did the previous method (P = 0.001), and consistently achieved 12%-21% higher sensitivity of CTC detection in all seven HCC patients with more than 40 CTCs. CONCLUSION: Negative depletion enrichment combined with identification using a mixture of antibodies against ASGPR and CPS1 improves sensitivity and specificity for detecting circulating HCC cells. PMID:25780289

Correspondence between hair cortisol concentrations and 30-day integrated daily salivary and weekly urinary cortisol measures

PubMed Central

Short, Sarah J.; Stalder, Tobias; Marceau, Kristine P.; Entringer, Sonja; Moog, Nora K.; Shirtcliff, Elizabeth A.; Wadhwa, Pathik D.; Buss, Claudia

2016-01-01

Characterization of cortisol production, regulation and function is of considerable interest and relevance given its ubiquitous role in virtually all aspects of physiology, health and disease risk. The quantification of cortisol concentration in hair has been proposed as a promising approach for the retrospective assessment of integrated, long-term cortisol production. However, human research is still needed to directly test and validate current assumptions about which aspects of cortisol production and regulation are reflected in hair cortisol concentrations (HCC). Here, we report findings from a validation study in a sample of 17 healthy adults (mean ± SD age: 34 ± 8.6 yrs). To determine the extent to which HCC captures cumulative cortisol production, we examined the correspondence of HCC, obtained from the first 1cm scalp-near hair segment, assumed to retrospectively reflect 1-month integrated cortisol secretion, with 30-day average salivary cortisol area-under-the curve (AUC) based on 3 samples collected per day (on awakening, +30 min, at bedtime) and the average of 4 weekly 24-hr urinary free cortisol (UFC) assessments. To further address which aspects of cortisol production and regulation are best reflected in the HCC measure, we also examined components of the salivary measures that represent: 1) production in response to the challenge of awakening (using the cortisol awakening response [CAR]), and 2) chronobiological regulation of cortisol production (using diurnal slope). Finally, we evaluated the test-retest stability of each cortisol measure. Results indicate that HCC was most strongly associated with the prior 30-day integrated cortisol production measure (average salivary cortisol AUC) (r = 0.61, p = 0.01). There were no significant associations between HCC and the 30-day summary measures using CAR or diurnal slope. The relationship between 1-month integrated 24-hr UFC and HCC did not reach statistical significance (r = 0.30, p = 0.28). Lastly, of all cortisol measures, test-retest correlations of serial measures were highest for HCC (month-to-month: r = 0.84, p < 0.001), followed by 24-hr UFC (week-to-week: r’s between 0.59 and 0.68, ps < 0.05) and then integrated salivary cortisol concentrations (week-to-week: r’s between 0.38 and 0.61, p’s between 0.13 and 0.01). These findings support the contention that HCC provides a reliable estimate of long-term integrated free cortisol production that is aligned with integrated salivary cortisol production measured over a corresponding one-month period. PMID:27235635

Correspondence between hair cortisol concentrations and 30-day integrated daily salivary and weekly urinary cortisol measures.

PubMed

Short, Sarah J; Stalder, Tobias; Marceau, Kristine; Entringer, Sonja; Moog, Nora K; Shirtcliff, Elizabeth A; Wadhwa, Pathik D; Buss, Claudia

2016-09-01

Characterization of cortisol production, regulation and function is of considerable interest and relevance given its ubiquitous role in virtually all aspects of physiology, health and disease risk. The quantification of cortisol concentration in hair has been proposed as a promising approach for the retrospective assessment of integrated, long-term cortisol production. However, human research is still needed to directly test and validate current assumptions about which aspects of cortisol production and regulation are reflected in hair cortisol concentrations (HCC). Here, we report findings from a validation study in a sample of 17 healthy adults (mean±SD age: 34±8.6 yrs). To determine the extent to which HCC captures cumulative cortisol production, we examined the correspondence of HCC, obtained from the first 1cm scalp-near hair segment, assumed to retrospectively reflect 1-month integrated cortisol secretion, with 30-day average salivary cortisol area-under-the curve (AUC) based on 3 samples collected per day (on awakening, +30min, at bedtime) and the average of 4 weekly 24-h urinary free cortisol (UFC) assessments. To further address which aspects of cortisol production and regulation are best reflected in the HCC measure, we also examined components of the salivary measures that represent: (1) production in response to the challenge of awakening (using the cortisol awakening response [CAR]), and (2) chronobiological regulation of cortisol production (using diurnal slope). Finally, we evaluated the test-retest stability of each cortisol measure. Results indicate that HCC was most strongly associated with the prior 30-day integrated cortisol production measure (average salivary cortisol AUC) (r=0.61, p=0.01). There were no significant associations between HCC and the 30-day summary measures using CAR or diurnal slope. The relationship between 1-month integrated 24-h UFC and HCC did not reach statistical significance (r=0.30, p=0.28). Lastly, of all cortisol measures, test-retest correlations of serial measures were highest for HCC (month-to-month: r=0.84, p<0.001), followed by 24-h UFC (week-to-week: r's between 0.59 and 0.68, ps<0.05) and then integrated salivary cortisol concentrations (week-to-week: r's between 0.38 and 0.61, p's between 0.13 and 0.01). These findings support the contention that HCC provides a reliable estimate of long-term integrated free cortisol production that is aligned with integrated salivary cortisol production measured over a corresponding one-month period. Copyright © 2016 Elsevier Ltd. All rights reserved.

Controversies in imaging of hepatocellular carcinoma: multidetector CT (MDCT)

PubMed Central

Silverman, Paul M; Szklaruk, Janio

2005-01-01

Primary hepatocellular carcinoma (HCC) is a significant tumor worldwide and represents the most common primary hepatic neoplasm. Staging criteria are important for appreciation of timely work up of these neoplasms in contradiction with surgical colleagues. This article demonstrates the appearance of HCC on multiphasic, multidetector CT (MDCT) and relates these findings to current staging criteria. The variable appearance on different planes of contrast is critical to appreciate in staging this neoplasm. The hypervascular nature of the primary tumor makes MDCT and three-phase imaging a critical feature in the detection and characterization of this tumor. This is especially critical in the patients who are candidates for surgical resection. Additionally, MDCT has allowed arterial phase imaging to define the vascular supply of the tumor. An accurate representation of the size and number of lesions is critical in not only the initial staging but also the follow-up of hepatocellular carcinoma. The post-treatment features including the appearance post-surgically and after radiofrequency ablation can be well appreciated on MDCT. PMID:16361147

Non-viral causes of liver cancer: does obesity led inflammation play a role?

PubMed

Alzahrani, Badr; Iseli, Tristan J; Hebbard, Lionel W

2014-04-10

Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for around 90% of primary liver cancers. Chronic infection with hepatitis B and hepatitis C viruses are two of most common causes of liver cancer. However, there are non-viral factors that are associated with liver cancer development. Numerous population studies have revealed strong links between obesity and the development of liver cancer. Obesity can alter hepatic pathology, metabolism and promote inflammation, leading to nonalcoholic fatty liver disease (NAFLD) and the progression to the more severe form, non-alcoholic steatohepatitis (NASH). NASH is characterised by prominent steatosis and inflammation, and can lead to HCC. Here, we discuss the role of obesity in inflammation and the principal signalling mechanisms involved in HCC formation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Genetic Polymorphisms of Cytochrome P4501A1 (CYP1A1) and Glutathione S-Transferase P1 (GSTP1) and Risk of Hepatocellular Carcinoma Among Chronic Hepatitis C Patients in Egypt.

PubMed

Abo-Hashem, Ekbal M; El-Emshaty, Wafaa M; Farag, Raghda El Sayed; Zakaria, Sahar; Abd El-Aziz, Mohammed; Ghonaim, Azza

2016-10-01

Cytochrome P450 1A1 (CYP1A1) and Glutathione S-transferase P1 (GSTP1) genes are involved in the metabolism of many carcinogens. Polymorphisms in these genes with altered enzyme activity have been reported. The present study evaluated the synergistic effect between CYP1A1 and GSTP1 gene polymorphisms and smoking on development of HCV-related liver disease and hepatocellular carcinoma (HCC). The patients group comprised 40 patients with HCC and 40 patients with liver cirrhosis. The control group comprised 40 healthy subjects having no history of malignancy. The genetic polymorphisms were studied using polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) technique on blood samples. The number of current or former smoker among HCC and cirrhotic patients as well as the median Pack/year of cigarette smoked were significantly higher in HCC and liver cirrhotic patients than in control group. Subjects with CYP1A1 gene variants (m1 and m3) had no significant risk to develop cirrhosis or HCC compared to control group. Individuals carrying the Ile/Val genotype of GSTP1 had a significant increased risk of HCC (OR of 2.2, 95 % CI 1.143-4.261) and had larger tumor size. No significant risk was observed on combining both genes variants or on combining smoking with variants of both genes. In conclusion, the GSTP1 Ile/Val genotype and Val allele are associated with an increased risk of HCC. CYP1A1 and GSTP1 genes variants interaction did not increase the risk of HCC.

Dietary fat, fat subtypes and hepatocellular carcinoma in a large European cohort.

PubMed

Duarte-Salles, Talita; Fedirko, Veronika; Stepien, Magdalena; Aleksandrova, Krasimira; Bamia, Christina; Lagiou, Pagona; Laursen, Anne Sofie Dam; Hansen, Louise; Overvad, Kim; Tjønneland, Anne; Boutron-Ruault, Marie-Christine; Fagherazzi, Guy; His, Mathilde; Boeing, Heiner; Katzke, Verena; Kühn, Tilman; Trichopoulou, Antonia; Valanou, Elissavet; Kritikou, Maria; Masala, Giovanna; Panico, Salvatore; Sieri, Sabina; Ricceri, Fulvio; Tumino, Rosario; Bueno-de-Mesquita, H B As; Peeters, Petra H; Hjartåker, Anette; Skeie, Guri; Weiderpass, Elisabete; Ardanaz, Eva; Bonet, Catalina; Chirlaque, Maria-Dolores; Dorronsoro, Miren; Quirós, J Ramón; Johansson, Ingegerd; Ohlsson, Bodil; Sjöberg, Klas; Wennberg, Maria; Khaw, Kay-Tee; Travis, Ruth C; Wareham, Nick; Ferrari, Pietro; Freisling, Heinz; Romieu, Isabelle; Cross, Amanda J; Gunter, Marc; Lu, Yunxia; Jenab, Mazda

2015-12-01

The role of amount and type of dietary fat consumption in the etiology of hepatocellular carcinoma (HCC) is poorly understood, despite suggestive biological plausibility. The associations of total fat, fat subtypes and fat sources with HCC incidence were investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which includes 191 incident HCC cases diagnosed between 1992 and 2010. Diet was assessed by country-specific, validated dietary questionnaires. A single 24-hr diet recall from a cohort subsample was used for measurement error calibration. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated from Cox proportional hazard models. Hepatitis B and C viruses (HBV/HCV) status and biomarkers of liver function were assessed separately in a nested case-control subset with available blood samples (HCC = 122). In multivariable calibrated models, there was a statistically significant inverse association between total fat intake and risk of HCC (per 10 g/day, HR = 0.80, 95% CI: 0.65-0.99), which was mainly driven by monounsaturated fats (per 5 g/day, HR = 0.71, 95% CI: 0.55-0.92) rather than polyunsaturated fats (per 5 g/day, HR = 0.92, 95% CI: 0.68-1.25). There was no association between saturated fats (HR = 1.08, 95% CI: 0.88-1.34) and HCC risk. The ratio of polyunsaturated/monounsaturated fats to saturated fats was not significantly associated with HCC risk (per 0.2 point, HR = 0.86, 95% CI: 0.73-1.01). Restriction of analyses to HBV/HCV free participants or adjustment for liver function did not substantially alter the findings. In this large prospective European cohort, higher consumption of monounsaturated fats is associated with lower HCC risk. © 2015 UICC.

Hepatitis B virus DNA integration in hepatocellular carcinoma after interferon-induced disappearance of hepatitis C virus.

PubMed

Tamori, Akihiro; Nishiguchi, Shuhei; Shiomi, Susumu; Hayashi, Takehiro; Kobayashi, Sawako; Habu, Daiki; Takeda, Tadashi; Seki, Shuichi; Hirohashi, Kazuhiro; Tanaka, Hiromu; Kubo, Shoji

2005-08-01

Hepatocellular carcinoma (HCC) has been reported in patients in whom hepatitis C virus (HCV) was eliminated by interferon (IFN) therapy. We examined the pathogenesis of HCC in patients with sustained viral response. Operable HCC developed in 7 of 342 patients cured of HCV infection by IFN monotherapy. No patient abused alcohol or had diabetes mellitus or obesity. Resected specimens of HCC were histologically evaluated. DNA extracted from HCC was examined by polymerase chain reaction (PCR) to locate hepatitis B virus (HBV) DNA. HBV integration sites in human genome were identified by cassette-ligation-mediated PCR. HBV DNA was not amplified in serum samples from any of the seven patients with HCC and was found in liver in four patients. In the latter four patients, HBV DNA was integrated into the human genome of HCC. In two of these patients, covalently closed circular HBV (cccHBV) was also detected. The patients with HBV DNA integration were free of HCV for more than 3 yr. In two of the three patients without HBV DNA integration, the surrounding liver showed cirrhosis. The liver of HCC with HBV DNA integration had not progressed to cirrhosis. Three of the four tumors with HBV integration had one integration site each, located at chromosomes 11q12, 11q22-23, and 22q11, respectively. The other tumor had two integration sites, situated at chromosomes 11q13 and 14q32. At chromosome 11q12, HBV DNA was integrated into protein-coding genome, the function of which remains unclear. Integrated HBV DNA may play a role in hepatocarcinogenesis after the clearance of HCV by IFN treatment.

Metabolomics Profiles of Hepatocellular Carcinoma in a Korean Prospective Cohort: The Korean Cancer Prevention Study-II.

PubMed

Jee, Sun Ha; Kim, Minjoo; Kim, Minkyung; Yoo, Hye Jin; Kim, Hyungyoon; Jung, Keum Ji; Hong, Seri; Lee, Jong Ho

2018-05-01

In the prospective Korean Cancer Prevention Study-II (KCPS-II), we investigated the application of metabolomics to differentiate subjects with incident hepatocellular carcinoma (HCC group) from subjects who remained free of cancer (control group) during a mean follow-up period of 7 years with the aim of identifying valuable metabolic biomarkers for HCC. We used baseline serum samples from 75 subjects with incident HCC and 134 age- and gender-matched cancer-free subjects. Serum metabolic profiles associated with HCC incidence were investigated via metabolomics analysis. Compared with the control group, the HCC group showed significantly higher serum levels of aspartate aminotransferase (AST), alanine aminotransferase, and γ-glutamyl transpeptidase. At baseline, compared with the control group, the HCC group showed significantly higher levels of 9 metabolites, including leucine, 5-hydroxyhexanoic acid, phenylalanine, tyrosine, arachidonic acid, and tauroursodeoxycholic acid (TUDCA), but lower levels of 28 metabolites, including oleamide, androsterone sulfate, L-palmitoylcarnitine, lysophosphatidic acid (LPA) 16:0, LPA 18:1, and lysophosphatidylcholines (lysoPC). Multiple linear regression revealed that the incidence of HCC was associated with the levels of tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA (adjusted R 2 = 0.514, P = 0.036). This study showed the clinical relevance of the dysregulation of not only branched amino acids, aromatic amino acids, and lysoPCs but also bile acid biosynthesis and linoleic acid, arachidonic acid, and fatty acid metabolism. In addition, tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA were identified as independent variables associated with the incidence of HCC. Cancer Prev Res; 11(5); 303-12. ©2018 AACR . ©2018 American Association for Cancer Research.

Clinical features of hepatitis B and C virus infections, with high α-fetoprotein levels but not hepatocellular carcinoma

PubMed Central

Kim, Cha Young; Kim, Bo Ra; Lee, Sang Soo; Jeon, Dae-Hong; Lee, Chang Min; Kim, Wan Soo; Cho, Hyun Chin; Kim, Jin Joo; Lee, Jae Min; Kim, Hong Jun; Ha, Chang Yoon; Kim, Hyun Jin; Kim, Tae Hyo; Jung, Woon Tae; Lee, Ok-Jae

2017-01-01

Abstract The appropriate α-fetoprotein (AFP) level to confirm hepatocellular carcinoma (HCC) could be 100 ng/mL; however, the clinical significance of falsely elevated AFP in patients without HCC has not been fully studied. We investigated the clinical features and outcome of patients without HCC but with high AFP levels (100 ng/mL), especially with chronic hepatitis B (CHB) or C (CHC). The sample included 124 consecutive patients with CHB (n = 97) or CHC (n = 27), with AFP levels >100 ng/mL and without HCC at baseline. Multivariate Cox proportional regression analysis was performed to determine the factors associated with AFP normalization and HCC development. During the mean 52-month follow-up, the proportion of patients with CHB with AFP normalization (90.7%) was significantly higher than the proportion of patients with CHC (59.3%, P < 0.001). Initial aspartate aminotransferase levels (hazard ratio [HR] = 1.02 per 10 U/L increase, P = 0.021) and antiviral therapy (HR = 2.89, P < 0.001) were significantly associated with AFP normalization. Of the 16 (12.9%) patients who developed HCC, hepatitis B virus infection (HR = 10.82, P = 0.001), initiation of antiviral treatment postenrollment (HR = 0.23, P = 0.030), and AFP normalization within 12 months (HR = 0.13, P = 0.011) were associated with HCC development. CHB and CHC were the most common causes of falsely elevated AFP (>100 ng/mL). With either CHB or CHC, persistent AFP elevation (>12 months), regardless of antiviral treatment, might be an important marker of HCC development. PMID:28079817

Increased expression of Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2 correlated with poor prognosis of hepatocellular carcinoma.

PubMed

Yang, Lian-Yue; Tao, Yi-Ming; Ou, Di-Peng; Wang, Wei; Chang, Zhi-Gang; Wu, Fan

2006-10-01

Because of its role in cell migration, the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) 2 has been implicated in cancer metastasis. Evidence to support such a role of WAVE2 in human cancer, however, is lacking. We thus examined the expression of WAVE2 in hepatocellular carcinoma (HCC) tissues to test whether the levels of WAVE2 expression correlated to the progression of HCC. Samples of 112 HCC patients were determined immunohistochemically for WAVE2 expression and the correlation of WAVE2 levels with prognosis was analyzed. Among the 112 cases, 31 paired HCC and paracarcinomatous liver tissue specimens were analyzed for WAVE2 levels by reverse transcription-PCR and Western blotting, respectively. Among 112 cases of HCCs, the immunohistochemistry data indicated significant increase of WAVE2 expression levels in 71 cases. Importantly, the increased WAVE2 expression correlated with the multiple tumor nodules (P = 0.008), the absence of capsular formation (P = 0.035), Edmondson-Steiner grade (P = 0.009), vein invasion (P = 0.023), and a shortened median survival time (326 versus 512 days; P = 0.003). Multivariable Cox regression analysis revealed the WAVE2 expression level was an independent factor for prognosis. The immunohistochemistry data were further confirmed by results of reverse transcription-PCR and Western analysis of 31 HCC cases, in which the WAVE2 mRNA and protein in HCC tissues were significantly elevated when compared with paracarcinomatous liver tissue (P < 0.001). WAVE2 expression is elevated in HCC tissues, which correlates with a poor prognosis, suggesting WAVE2 as a candidate prognostic marker of HCC.

Diagnostic cost groups (DCGs) and concurrent utilization among patients with substance abuse disorders.

PubMed

Rosen, Amy K; Loveland, Susan A; Anderson, Jennifer J; Hankin, Cheryl S; Breckenridge, James N; Berlowitz, Dan R

2002-08-01

To assess the performance of Diagnostic Cost Groups (DCGs) in explaining variation in concurrent utilization for a defined subgroup, patients with substance abuse (SA) disorders, within the Department of Veterans Affairs (VA). A 60 percent random sample of veterans who used health care services during Fiscal Year (FY) 1997 was obtained from VA administrative databases. Patients with SA disorders (13.3 percent) were identified from primary and secondary ICD-9-CM diagnosis codes. Concurrent risk adjustment models were fitted and tested using the DCG/HCC model. Three outcome measures were defined: (1) "service days" (the sum of a patient's inpatient and outpatient visit days), (2) mental health/substance abuse (MH/SA) service days, and (3) ambulatory provider encounters. To improve model performance, we ran three DCG/HCC models with additional indicators for patients with SA disorders. To create a single file of veterans who used health care services in FY 1997, we merged records from all VA inpatient and outpatient files. Adding indicators for patients with mild/moderate SA disorders did not appreciably improve the R-squares for any of the outcome measures. When indicators were added for patients with severe SA who were in the most costly category, the explanatory ability of the models was modestly improved for all three outcomes. Modifying the DCG/HCC model with additional markers for SA modestly improved homogeneity and model prediction. Because considerable variation still remained after modeling, we conclude that health care systems should evaluate "off-the-shelf" risk adjustment systems before applying them to their own populations.

Diagnostics Cost Groups and Concurrent Utilization among Patients

PubMed Central

Rosen, Amy K; Loveland, Susan A; Anderson, Jennifer J; Hankin, Cheryl S; Breckenridge, James N; Berlowitz, Dan R

2002-01-01

Objective To assess the performance of Diagnostic Cost Groups (DCGs) in explaining variation in concurrent utilization for a defined subgroup, patients with substance abuse (SA) disorders, within the Department of Veterans Affairs (VA). Data Sources A 60 percent random sample of veterans who used health care services during Fiscal Year (FY) 1997 was obtained from VA administrative databases. Patients with SA disorders (13.3 percent) were identified from primary and secondary ICD-9-CM diagnosis codes. Study Design Concurrent risk adjustment models were fitted and tested using the DCG/HCC model. Three outcome measures were defined: (1) “service days” (the sum of a patient's inpatient and outpatient visit days), (2) mental health/substance abuse (MH/SA) service days, and (3) ambulatory provider encounters. To improve model performance, we ran three DCG/HCC models with additional indicators for patients with SA disorders. Data Collection To create a single file of veterans who used health care services in FY 1997, we merged records from all VA inpatient and outpatient files. Principal Findings Adding indicators for patients with mild/moderate SA disorders did not appreciably improve the R-squares for any of the outcome measures. When indicators were added for patients with severe SA who were in the most costly category, the explanatory ability of the models was modestly improved for all three outcomes. Conclusions Modifying the DCG/HCC model with additional markers for SA modestly improved homogeneity and model prediction. Because considerable variation still remained after modeling, we conclude that health care systems should evaluate “off-the-shelf” risk adjustment systems before applying them to their own populations. PMID:12236385

WNT10B Functional Dualism: β-Catenin/Tcf-dependent Growth Promotion or Independent Suppression with Deregulated Expression in Cancer

PubMed Central

Yoshikawa, Hirohide; Matsubara, Kenichi; Zhou, Xiaoling; Okamura, Shu; Kubo, Takahiko; Murase, Yaeko; Shikauchi, Yuko; Esteller, Manel; Herman, James G.; Wei Wang, Xin

2007-01-01

We found aberrant DNA methylation of the WNT10B promoter region in 46% of primary hepatocellular carcinoma (HCC) and 15% of colon cancer samples. Three of 10 HCC and one of two colon cancer cell lines demonstrated low or no expression, and 5-aza-2′deoxycytidine reactivated WNT10B expression with the induction of demethylation, indicating that WNT10B is silenced by DNA methylation in some cancers, whereas WNT10B expression is up-regulated in seven of the 10 HCC cell lines and a colon cancer cell line. These results indicate that WNT10B can be deregulated by either overexpression or silencing in cancer. We found that WNT10B up-regulated β-catenin/Tcf activity. However, WNT10B-overexpressing cells demonstrated a reduced growth rate and anchorage-independent growth that is independent of the β-catenin/Tcf activation, because mutant β-catenin–transduced cells did not suppress growth, and dominant-negative hTcf-4 failed to alleviate the growth suppression by WNT10B. Although WNT10B expression alone inhibits cell growth, it acts synergistically with the fibroblast growth factor (FGF) to stimulate cell growth. WNT10B is bifunctional, one function of which is involved in β-catenin/Tcf activation, and the other function is related to the down-regulation of cell growth through a different mechanism. We suggest that FGF switches WNT10B from a negative to a positive cell growth regulator. PMID:17761539

Is exposure to Agent Orange a risk factor for hepatocellular cancer?-A single-center retrospective study in the U.S. veteran population.

PubMed

Krishnamurthy, Padmini; Hazratjee, Nyla; Opris, Dan; Agrawal, Sangeeta; Markert, Ronald

2016-06-01

Approximately 15% to 35% of those with chronic hepatitis C (CHC) related cirrhosis will develop hepatocellular cancer (HCC). With this burden increasing across the globe, identification of risk factors for HCC has become imperative. Exposure to Agent Orange has been implicated as a possible risk factor for liver cancer in a study from the Republic of Korea. However, there has been no study in U.S. veterans with CHC and cirrhosis that has evaluated exposure to Agent Orange as a risk factor for HCC. We conducted a retrospective study of U.S. military veterans diagnosed with CHC and cirrhosis over a period of 14 years to evaluate potential risk factors for HCC including exposure to Agent Orange. We retrospectively reviewed 390 patients with confirmed CHC-related cirrhosis between 2000 and 2013 and identified patients with HCC. We compared demographic, laboratory, and other clinical characteristics of patients with and without HCC. The mean age of the cohort was 51 years (SD =7.5), with the majority being male (98.5%). Seventy-nine of 390 (20.2%) patients developed HCC, diagnosed on average 8 (SD =4.8) years after diagnosis of CHC. Nearly half (49.4%) were Childs A, 40.5% were Childs B, and 10.1% were Childs C. HCC patients were more likely to be African American than non-HCC patients (40.5% vs. 25.4%, P=0.009) and to be addicted to alcohol (86.1% vs. 74.3%, P=0.027). A trend toward significance was seen in the HCC group for exposure to Agent Orange (16.5% vs. 10.0%, P=0.10) and smoking addiction (88.6% vs. 80.7%, P=0.10). Consequently, race, alcohol addiction, Agent Orange exposure, and smoking addiction were included in the multivariable logistic regression (MLR) analysis. Alcohol addiction [odds ratio (OR) =2.17; 95% confidence interval (CI), 1.07-4.43] and African American race (OR =2.07; 95% CI, 1.22-3.51) were found to be the only two definitive independent risk factors for HCC in our sample. African American race and alcohol addiction were independent risk factors for HCC development in this U.S. veteran population. There was no significant association between exposure to Agent Orange and HCC, although larger studies are needed in the U.S. military veteran population to evaluate further this toxic herbicide from the Vietnam War era.

Management of hepatocellular carcinoma: an overview of major findings from meta-analyses

PubMed Central

Guo, Xiaozhong; Han, Guohong

2016-01-01

This paper aims to systematically review the major findings from meta-analyses comparing different treatment options for hepatocellular carcinoma (HCC). A total of 153 relevant papers were searched via the PubMed, EMBASE, and Cochrane library databases. They were classified according to the mainstay treatment modalities (i.e., liver transplantation, surgical resection, radiofrequency ablation, transarterial embolization or chemoembolization, sorafenib, and others). The primary outcome data, such as overall survival, diseases-free survival or recurrence-free survival, progression-free survival, and safety, were summarized. The recommendations and uncertainties regarding the treatment of HCC were also proposed. PMID:27167195

Miki (Mitotic Kinetics Regulator) Immunoexpression in Normal Liver, Cirrhotic Areas and Hepatocellular Carcinomas: a Preliminary Study with Clinical Relevance.

PubMed

Fernández-Vega, Iván; Santos-Juanes, Jorge; Camacho-Urkaray, Emma; Lorente-Gea, Laura; García, Beatriz; Gutiérrez-Corres, Francisco Borja; Quirós, Luis M; Guerra-Merino, Isabel; Aguirre, José Javier

2018-02-12

Hepatocellular carcinoma (HCC) is the most common type of primary malignant tumor in the liver. One of the main features of cancer survival is the generalized loss of growth control exhibited by cancer cells, and Miki is a protein related to the immunoglobulin superfamily that plays an important role in mitosis. We aim to study protein expression levels of Miki in non-tumoral liver and 20 HCCs recruited from a Pathology Department. Clinical information was also obtained. A tissue microarray was performed, and immunohistochemical techniques applied to study protein expression levels of Miki. In normal liver, Miki was weakly expressed, showing nuclear staining in the hepatocytes. Cirrhotic areas and HCCs showed a variety of staining patterns. Most HCC samples showed positive expression, with three different staining patterns being discernible: nuclear, cytoplasmic and mixed. Statistical analysis showed a significant association between grade of differentiation, Ki-67 proliferative index, survival rates and staining patterns. This study has revealed the positive expression of Miki in normal liver, cirrhotic areas and HCCs. Three different staining patterns of Miki expression with clinical relevance were noted in HCCs.

Stem cell origins and animal models of hepatocellular carcinoma.

PubMed

Aravalli, Rajagopal N; Steer, Clifford J; Sahin, M Behnan; Cressman, Erik N K

2010-05-01

Hepatocellular carcinoma (HCC) is a common malignant tumor that almost always occurs within a preexisting background of chronic liver disease and cirrhosis. Currently, medical therapy is not effective in treating most HCC, and the only hope of cure is either resection or liver transplantation. A small minority of patients is eligible for these therapies, which entail major morbidity at the very least. In spite of immense scientific advances during the past 3 decades, patient survival has improved very little. In order to reduce morbidity and mortality from HCC, improvements in early diagnosis and development of novel local and systemic therapies for advanced disease are essential, in addition to efforts geared towards primary prevention. Studies with experimental animal models that closely mimic human disease are very valuable in understanding physiological, cellular and molecular mechanisms underlying the disease. Furthermore, appropriate animal models have the potential to increase our understanding of the effects of image-guided minimally invasive therapies and thereby help to improve such therapies. In this review, we examine the evidence for stem cell origins of such tumors, critically evaluate existing models and reflect on how to develop new models for minimally invasive, image-guided treatment of HCC.

Family physicians' knowledge and screening of chronic hepatitis and liver cancer.

PubMed

Ferrante, Jeanne M; Winston, Dock G; Chen, Ping-Hsin; de la Torre, Andrew N

2008-05-01

Studies show that primary care providers may suboptimally diagnose, treat, or refer patients with hepatitis C virus (HCV) infection. In addition, little is known about family physicians' knowledge and practices regarding chronic hepatitis B virus (HBV) infection or monitoring for hepatocellular carcinoma (HCC). We used a cross-sectional mail survey of members of the New Jersey Academy of Family Physicians (n=217). Outcome measures were knowledge of risk factors, screening, counseling for chronic HCV and HBV, and screening for HCC. Mean knowledge score for risk factors was 79% (HBV) and 70% (HCV). Physicians who diagnosed >or= six cases per year had higher knowledge of HBV risk factors. Physicians in practice >20 years had lower knowledge of HCV risk factors. Mean knowledge score for counseling was 77%. About 25% screened for liver cancer. Screening for HCC in patients with HBV was related to years in practice, female physicians, and group practice. Physicians in academic settings were more likely to screen patients with HCV for HCC. Forty-two percent and 51% referred patients with chronic HBV and chronic HCV, respectively, to the specialist for total management. Family physicians have insufficient knowledge about screening and counseling for chronic hepatitis and hepatocellular carcinoma.

Adrenalectomy for metastases from hepatocellular carcinoma - a single center experience.

PubMed

Popescu, Irinel; Alexandrescu, Sorin; Ciurea, Silviu; Brasoveanu, Vlad; Hrehoret, Doina; Gangone, Eliza; Boros, Mirela; Herlea, Vlad; Croitoru, Adina

2007-05-01

Adrenal metastases (AM) from hepatocellular carcinoma (HCC) are rarely seen in clinical practice. The treatment is not standardized, the indications and efficacy of different therapeutic approaches being still controversial. Between January 1995 and December 2005, 174 patients underwent liver resection for HCC in our center. AM were detected in four patients (2.3%): three of them had HCC and synchronous AM, and the remaining one developed AM 10 months after liver resection. All the patients with AM were treated by adrenalectomy (simultaneously with liver resection in synchronous metastases), followed by systemic chemotherapy. Non-resectable multifocal liver recurrences occurred in two patients, one of them having also a contralateral adrenal metastasis; these two patients are presently alive 26 and 43 months after adrenalectomy, respectively. Another patient died by liver recurrence 27 months postoperatively. The fourth patient is disease-free at 17 months after the initial operation. Adrenalectomy for AM from HCC should be performed whenever the primary tumor is well therapeutically controlled and the patient has a good performance status. Adrenalectomy offers the chance of more than 2 years survival in many patients. However, once AM are detected, the prognosis remains poor.

Prioritizing Popular Proteins in Liver Cancer: Remodelling One-Carbon Metabolism.

PubMed

Mora, María Isabel; Molina, Manuela; Odriozola, Leticia; Elortza, Félix; Mato, José María; Sitek, Barbara; Zhang, Pumin; He, Fuchu; Latasa, María Uxue; Ávila, Matías Antonio; Corrales, Fernando José

2017-12-01

Primary liver cancer (HCC) is recognized as the fifth most common neoplasm and the second leading cause of cancer death worldwide. Most risk factors are known, and the molecular pathogenesis has been widely studied in the past decade; however, the underlying molecular mechanisms remain to be unveiled, as they will facilitate the definition of novel biomarkers and clinical targets for more effective patient management. We utilize the B/D-HPP popular protein strategy. We report a list of popular proteins that have been highly cocited with the expression "liver cancer". Several enzymes highlight the known metabolic remodeling of liver cancer cells, four of which participate in one-carbon metabolism. This pathway is central to the maintenance of differentiated hepatocytes, as it is considered the connection between intermediate metabolism and epigenetic regulation. We designed a targeted selective reaction monitoring (SRM) method to follow up one-carbon metabolism adaptation in mouse HCC and in regenerating liver following exposure to CCl 4 . This method allows systematic monitoring of one-carbon metabolism and could prove useful in the follow-up of HCC and of chronically liver-diseased patients (cirrhosis) at risk of HCC. The SRM data are available via ProteomeXchange in PASSEL (PASS01060).

Alleles and genotypes of polymorphisms of IL-18, TNF-α and IFN-γ are associated with a higher risk and severity of hepatocellular carcinoma (HCC) in Brazil.

PubMed

Teixeira, A C; Mendes, C T; Marano, L A; Deghaide, N H S; Secaf, M; Elias, J; Muglia, V; Donadi, E A; Martinelli, A L C

2013-08-01

Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver. We evaluated the association of alleles and genotypes of polymorphisms of IL-18 (-607C/A and -137G/C), IFN-γ (+874T/A) and TNF-α (-238G/A and -308G/A) with the risk and severity of HCC. One-hundred-and-twelve patients with HCC and 202 healthy controls were studied. Single nucleotide polymorphisms (SNPs) were amplified by PCR with specific primers and the products were submitted to polyacrylamide gel electrophoresis and stained with silver. We evaluated tumor presentation, tumor size and presence of metastasis. Significant higher risk of HCC was associated with: alleles IL-18 -607(*)A (P=0.0235; OR=1.48; 95%CI=1.06-2.08); TNF-α -238(*)A (P=0.0025; OR=2.12; 95%CI=1.32-3.40) and TNF-α -308(*)A (P=0.0351; OR=1.82; 95%CI=1.07-3.08); and genotypes IL-18-607AA (P=0.0048; OR=3.03; 95%CI=1.40-6.55); TNF-α -238GA (P=0.0011; OR=2.44; 95%CI=1.45-4.12); and TNF-α -308GA (P=0.0031; OR=2.51; 95%CI=1.39-4.51). Significant association was found between multinodular HCC and IL-18 -607(*)C allele (P=0.029; OR=2.40, 95%CI: 1.09-5.28), and IL-18 -607CC genotype (P=0.028; OR=3.5, 95%CI: 1.24-9.86). Diffuse HCC was significantly associated with IFN-γ +874TA genotype (P=0.044; OR=3.6, 95%CI: 1.03-12.47). The IL-18 -137(∗)C allele showed a significant association with the presence of metastasis. Thus, IL-18 -607(*)A and TNF-α (-238(*)A and -308(*)A) alleles may confer susceptibility to HCC, while IL-18 -607(*)C and -137(*)C alleles more severe disease. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

MicroRNA-876-5p inhibits epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by targeting BCL6 corepressor like 1.

PubMed

Xu, Qiuran; Zhu, Qiaojuan; Zhou, Zhenyu; Wang, Yufeng; Liu, Xin; Yin, Guozhi; Tong, Xiangmin; Tu, Kangsheng

2018-07-01

Our previous study has reported that BCL6 corepressor like 1 (BCORL1) plays an oncogenic role in hepatocellular carcinoma (HCC) via promoting epithelial-mesenchymal transition (EMT) and tumor metastasis. However, the regulation of BCORL1 mediated by microRNAs (miRNAs) remains poorly known. The analysis of our clinical samples indicated that BCORL1 expression was markedly higher in HCC tissues than that in tumor-adjacent normal tissues. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed that high BCORL1 expression associated with high tumor grade, advanced tumor stage and poor survival of HCC patients. miR-875-5p expression was down-regulated and negatively correlated with BCORL1 mRNA expression in HCC tissues. Furthermore, miR-876-5p inversely regulated BCORL1 abundance in HCC cells by directly targeting the 3'-untranslated region (3'-UTR) of BCORL1. Ectopic expression of miR-876-5p suppressed cell migration and invasion in both HCCLM3 and MHCC97H cells. In accordance, miR-876-5p knockdown promoted the metastatic behaviors of Hep3B cells. Mechanistically, miR-876-5p suppressed the EMT progression of HCC cells. HCC tissues with high miR-876-5p level showed a higher E-cadherin staining compared to cases with low miR-876-5p level. Moreover, the repression of cell metastasis mediated by miR-876-5p was rescued by BCORL1 restoration in HCCLM3 cells. Notably, low miR-876-5p expression associated with venous infiltration, high tumor grade and advanced tumor stage. HCC patients with low miR-876-5p expression had a significant poorer overall survival and disease-free survival. To conclude, miR-876-5p inhibits EMT progression, migration and invasion of HCC cells by targeting BCORL1. Therefore, miR-876-5p/BCORL1 axis may represent as a novel therapeutic target for HCC treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Phase 2 study of stereotactic body radiotherapy and optional transarterial chemoembolization for solitary hepatocellular carcinoma not amenable to resection and radiofrequency ablation.

PubMed

Takeda, Atsuya; Sanuki, Naoko; Tsurugai, Yuichiro; Iwabuchi, Shogo; Matsunaga, Kotaro; Ebinuma, Hirotoshi; Imajo, Kento; Aoki, Yousuke; Saito, Hidetsugu; Kunieda, Etsuo

2016-07-01

Curative treatment options for patients with early stage hepatocellular carcinoma (HCC) include resection, liver transplantation, and percutaneous ablation therapy. However, even patients with solitary HCC are not always amenable to these treatments. The authors prospectively investigated the clinical outcomes of patients who received stereotactic body radiotherapy (SBRT) for solitary HCC. A phase 2 study involving SBRT and optional transarterial chemoembolization (TACE) was conducted in patients with Child-Pugh grade A or B and underlying, solitary HCC (greatest tumor dimension, ≤4 cm) who were unsuitable candidates for resection and radiofrequency ablation. The prescription dose was 35 to 40 grays in 5 fractions. The primary endpoint was 3-year local tumor control. From 2007 to 2012, 101 patients were enrolled, and 90 were evaluable with a median follow-up of 41.7 months (range, 6.8-96.2 months). Thirty-two patients were treatment-naïve, 20 were treated for newly diagnosed intrahepatic failure, and 38 were treated for residual or recurrent HCC as salvage therapy. Thirty-two patients did not receive TACE, 48 received insufficient TACE, and 10 attained full lipiodol accumulation. The 3-year local control rate was 96.3%, the 3-year liver-related cause-specific survival rate was 72.5%, and the overall survival rate was 66.7%. Grade 3 laboratory abnormalities were observed in 6 patients, and 8 patients had Child-Pugh scores that worsened by 2 points. SBRT achieved high local control and overall survival with feasible toxicities for patients with solitary HCC, despite rather stringent conditions. SBRT can be effective against solitary HCC in treatment-naive, intrahepatic failure, residual disease, and recurrent settings, taking advantage of its distinctive characteristics. Cancer 2016;122:2041-9. © 2016 American Cancer Society. © 2016 American Cancer Society.

Dual-Selective and Dual-Enhanced SERS Nanoprobes Strategy for Circulating Hepatocellular Carcinoma Cells Detection.

PubMed

Pang, Yuanfeng; Wang, Chongwen; Xiao, Rui; Sun, Zhiwei

2018-05-11

The detection of hepatocellular carcinoma (HCC) circulating tumor cells (CTCs) from a blood sample can be a very powerful noninvasive approach for the early detection and therapy of liver cancer. However, the extreme rarity of tumor cells in blood containing billions of other cells makes the capture and identification of CTCs with sufficient sensitivity and specificity a real challenge. Here, a magnetically assisted surface-enhanced Raman scattering (SERS) biosensor for HCC CTC detection is reported for the first time. The biosensor consists of two basic elements: anti-ASGPR antibody-Fe 3 O 4 @Ag magnetic nanoparticles and anti-GPC3 antibody-Au@Ag@DTNB nanorods. According to the dual-selectivity of the anti-ASGPR and anti-GPC3 antibodies and the dual-enhancement SERS signal of the MNPs silver shell and the Au@Ag NRs SERS tags, a limit of detection of 1 cell mL -1 for HCC CTC in human peripheral blood samples with a linear relationship from 1 to 100 cells mL -1 can be obtained. The system shows good performance in real serum, which suggests it may be a promising tool for HCC clinical diagnosis. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

MiR-20a Induces Cell Radioresistance by Activating the PTEN/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Yuqin; Zheng, Lin; Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province

2015-08-01

Purpose: To investigate the role of miR-20a in hepatocellular carcinoma (HCC) cell radioresistance, which may reveal potential strategies to improve treatment. Methods and Materials: The expression of miR-20a and PTEN were detected in HCC cell lines and paired primary tissues by quantitative real-time polymerase chain reaction. Cell radiation combined with colony formation assays was administrated to discover the effect of miR-20a on radiosensitivity. Bioinformatics prediction and luciferase assay were used to identify the target of miR-20a. The phosphatidylinositol 3-kinase inhibitor LY294002 was used to inhibit phosphorylation of Akt, to verify whether miR-20a affects HCC cell radioresistance through activating the PTEN/PI3K/Aktmore » pathway. Results: MiR-20a levels were increased in HCC cell lines and tissues, whereas PTEN was inversely correlated with it. Overexpression of miR-20a in Bel-7402 and SMMC-7721 cells enhances their resistance to the effect of ionizing radiation, and the inhibition of miR-20a in HCCLM3 and QGY-7701 cells sensitizes them to it. PTEN was identified as a direct functional target of miR-20a for the induction of radioresistance. Overexpression of miR-20a activated the PTEN/PI3K/Akt signaling pathway. Additionally, the kinase inhibitor LY294002 could reverse the effect of miR-20a–induced radioresistance. Conclusion: MiR-20a induces HCC cell radioresistance by activating the PTEN/PI3K/Akt pathway, which suggests that miR-20a/PTEN/PI3K/Akt might represent a target of investigation for developing effective therapeutic strategies against HCC.« less

PCDH20 functions as a tumour-suppressor gene through antagonizing the Wnt/β-catenin signalling pathway in hepatocellular carcinoma

PubMed Central

Lv, J; Zhu, P; Yang, Z; Li, M; Zhang, X; Cheng, J; Chen, X; Lu, F

2015-01-01

Several members of protocadherins have been found involved in human carcinogenesis, but little is known about PCDH20 in HCC. Here in this study, using quantitative real-time RT-PCR assay, we demonstrated the downregulation of PCDH20 expression in 6 of 7 HCC cell lines tested. Similarly, PCDH20 expression in primary HCC tissues was also significantly downregulated in comparison with that in either disease-free normal liver tissues or the adjacent nontumour liver tissues (P < 0.001, respectively). Among HCC tumour tissues studied, about 48% (51/107) of them showed reduced PCDH20 mRNA level. Further statistic analysis revealed that the reduced PCDH20 mRNA level in tumour tissues was much more common in younger patients group (aged <50 years) than that in older group (≥50 years) (60% vs 33%, P = 0.0303). Loss of heterozygosity (LOH) and promoter hypermethylation analysis revealed that deletion and/or aberrant epigenetic modulation of PCDH20 gene account for its downregulation, at least in a fraction of tumour specimens. Moreover, ectopic expression of PCDH20 in HCC cells significantly suppressed cell proliferation, clonogenicity, migration and tumour formation. Notably, we proved for the first time that, via activating GSK-3β, PCDH20 could inhibit Wnt/β-catenin signalling pathway. Furthermore, our data suggest that PCDH20 may conduct its Wnt/β-catenin signalling antagonizing function through suppressing Akt and Erk activities and promoting GSK-3β signalling activities. However, the detailed mechanism remained undiscovered. In conclusion, our data here strongly suggested that PCDH20 may act as a candidate tumour suppressor in HCC. PMID:24910204

Niemann-Pick type C2 protein regulates liver cancer progression via modulating ERK1/2 pathway: Clinicopathological correlations and therapeutical implications.

PubMed

Liao, Yi-Jen; Fang, Cheng-Chieh; Yen, Chia-Hung; Hsu, Shih-Ming; Wang, Chung-Kwe; Huang, Shiu-Feng; Liang, Yu-Chih; Lin, Ying-Yu; Chu, Yu-Tseng; Arthur Chen, Yi-Ming

2015-09-15

Primary hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related death. It is important to identify new targets for early diagnosis and treatment of HCC. Niemann-Pick type C2 (NPC2) plays an important role in the regulation of intracellular cholesterol homeostasis via direct binding with free cholesterol. However, little is known about the significance of NPC2 in HCC tumorigenesis. In this study, we showed that NPC2 is abundantly expressed in normal liver, but is downregulated in human HCC tissues. The patients with NPC2 downregulation expressed much higher α-fetoprotein, multiple tumor type, vascular invasion, later pathological stage and shorter survival rate. Knockdown NPC2 in liver cancer cell lines promote cell proliferation, migration and xenograft tumorigenesis. In contrast, NPC2 overexpression inhibits HuH7 promoted tumor growth. Furthermore, administration of hepatotropic adeno-associated virus 8 (AAV8) delivered NPC2 decreased the inflammatory infiltration, the expression of two early HCC markers-glypican 3 and survivin and suppressed the spontaneous HCC development in mice. To identify the NPC2-dependent mechanism, we emphasized on the status of MAPK/ERK signaling. MEK1/2 inhibitor treatment demonstrated that the expression of NPC2 affected the activation of ERK1/2 but not MEK1/2. In addition, cholesterol trafficking inhibitor treatment did not alter the cell proliferation and the activation of MEK/ERK. In conclusion, our study demonstrates that NPC2 may play an important role in negatively regulate cell proliferation and ERK1/2 activation that were independent of cholesterol accumulation. AAV-NPC2 may thus represent a new treatment strategy for liver cancer. © 2015 UICC.

Hepatocellular Carcinoma Surveillance Among Cirrhotic Patients With Commercial Health Insurance.

PubMed

Goldberg, David S; Valderrama, Adriana; Kamalakar, Rajesh; Sansgiry, Sujit S; Babajanyan, Svetlana; Lewis, James D

2016-03-01

To evaluate hepatocellular carcinoma (HCC) surveillance rates among commercially insured patients, and evaluate factors associated with compliance with surveillance recommendations. Most HCC occurs in patients with cirrhosis. American Association for the Study of Liver Diseases and European Association for the Study of the Liver guidelines each recommend biannual HCC surveillance for cirrhotic patients to diagnose HCC at an early, curable stage. However, compliance with these guidelines in commercially insured patients is unknown. We used the Truven Health Analytics databases from 2006 to 2010, using January 1, 2006 as the anchor date for evaluating outcomes. The primary outcome was continuous surveillance measure, defined as the proportion of time "up-to-date" with surveillance (PTUDS), with the 6-month interval immediately following each ultrasound categorized as "up-to-date." During a median follow-up of 22.9 (interquartile range, 16.3 to 33.9) months among 8916 cirrhotic patients, the mean PTUDS was 0.34 (SD, 0.29), and the median was 0.31 (interquartile range, 0.03 to 0.52). These values increased only modestly with inclusion of serum alpha-fetoprotein testing, contrast-enhanced abdominal computed tomographic scans or magnetic resonance imagings, and/or extension of up-to-date time to 12 months. Being diagnosed by a nongastroenterology provider and increasing age were significantly associated with decreased HCC surveillance (P<0.05), whereas a history of a hepatic decompensation event, presence of any component of the metabolic syndrome, and diagnosis of hepatitis B or hepatitis C were significantly associated with increased surveillance (P<0.05). However, even among patients with the most favorable characteristics, surveillance rates remained low. HCC surveillance rates in commercially insured at-risk patients remain poor despite formalized guidelines, highlighting the need to develop interventions to improve surveillance rates.

Low-dose intermittent interferon-alpha therapy for HCV-related liver cirrhosis after curative treatment of hepatocellular carcinoma

PubMed Central

Jeong, Soocheol; Aikata, Hiroshi; Katamura, Yoshio; Azakami, Takahiro; Kawaoka, Tomokazu; Saneto, Hiromi; Uka, Kiminori; Mori, Nami; Takaki, Shintaro; Kodama, Hideaki; Waki, Koji; Imamura, Michio; Shirakawa, Hiroo; Kawakami, Yoshiiku; Takahashi, Shoichi; Chayama, Kazuaki

2007-01-01

AIM: To assess the efficacy of low-dose intermittent interferon (IFN) therapy in patients with hepatitis C virus (HCV)-related compensated cirrhosis who had received curative treatment for primary hepatocellular carcinoma (HCC). METHODS: We performed a prospective case controlled study. Sixteen patients received 3 MIU of natural IFN-alpha intramuscularly 3 times weekly for at least 48 wk (IFN group). They were compared with 16 matched historical controls (non-IFN group). RESULTS: The cumulative rate of first recurrence of HCC was not significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 68.6% vs 80% at 1- and 3-year, P = 0.157, respectively). The cumulative rate of second recurrence was not also significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 35.9% vs 67% at 1- and 3-year, P = 0.056, respectively). Although the difference in the Child-Pugh classification score between the groups at initial treatment of HCC was not significant, the score was significantly worse at the time of data analysis in the non-IFN group than IFN group (7.19 ± 1.42 vs 5.81 ± 0.75, P = 0.0008). The cumulative rate of deviation from objects of any treatment for recurrent HCC was also higher in the non-IFN group than IFN group (6.7% and 27% vs 0 and 0% at 1- and 3-year, P = 0.048, respectively). CONCLUSION: Low-dose intermittent IFN-alpha therapy for patients with HCV-related compensated cirrhosis after curative HCC treatment was effective by making patients tolerant to medical or surgical treatment for recurrent HCC in the later period of observation. PMID:17876889

Transjugular Intrahepatic Portosystemic Shunt for Portal Hypertension in Hepatocellular Carcinoma with Portal Vein Tumor Thrombus.

PubMed

Qiu, Bin; Li, Kai; Dong, Xiaoqun; Liu, Fu-Quan

2017-09-01

In patients with hepatocellular carcinoma (HCC), limited therapeutic options are available for portal hypertension resulted from portal vein tumor thrombus (PVTT). We aimed to determine safety and efficacy of TIPS for treatment of symptomatic portal hypertension in HCC with PVTT. We evaluated clinical characteristics of 95 patients with HCC and PVTT out of 992 patients who underwent TIPS. The primary endpoints included success rate, procedural mortality, serious complications, decrease in portosystemic pressure gradient, and symptom relief. The secondary endpoints included recurrence of portal hypertension, overall survival, adverse events related to treatments for HCC, and quality of life measured by Karnofsky Performance Status Scale (KPS). Success rate of TIPS was 95.8% (91/95), with procedural mortality of 1.1%. Serious complications related to TIPS procedure occurred in 2.1% (2/95) of patients. The symptoms of portal hypertension were well relieved. Variceal bleeding was successfully controlled and terminated in 100% of patients, with a recurrence rate of 39.2% in 12 months. Refractory ascites/hydrothorax was controlled partially or completely in 92.9% of patients during 1 month after TIPS, with a recurrence rate of 17.9% in 12 months. Survival rate at 6, 12, 24, and 36 months was 75.8, 52.7, 26.4, and 3.3%, respectively. No unexpected adverse event related to treatments for HCC was observed. The KPS score was 49 ± 4.5 and 63 ± 4.7 before and 1 month after TIPS, respectively (p < 0.001). TIPS is a safe and efficacious treatment for symptomatic portal hypertension in HCC with PVTT.

Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma

PubMed Central

Lacotte, Stéphanie; Slits, Florence; Orci, Lorenzo A.; Meyer, Jeremy; Oldani, Graziano; Gonelle-Gispert, Carmen; Morel, Philippe; Toso, Christian

2016-01-01

ABSTRACT Kupffer cells represent the first line of defense against tumor cells in the liver. Myeloid-derived suppressor cells (MDSC) have recently been observed in the liver parenchyma of tumor-bearing animals. The present study investigates the function of the MDSC subsets, and their impact on Kupffer cell phenotype and function. RIL-175 mouse hepatocellular carcinoma (HCC) cells were injected into the median liver lobe of C57BL/6 mice. Three weeks later, the median lobe hosting the tumor nodule was removed, and Kupffer cells and MDSCs were sorted from the remaining liver. Mouse livers devoid of HCC served as control. Kupffer cells expressed less co-stimulatory CD86 and MHCII and more co-inhibitory CD274 molecules in HCC-bearing livers than in control livers. Corresponding to this phenotype, Kupffer cells from HCC-bearing mice were less efficient in their function as antigen-presenting cells. Three CD11b+ cell populations were identified and sorted from HCC-bearing mice. These cells had various phenotypes with different levels of MDSC-specific surface markers (Ly6Ghigh cells, Gr1high cells, and Ly6Clow cells), and may be considered as bonafide MDSCs given their suppression of antigen-specific T cell proliferation. Primary isolated Kupffer cells in co-culture with the three MDSC subsets showed a decrease in CCL2 and IL-18 secretion, and an increase in IL-10 and IL-1β secretion, and an increased expression of CD86, CD274, and MHCII. In conclusion, these data demonstrated the existence of three MDSC subsets in HCC-bearing animals. These cells altered Kupffer cell function and may decrease the migration and activation of anticancer effector cells in the liver. PMID:27999748

Diagnostic accuracy of des-gamma-carboxy prothrombin for hepatocellular carcinoma in a French cohort using the Lumipulse® G600 analyzer.

PubMed

Sultanik, P; Ginguay, A; Vandame, J; Popovici, T; Meritet, J-F; Cynober, L; Pol, S; Bories, P-N

2017-01-01

The increasing incidence of hepatocellular carcinoma (HCC) in Western countries requests reliable tumour markers for preclinical diagnosis. We evaluated the diagnostic accuracy of des-gamma-carboxy prothrombin (DCP), in comparison with alpha-fetoprotein (AFP) in a French cohort using a new analyser. One hundred and sixty-two patients with virus-related cirrhosis (46 HCC patients and 116 controls) were recruited in this retrospective proof-of-concept study. DCP was measured on new Lumipulse ® G600 analyzer and AFP on usual Cobas e602 analyzer in serum samples that were collected at the time of HCC diagnosis for HCC patients or during follow-up for controls. DCP and AFP levels were higher in HCC patients. The area under receiver operating characteristic curve was larger for DCP than for AFP (0.89 vs 0.77, P=.03). At the cut-off value of 128 mAU/mL, sensitivity and specificity for DCP were 74% and 92%. At the cut-off value of 20 μg/L, sensitivity and specificity for AFP were 63% and 82%. NRI >0 for the association of "AFP+DCP" were 101%, P<.0001, and 23%, P=.03, compared to "AFP" or "DCP" alone, respectively. We conclude that DCP outperformed AFP for the detection of HCC. © 2016 John Wiley & Sons Ltd.

Associations of work stress with hair cortisol concentrations - initial findings from a prospective study.

PubMed

Herr, Raphael M; Almer, Christian; Loerbroks, Adrian; Barrech, Amira; Elfantel, Irina; Siegrist, Johannes; Gündel, Harald; Angerer, Peter; Li, Jian

2018-03-01

There is ample evidence supporting the link between stress at the workplace and physical and mental health. One of the pathways potentially mediating those associations may involve the hypothalamic-pituitary-adrenal (HPA) axis, with cortisol as an end product. While theoretically plausible, findings on the association of self-reported work stress with hair cortisol concentrations (HCC) are inconclusive, being potentially biased by omitted pertinent factors. This issue can be addressed, among others, by eliminating time-invariant factors through consideration of variation within persons over time. To this end, the present study examined the association between variation in HCC and perceived work stress - as assessed by the Effort-Reward-Imbalance (ERI) model - between two points in time (t1 and t2) over one year in a sample of 40 male factory workers. Neither a cross-sectional association, nor a link between change in ERI and HCC levels at t2 was observed. There was however a robust association of the change in ERI with the change of HCC. This effect was independent of baseline HCC and other confounders (Beta = 0.414, S.E. = 0.155, p = 0.012). Accordingly, this is the first study revealing prospective evidence for the associations of work stress with HCC, while excluding potentially time-stable confounding factors, like genetic factors or phenotypic hair color. Copyright © 2018 Elsevier Ltd. All rights reserved.

Analysis of Serum Haptoglobin Fucosylation in Hepatocellular Carcinoma and Liver Cirrhosis of Different Etiologies

PubMed Central

2015-01-01

We have developed herein a quantitative mass spectrometry-based approach to analyze the etiology-related alterations in fucosylation degree of serum haptoglobin in patients with liver cirrhosis and hepatocellular carcinoma (HCC). The three most common etiologies, including infection with hepatitis B virus (HBV), infection with hepatitis C virus (HCV), and heavy alcohol consumption (ALC), were investigated. Only 10 μL of serum was used in this assay in which haptoglobin was immunoprecipitated using a monoclonal antibody. The N-glycans of haptoglobin were released with PNGase F, desialylated, and permethylated prior to MALDI-QIT-TOF MS analysis. In total, N-glycan profiles derived from 104 individual patient samples were quantified (14 healthy controls, 40 cirrhosis, and 50 HCCs). A unique pattern of bifucosylated tetra-antennary glycan, with both core and antennary fucosylation, was identified in HCC patients. Quantitative analysis indicated that the increased fucosylation degree was highly associated with HBV- and ALC-related HCC patients compared to that of the corresponding cirrhosis patients. Notably, the bifucosylation degree was distinctly increased in HCC patients versus that in cirrhosis of all etiologies. The elevated bifucosylation degree of haptoglobin can discriminate early stage HCC patients from cirrhosis in each etiologic category, which may be used to provide a potential marker for early detection and to predict HCC in patients with cirrhosis. PMID:24807840

Global profiling of alternative RNA splicing events provides insights into molecular differences between various types of hepatocellular carcinoma.

PubMed

Tremblay, Marie-Pier; Armero, Victoria E S; Allaire, Andréa; Boudreault, Simon; Martenon-Brodeur, Camille; Durand, Mathieu; Lapointe, Elvy; Thibault, Philippe; Tremblay-Létourneau, Maude; Perreault, Jean-Pierre; Scott, Michelle S; Bisaillon, Martin

2016-08-26

Dysregulations in alternative splicing (AS) patterns have been associated with many human diseases including cancer. In the present study, alterations to the global RNA splicing landscape of cellular genes were investigated in a large-scale screen from 377 liver tissue samples using high-throughput RNA sequencing data. Our study identifies modifications in the AS patterns of transcripts encoded by more than 2500 genes such as tumor suppressor genes, transcription factors, and kinases. These findings provide insights into the molecular differences between various types of hepatocellular carcinoma (HCC). Our analysis allowed the identification of 761 unique transcripts for which AS is misregulated in HBV-associated HCC, while 68 are unique to HCV-associated HCC, 54 to HBV&HCV-associated HCC, and 299 to virus-free HCC. Moreover, we demonstrate that the expression pattern of the RNA splicing factor hnRNPC in HCC tissues significantly correlates with patient survival. We also show that the expression of the HBx protein from HBV leads to modifications in the AS profiles of cellular genes. Finally, using RNA interference and a reverse transcription-PCR screening platform, we examined the implications of cellular proteins involved in the splicing of transcripts involved in apoptosis and demonstrate the potential contribution of these proteins in AS control. This study provides the first comprehensive portrait of global changes in the RNA splicing signatures that occur in hepatocellular carcinoma. Moreover, these data allowed us to identify unique signatures of genes for which AS is misregulated in the different types of HCC.

[Comparative analysis of TACE alone or plus RFA in the treatment of 167 cases of intermediate and advanced staged primary hepatocellular carcinoma].

PubMed

Zhao, Ming; Wang, Jian-peng; Wu, Pei-hong; Zhang, Fu-jun; Huang, Zi-lin; Li, Wang; Zhang, Liang; Pan, Chang-chuan; Li, Chuan-xing; Jiang, Yong

2010-11-09

To evaluate the clinical efficacy and survival rate of transarterial chemoembolization (TACE) alone or plus radiofrequency ablation (RFA) in patients with intermediate or advanced stage primary hepatocellular carcinoma (HCC). In this retrospective study, 467 cases received RFA or TACE plus RFA. Among them, 167 cases with strict clinical procedure (TACE alone or plus RFA) and complete follow-up data were included. Eighty-seven cases received TACE and 80 cases had TACE plus RFA between January 2000 and December 2006. Hierarchical analyses were performed using log-rank tests and survival curve was estimated by Kaplan-Meier method. A total of 167 patients received TACE alone or plus RFA for a follow-up period of 1 to 89 months. In the TACE alone group, the time-to-progression (TTP) was an average of 3.6 months. The median survival was 13 months, one-year survival rate 52.9%, three-year survival rate 11.5% and five-year survival rate 4.6%. In the TACE plus RFA group, the TTP time was an average of 10.8 months. The median survival time was 30 months, one-year survival rate 85.0%, three-year survival rate 45.0% and five-year survival rate 11.3%. In the TACE alone group, the median survival of intermediate stage HCC was 14 months, one-year survival rate 62.2%, three-year survival rate 13.3% and five-year survival rate 4.4%; In the TACE plus RFA group, the median survival of intermediate stage HCC was 14 months, one-year survival rate 90.1%, three-year survival rate 52.9% and five-year survival rate 13.7%. All differences of two groups has statistical significance (P < 0.05). In intermediate stage HCC, the median survival of TACE alone group was 14 months, one-year survival rate 62.2%, three-year survival rate 13.3%, five-year survival rate 4.4% versus 32 months, 90.1%, 52.9%, 13.7% in the TACE plus RFA group respectively. For the advanced stage HCC, the median survival time was 12 months, one-year survival rate 35%, three-year survival rate 7.1% and five-year survival rate 0 in the TACE alone group versus 28 months, 62.1%, 24.1% and 6.9% in the TACE plus RFA group (P = 0.00). There was significantly statistic difference between both groups in intermediate and advanced staging HCC. Among them, 60/485 (12.4%) patients required a therapy of post-TACE hepatic dysfunctions versus 13/168 (7.7%) in the TACE plus RFA group (P = 0.004, ANOVA method). The regimen of TACE plus RFA has the advantages of tumor control, liver function protection and survival extending in the treatment of HCC than TACE alone in intermediate or advanced stage HCC.

NOTE: Characterization of cirrhosis and hepatocellular carcinoma using low-angle x-ray scattering signatures of serum

NASA Astrophysics Data System (ADS)

Elshemey, Wael M.; Desouky, Omar S.; Mohammed, Mohammed S.; Elsayed, Anwar A.; El-houseini, Motawa E.

2003-09-01

The diagnosis of hepatocellular carcinoma (HCC) usually occurs at late stages in the disease when there are few effective treatment options. The measurement of the concentration of tumour markers in the serum of patients is a complementary tool frequently used for the interpretation of diagnostic imaging results. It is also used as a prognostic tool for the detection of cancer. Unfortunately, the sensitivity of tumour markers is still low and many times it yields normal results for cirrhotic and HCC patients. In the current work, the detection possibility of the structural changes in serum proteins accompanying cirrhosis and HCC is investigated using a low-angle x-ray scattering (LAXS) technique. The results show that there are significant differences in the LAXS profiles of cirrhosis and HCC lyophilized serum samples compared to normal. The changes in shape, total counts and position of the first scattering peak at 4.8°, which was previously reported to be sensitive to the structural changes in protein, showed the most characteristic deviations from normal serum. The present results are promising and would offer a potentially helpful complementary tool for monitoring cirrhosis and HCC.

[Regression and therapy-resistance of primary liver tumors and liver metastases after regional chemotherapy and local tumor ablation].

PubMed

Fischer, H-P

2005-05-01

High dosage regional chemotherapy, chemoembolization and other methods of regional treatment are commonly used to treat unresectable primary liver malignancies and liver metastases. In liver malignancies of childhood neoadjuvant chemotherapy is successfully combined with surgical treatment. Chemotherapy and local tumor ablation lead to characteristic histomorphologic changes: Complete destruction of the tumor tissue and its vascular bed is followed by encapsulated necroses. After selective eradication of the tumor cells under preservation of the fibrovasular bed the tumor is replaced by hypocellular edematous and fibrotic tissue. If completely damaged tumor tissue is absorbed quickly, the tumor area is replaced by regenerating liver tissue. Obliterating fibrohyalinosis of tumor vessels, and perivascular edema or necrosis indicate tissue damage along the vascular bed. Degenerative pleomorphism of tumor cells, steatosis, hydropic swelling and Malloryhyalin in HCC can represent cytologic findings of cytotoxic cellular damage. Macroscopic type of HCC influences significantly the response to treatment. Multinodular HCC often contain viable tumor nodules close to destroyed nodules after treatment. Encapsulated uninodular tumors undergo complete necrosis much easier. Large size and a tumor capsule limitate the effect of percutaneous injection of ethanol into HCC. In carcinomas with an infiltrating border, especially in metastases of adenocarcinomas and hepatic cholangiocarcinoma cytostatic treatment damages the tumor tissue mainly in the periphery. Nevertheless the infiltrating rim, portal veins, lymphatic spaces and bile ducts as well as the angle between liver capsule, tumor nodule and bordering parenchyma are the main refugees of viable tumor tissue even after high dosage regional chemotherapy. This local resistance is caused by special local conditions of vascularization and perfusion. These residues are the source of local tumor progression and distant metastases. Besides intrinsic cellular mechanisms architectural, and microenvironmental factors relevantly limitate the effect of intensive locoregional therapy.

Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

PubMed Central

Kawata, S; Yamasaki, E; Nagase, T; Inui, Y; Ito, N; Matsuda, Y; Inada, M; Tamura, S; Noda, S; Imai, Y; Matsuzawa, Y

2001-01-01

Chemotherapy is not effective for hepatocellular carcinoma (HCC). HMG-CoA redutase inhibitors have cytostatic activity for cancer cells, but their clinical usefulness is unknown. To investigate whether pravastatin, a potent HMG-CoA reductase inhibitor, prolongs survival in patients with advanced HCC, this randomized controlled trial was conducted between February 1990 and February 1998 at Osaka University Hospital. 91 consecutive patients <71 years old (mean age 62) with unresectable HCC were enroled in this study. 8 patients were withdrawn because of progressive liver dysfunction; 83 patients were randomized to standard treatment with or without pravastatin. All patients underwent transcatheter arterial embolization (TAE) followed by oral 5-FU 200 mg−1d for 2 months. Patients were then randomly assigned to control (n = 42) and pravastatin (n = 41) groups. Pravastatin was administered at a daily dose of 40 mg. The effect of pravastatin on tumour growth was assessed by ultrasonography. Primary endpoint was death due to progression of HCC. The duration of pravastatin administration was 16.5 ± 9.8 months (mean ± SD). No patients in either group were lost to follow-up. Median survival was 18 months in the pravastatin group versus 9 months in controls (P = 0.006). The Cox proportional hazards model showed that pravastatin was a significant factor contributing to survival. Pravastatin prolonged the survival of patients with advanced HCC, suggesting its value for adjuvant treatment. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11286466

Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice

PubMed Central

Yamada, Shoji; Takashina, Yoko; Watanabe, Mitsuhiro; Nagamine, Ryogo; Saito, Yoshimasa; Kamada, Nobuhiko; Saito, Hidetsugu

2018-01-01

Gut microbiota plays a significant role in the development of hepatocellular carcinoma (HCC) in non-alcoholic steatohepatitis (NASH). However, understanding of the precise mechanism of this process remains incomplete. A new class steatohepatitis-inducing high-fat diet (HFD), namely STHD-01, can promote the development of HCC without the administration of chemical carcinogens. Using this diet, we comprehensively analyzed changes in the gut microbiota and its metabolic functions during the development of HCC in NASH. Mice fed the STHD-01 developed NASH within 9 weeks. NASH further progressed into HCC by 41 weeks. Treatment with antibiotics significantly attenuated liver pathology and suppressed tumor development, indicating the critical role of the gut microbiota in tumor development in this model. Accumulation of cholesterol and bile acids in the liver and feces increased after feeding the mice with STHD-01. Treatment with antibiotics did not reverse these phenotypes. In contrast, accumulation of secondary bile acids was dramatically reduced after the treatment with antibiotics, suggesting the critical role of the gut microbiota in the conversion of primary bile acids to secondary bile acids. Secondary bile acids such as deoxycholic acid activated the mTOR, pathway in hepatocytes. Activation of mTOR was observed in the liver of mice fed STHD-01, and the activation was reduced when mice were treated with antibiotics. Collectively, bile acid metabolism by the gut microbiota promotes HCC development in STHD-01-induced NASH. PMID:29515780

A systematic review of publications on charged particle therapy for hepatocellular carcinoma.

PubMed

Igaki, Hiroshi; Mizumoto, Masashi; Okumura, Toshiyuki; Hasegawa, Kiyoshi; Kokudo, Norihiro; Sakurai, Hideyuki

2018-06-01

Charged particle therapy (proton beam therapy and carbon ion therapy) is a form of radiotherapy which has the unique characteristic of superior depth dose distribution, and has been used for the treatment of hepatocellular carcinoma (HCC) in a limited number of patients, especially in Japan. We undertook a systematic review to define the clinical utility of charged particle therapy for patients with HCC. We searched the MEDLINE database from 1983 to June 2016 to identify clinical studies on charged particle therapy for HCC. Primary outcomes of interest were local control, overall survival, and late radiation morbidities. A total of 13 cohorts from 11 papers were selected from an initial dataset of 78 papers. They included a randomized controlled trial comparing proton beam therapy with transarterial chemoembolization, 9 phase I or II trials and 2 retrospective studies. The reported actuarial local control rates ranged from 71.4-95% at 3 years, and the overall survival rates ranged from 25-42.3% at 5 years. Late severe radiation morbidities were uncommon, and a total of 18 patients with grade ≥3 late adverse events were reported among the 787 patients included in this analysis. Charged particle therapy for HCC was associated with good local control with limited probability of severe morbidities. The cost-effectiveness and the distinctive clinical advantages of charged particle therapies should be clarified in order to become a socially accepted treatment modality for HCC.

Epigenetic Upregulation of HGF and c-Met Drives Metastasis in Hepatocellular Carcinoma

PubMed Central

Ogunwobi, Olorunseun O.; Puszyk, William; Dong, Hui-Jia; Liu, Chen

2013-01-01

Hepatocyte growth factor (HGF) and its receptor, c-Met, are important regulators of growth and differentiation of healthy hepatocytes. However, upregulation of HGF and c-Met have been associated with tumor progression and metastasis in hepatocellular carcinoma (HCC). Hematogenous dissemination is the most common route for cancer metastasis, but the role of HGF and c-Met in circulating tumor cells (CTCs) is unknown. We have isolated and established a circulating tumor cell line from the peripheral blood of a mouse HCC model. Our studies show that these CTCs have increased expression of HGF and c-Met in comparison to the primary tumor cells. The CTCs display phenotypic evidence of epithelial-mesenchymal transition (EMT) and the EMT appears to be inducible by HGF. Epigenetic analysis of the c-Met promoter identified significant loss of DNA methylation in CTCs which correlated with overexpression of c-Met and increased expression of HGF. Six specific CpG sites of c-Met promoter demethylation were identified. CTCs show significantly increased tumorigenicity and metastatic potential in a novel orthotopic syngeneic model of metastatic HCC. We conclude that during hematogenous dissemination in HCC, CTCs undergo EMT under the influence of increased HGF. This process also involves up regulation of c-Met via promoter demethylation at 6 CpG sites. Consequently, targeting HGF and c-Met expression by CTCs may be a novel non-invasive approach with potential clinical applications in HCC management. PMID:23723997

Transarterial chemoembolization for early stage hepatocellular carcinoma decrease local tumor control and overall survival compared to radiofrequency ablation

PubMed Central

Hocquelet, Arnaud; Seror, Olivier; Blanc, Jean-Frédéric; Frulio, Nora; Salut, Cécile; Nault, Jean-Charles; Hervé Trillaud

2017-01-01

Background & Aims To compare treatment failure and survival associated with ultrasound-guided radiofrequency ablation (RFA) and trans-arterial chemoembolization (TACE) for early-stage HCC in Child-Pugh A cirrhosis patients. Methods 122 cirrhotic patients (RFA: 61; TACE: 61) were well matched according to cirrhosis severity; tumor size and serum alpha-fetoprotein. TACE was performed in case of inconspicuous nodule on US or nodule with “at risk location”. Treatment failure was defined as local tumor progression (LTP) and primary treatment failure (failing to obtain complete response after two treatment session). Treatment failure and overall survival (OS) were compared after coarsened exact matching. Cox proportional model to assess independent predictive factors was performed. Results No significant difference was seen for baseline characteristics between the two groups. Mean tumor size was 3cm in both group with 41% HCC>3cm. Treatment failure rates after TACE was 42.6% (14 primary treatment failures and 12 LTP) and 9.8% after RFA (no primary treatment failure and 6 LTP) P < 0.001. TACE was the only predictive factor of treatment failure (Hazard ratio: 5.573). The 4-years OS after RFA and TACE were 54.1% and 31.5% (P = 0.042), respectively. Conclusion For Child-Pugh A patients with early-stage HCC, alternative treatment as supra-selective TACE to RFA regarded as too challenging using common US guidance decrease significantly the local tumor control and overall survival. Efforts to improve feasibility of RFA especially for inconspicuous target have to be made. PMID:27793027

Interobserver variability in target definition for hepatocellular carcinoma with and without portal vein thrombus: radiation therapy oncology group consensus guidelines.

PubMed

Hong, Theodore S; Bosch, Walter R; Krishnan, Sunil; Kim, Tae K; Mamon, Harvey J; Shyn, Paul; Ben-Josef, Edgar; Seong, Jinsil; Haddock, Michael G; Cheng, Jason C; Feng, Mary U; Stephans, Kevin L; Roberge, David; Crane, Christopher; Dawson, Laura A

2014-07-15

Defining hepatocellular carcinoma (HCC) gross tumor volume (GTV) requires multimodal imaging, acquired in different perfusion phases. The purposes of this study were to evaluate the variability in contouring and to establish guidelines and educational recommendations for reproducible HCC contouring for treatment planning. Anonymous, multiphasic planning computed tomography scans obtained from 3 patients with HCC were identified and distributed to a panel of 11 gastrointestinal radiation oncologists. Panelists were asked the number of HCC cases they treated in the past year. Case 1 had no vascular involvement, case 2 had extensive portal vein involvement, and case 3 had minor branched portal vein involvement. The agreement between the contoured total GTVs (primary + vascular GTV) was assessed using the generalized kappa statistic. Agreement interpretation was evaluated using Landis and Koch's interpretation of strength of agreement. The S95 contour, defined using the simultaneous truth and performance level estimation (STAPLE) algorithm consensus at the 95% confidence level, was created for each case. Of the 11 panelists, 3 had treated >25 cases in the past year, 2 had treated 10 to 25 cases, 2 had treated 5 to 10 cases, 2 had treated 1 to 5 cases, 1 had treated 0 cases, and 1 did not respond. Near perfect agreement was seen for case 1, and substantial agreement was seen for cases 2 and 3. For case 2, there was significant heterogeneity in the volume identified as tumor thrombus (range 0.58-40.45 cc). For case 3, 2 panelists did not include the branched portal vein thrombus, and 7 panelists contoured thrombus separately from the primary tumor, also showing significant heterogeneity in volume of tumor thrombus (range 4.52-34.27 cc). In a group of experts, excellent agreement was seen in contouring total GTV. Heterogeneity exists in the definition of portal vein thrombus that may impact treatment planning, especially if differential dosing is contemplated. Guidelines for HCC GTV contouring are recommended. Copyright © 2014. Published by Elsevier Inc.

Interobserver Variability in Target Definition for Hepatocellular Carcinoma With and Without Portal Vein Thrombus: Radiation Therapy Oncology Group Consensus Guidelines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Theodore S., E-mail: tshong1@mgh.harvard.edu; Bosch, Walter R.; Krishnan, Sunil

2014-07-15

Purpose: Defining hepatocellular carcinoma (HCC) gross tumor volume (GTV) requires multimodal imaging, acquired in different perfusion phases. The purposes of this study were to evaluate the variability in contouring and to establish guidelines and educational recommendations for reproducible HCC contouring for treatment planning. Methods and Materials: Anonymous, multiphasic planning computed tomography scans obtained from 3 patients with HCC were identified and distributed to a panel of 11 gastrointestinal radiation oncologists. Panelists were asked the number of HCC cases they treated in the past year. Case 1 had no vascular involvement, case 2 had extensive portal vein involvement, and case 3more » had minor branched portal vein involvement. The agreement between the contoured total GTVs (primary + vascular GTV) was assessed using the generalized kappa statistic. Agreement interpretation was evaluated using Landis and Koch's interpretation of strength of agreement. The S95 contour, defined using the simultaneous truth and performance level estimation (STAPLE) algorithm consensus at the 95% confidence level, was created for each case. Results: Of the 11 panelists, 3 had treated >25 cases in the past year, 2 had treated 10 to 25 cases, 2 had treated 5 to 10 cases, 2 had treated 1 to 5 cases, 1 had treated 0 cases, and 1 did not respond. Near perfect agreement was seen for case 1, and substantial agreement was seen for cases 2 and 3. For case 2, there was significant heterogeneity in the volume identified as tumor thrombus (range 0.58-40.45 cc). For case 3, 2 panelists did not include the branched portal vein thrombus, and 7 panelists contoured thrombus separately from the primary tumor, also showing significant heterogeneity in volume of tumor thrombus (range 4.52-34.27 cc). Conclusions: In a group of experts, excellent agreement was seen in contouring total GTV. Heterogeneity exists in the definition of portal vein thrombus that may impact treatment planning, especially if differential dosing is contemplated. Guidelines for HCC GTV contouring are recommended.« less

miR-342-3p affects hepatocellular carcinoma cell proliferation via regulating NF-κB pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Liang; Zhang, Yubao, E-mail: zhyb880077@sina.com

2015-02-13

Recent research indicates that non-coding microRNAs (miRNAs) help regulate basic cellular processes in many types of cancer cells. We hypothesized that overexpression of miR-342-3p might affect proliferation of hepatocellular carcinoma (HCC) cells. After confirming overexpression of miR-342-3p with qRT-PCR, MTT assay showed that HCC cell proliferation was significantly inhibited by miR-342-3p, and that it significantly decreased BrdU-positive cell proliferation by nearly sixfold. Searching for targets using three algorithms we found that miR-342-3p is related to the NF-κB pathway and luciferase assay found that IKK-γ, TAB2 and TAB3 are miR-342-3p target genes. Results of western blot on extracted nuclear proteins ofmore » HepG2 and HCT-116 cells showed that miR-342-3p reduced and miR-342-3p-in increased p65 nuclear levels and qRT-PCR found that NF-κB pathway downstream genes were downregulated by miR-342-3p and upregulated by miR-342-3p-in, confirming that miR-342 targets NF-κB pathway. Overexpression of Ikk-γ, TAB2 and TAB3 partially rescued HCC cells proliferation inhibited by miR-342-3p. Using the GSE54751 database we evaluated expression from 10 HCC samples, which strongly suggested downregulation of miR-342-3p and we also found inverse expression between miR-342-3p and its targets IKK-γ, TAB2 and TAB3 from 71 HCC samples. Our results show that miR-342-3p has a significant role in HCC cell proliferation and is suitable for investigation of therapeutic targets. - Highlights: • MiR-342-3p suppresses hepatocellular carcinoma cell proliferation. • MiR-342-3p targets IKK-γ, TAB2 and TAB3 genes. • MiR-342-3p downregulates NF-kB signaling pathway. • MiR-342-3p is downregulated in clinical hepatocellular carcinoma samples. • The expression of miR-342-3p and its target gene is inversely related.« less

Stemness-Related Transcriptional Factors and Homing Gene Expression Profiles in Hepatic Differentiation and Cancer

PubMed Central

Toraih, Eman A; Fawzy, Manal S; El-Falouji, Abdullah I; Hamed, Elham O; Nemr, Nader A; Hussein, Mohammad H; Fadeal, Noha M Abd El

2016-01-01

Stem cell transcriptional signature activation is an essential event in the development of cancer. This study aimed to investigate the differential expression profiles of three pluripotency-associated genes, OCT4, NANOG and SOX2, G-protein-coupled chemokine receptor 4 (CXCR4) and the ligand CXCL2, and alpha-fetoprotein (AFP) in hepatogenic differentiated stem cells and in sera of hepatitis C virus (HCV) and HCV-induced hepatocellular carcinoma (HCC) patients. Mesenchymal stem cells derived from umbilical cord blood were differentiated using hepatogenic differentiation media. Serum specimens were collected from 96 patients (32 cirrhotic HCV, 32 early HCC and 32 late HCC) and 96 controls. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed for relative quantification of the six target genes using the Livak method. In silico network analysis was also executed to explore the pluripotency and tumorigenetic regulatory circuits in liver cancer. The expression levels of all genes declined gradually during the stages of stem cell differentiation. On univariate and multivariate analyses, NANOG, CXCR4 and AFP were significantly upregulated in late clinical stage HCC patients. In contrast, SOX2 and CXCL2 were markedly overexpressed in cirrhotic patients and could be used for clear demarcation between cirrhotic and HCC patients in our cases. In conclusion, our data highlight the potential role of the SOX2 stem cell marker and CXCL2 chemokine in liver cell degeneration and fibrogenesis in HCV-induced hepatic cirrhosis in our sample of the Egyptian population. In addition, the significant association of NANOG and CXCR4 high expression with late HCC could contribute to the acquisition of stem cell–like properties in hepatic cancer and dissemination in late stages, respectively. Taken together, our results could have potential application in HCC prognosis and treatment. PMID:27623812

Profile of Gut Microbiota Associated With the Presence of Hepatocellular Cancer in Patients With Liver Cirrhosis.

PubMed

Grąt, M; Wronka, K M; Krasnodębski, M; Masior, Ł; Lewandowski, Z; Kosińska, I; Grąt, K; Stypułkowski, J; Rejowski, S; Wasilewicz, M; Gałęcka, M; Szachta, P; Krawczyk, M

2016-06-01

Changes within the gut microbiota contribute to the progression of chronic liver diseases. According to the results of several studies performed in animal models, gut dysbiosis plays an important role in hepatocarcinogenesis. The aim of this study was to explore the characteristics of gut microbiota associated with the presence of hepatocellular cancer (HCC) in patients with cirrhosis of the liver undergoing liver transplantation. A total of 15 patients with HCC and 15 non-HCC patients matched according to etiology of cirrhosis and Model for End-Stage Liver Disease (MELD) scores who underwent liver transplantations between 2012 and 2014 were included. Analysis of their gut microbial profile was based on prospectively collected stool samples from the pretransplant period. Patients with and without HCC were similar with respect to age (P = .506), sex (P = .700), hepatitis C virus (P > .999) and hepatitis B virus (P = .715) infection status, alcoholic liver disease (P > .999), and MELD score (P = .337). Notably, the presence of HCC was associated with significantly increased fecal counts of Escherichia coli (P = .025). Prediction of HCC presence based on E coli counts was associated with the area under the receiver-operating curve of 0.742 (95% confidence interval, 0.564-0.920), with the optimal cutoff on the level of 17.728 (natural logarithm of colony-forming units per 1 g of feces). Sensitivity and specificity rates for the established cutoff were 66.7% and 73.3%, respectively. The profile of gut microbiota associated with the presence of HCC in cirrhotic patients is characterized by increased fecal counts of E coli. Therefore, intestinal overgrowth of E coli may contribute to the process of hepatocarcinogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

Somatostatin and CXCR4 chemokine receptor expression in hepatocellular and cholangiocellular carcinomas: tumor capillaries as promising targets.

PubMed

Kaemmerer, Daniel; Schindler, Robin; Mußbach, Franziska; Dahmen, Uta; Altendorf-Hofmann, Annelore; Dirsch, Olaf; Sänger, Jörg; Schulz, Stefan; Lupp, Amelie

2017-12-28

Hepatocellular (HCC) and cholangiocellular carcinomas (CCC) display an exceptionally poor prognosis. Especially for advanced disease no efficient standard therapy is currently available. Recently, somatostatin analogs have been evaluated for the treatment of HCC, however, with contradictory results. Besides, for both malignancies the chemokine receptor CXCR4 has been discussed as a possible new target structure. Expression of somatostatin receptor (SSTR) subtypes 1, 2A, 3, 4, and 5, and of CXCR4 was evaluated in a total of 71 HCCs and 27 CCCs by immunohistochemistry using well-characterized novel monoclonal antibodies. In HCC tumor cells, frequency and intensity of expression of SSTRs and CXCR4 were only low. CXCR4 was present in about 40% of the HCCs, although at a low intensity. SSTR5, SSTR2, and SSTR3 were detected in about 15%, 8%, and 5% of the HCC tumors, respectively. SSTR and CXCR4 expression was much higher in CCC than in HCC. CXCR4 and SSTR1 were present in 60% and 67% of the CCC samples, respectively, followed by SSTR2 and SSTR5, which were detected in 30% and 11% of the tumors, respectively. Most notably, CXCR4 was intensely expressed on the tumor capillaries in about 50% of the HCCs and CCCs. CXCR4 expression on tumor vessels was associated with poor patient outcomes. CCC, but not HCC, may be suitable for SSTR-based treatments. Because of the predominant expression of SSTR1, pan-somatostatin analogs should be preferred. In both HCC and CCC, indirect targeting of tumors via the CXCR4-positive tumor capillaries may represent a promising additional therapeutic strategy.

Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class I-positive hepatocellular carcinoma after curative hepatectomy.

PubMed

Umemoto, Yuichiroh; Okano, Shinji; Matsumoto, Yoshihiro; Nakagawara, Hidekazu; Matono, Rumi; Yoshiya, Shohei; Yamashita, Yo-Ichi; Yoshizumi, Tomoharu; Ikegami, Toru; Soejima, Yuji; Harada, Mamoru; Aishima, Shinichi; Oda, Yoshinao; Shirabe, Ken; Maehara, Yoshihiko

2015-01-01

Hepatocellular carcinoma (HCC) is one of the most common solid tumors worldwide. Surgery is potentially curative, but high recurrence rates worsen patient prognosis. The interaction between the proteins programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) is an important immune checkpoint. The significance of PD-L1 expression and human leukocyte antigen class I (HLA class I), recognized by CD8 T cells, in the prognosis of patients with HCC remains to be determined. We assessed the levels of PD-L1 and HLA class I expression on HCC samples from 80 patients who had undergone hepatectomy at our institution, and evaluated the correlations between PD-L1 and HLA class I expression and patient prognosis. High HLA class I expression was correlated with significantly better recurrence-free survival (RFS), but not overall survival (OS). Multivariate analysis showed that high HLA class I expression was an independent predictor of improved RFS. Low expression of PD-L1 on HCC tended to predict better OS, but the difference was not statistically significant. PD-L1 expression on HCC correlated with the number of CD163-positive macrophages and HLA class I expression with CD3-positive cell infiltration. Univariable and multivariable analyses showed that combined PD-L1 low/HLA class I high expression on HCCs was prognostic for improved OS and RFS. PD-L1 status may be a good predictor of prognosis in HCC patients with high HLA class I expression. Novel therapies targeting the PD-L1/PD-1 pathway may improve the prognosis of patients with HCC.

The Hepatitis Viral Status in Patients With Hepatocellular Carcinoma: a Study of 3843 Patients From Taiwan Liver Cancer Network.

PubMed

Chang, Il-Chi; Huang, Shiu-Feng; Chen, Pei-Jer; Chen, Chi-Ling; Chen, Chao-Long; Wu, Cheng-Chung; Tsai, Cheng-Chung; Lee, Po-Huang; Chen, Miin-Fu; Lee, Chuan-Mo; Yu, Hsien-Chung; Lo, Gin-Ho; Yeh, Chau-Ting; Hong, Chih-Chen; Eng, Hock-Liew; Wang, John; Tseng, Hui-Hwa; Hsiao, Cheng-Hsiang; Wu, Hong-Dar Isaac; Yen, Tseng-Chang; Liaw, Yun-Fan

2016-04-01

Hepatocellular carcinoma (HCC) is the leading cancer death in Taiwan. Chronic viral hepatitis infections have long been considered as the most important risk factors for HCC in Taiwan. The previously published reports were either carried out by individual investigators with small patient numbers or by large endemic studies with limited viral marker data. Through collaboration with 5 medical centers across Taiwan, Taiwan liver cancer network (TLCN) was established in 2005. All participating centers followed a standard protocol to recruit liver cancer patients along with their biosamples and clinical data. In addition, detailed viral marker analysis for hepatitis B virus (HBV) and hepatitis C virus (HCV) were also performed. This study included 3843 HCC patients with available blood samples in TLCN (recruited from November 2005 to April 2011). There were 2153 (56.02%) patients associated with HBV (HBV group); 969 (25.21%) with HCV (HCV group); 310 (8.07%) with both HBV and HCV (HBV+HCV group); and 411 (10.69%) were negative for both HBV and HCV (non-B non-C group). Two hundred two of the 2463 HBV patients (8.20%) were HBsAg(-), but HBV DNA (+). The age, gender, cirrhosis, viral titers, and viral genotypes were all significantly different between the above 4 groups of patients. The median age of the HBV group was the youngest, and the cirrhotic rate was lowest in the non-B non-C group (only 25%). This is the largest detailed viral hepatitis marker study for HCC patients in the English literatures. Our study provided novel data on the interaction of HBV and HCV in the HCC patients and also confirmed that the HCC database of TLCN is highly representative for Taiwan and an important resource for HCC research.

The Hepatitis Viral Status in Patients With Hepatocellular Carcinoma: a Study of 3843 Patients From Taiwan Liver Cancer Network

PubMed Central

Chang, Il-Chi; Huang, Shiu-Feng; Chen, Pei-Jer; Chen, Chi-Ling; Chen, Chao-Long; Wu, Cheng-Chung; Tsai, Cheng-Chung; Lee, Po-Huang; Chen, Miin-Fu; Lee, Chuan-Mo; Yu, Hsien-Chung; Lo, Gin-Ho; Yeh, Chau-Ting; Hong, Chih-Chen; Eng, Hock-Liew; Wang, John; Tseng, Hui-Hwa; Hsiao, Cheng-Hsiang; Wu, Hong-Dar Isaac; Yen, Tseng-Chang; Liaw, Yun-Fan

2016-01-01

Abstract Hepatocellular carcinoma (HCC) is the leading cancer death in Taiwan. Chronic viral hepatitis infections have long been considered as the most important risk factors for HCC in Taiwan. The previously published reports were either carried out by individual investigators with small patient numbers or by large endemic studies with limited viral marker data. Through collaboration with 5 medical centers across Taiwan, Taiwan liver cancer network (TLCN) was established in 2005. All participating centers followed a standard protocol to recruit liver cancer patients along with their biosamples and clinical data. In addition, detailed viral marker analysis for hepatitis B virus (HBV) and hepatitis C virus (HCV) were also performed. This study included 3843 HCC patients with available blood samples in TLCN (recruited from November 2005 to April 2011). There were 2153 (56.02%) patients associated with HBV (HBV group); 969 (25.21%) with HCV (HCV group); 310 (8.07%) with both HBV and HCV (HBV+HCV group); and 411 (10.69%) were negative for both HBV and HCV (non-B non-C group). Two hundred two of the 2463 HBV patients (8.20%) were HBsAg(-), but HBV DNA (+). The age, gender, cirrhosis, viral titers, and viral genotypes were all significantly different between the above 4 groups of patients. The median age of the HBV group was the youngest, and the cirrhotic rate was lowest in the non-B non-C group (only 25%). This is the largest detailed viral hepatitis marker study for HCC patients in the English literatures. Our study provided novel data on the interaction of HBV and HCV in the HCC patients and also confirmed that the HCC database of TLCN is highly representative for Taiwan and an important resource for HCC research. PMID:27082566

Expression of microRNA 638 and sex-determining region Y-box 2 in hepatocellular carcinoma: Association between clinicopathological features and prognosis.

PubMed

Ye, Weikang; Li, Jieke; Fang, Guan; Cai, Xiupeng; Zhang, Yan; Zhou, Chaojun; Chen, Lei; Yang, Wenjun

2018-05-01

The aim of the present study was to determine the expression profile of microRNA 638 (miR-638) and sex-determining region Y-box 2 (SOX2) in hepatocellular carcinoma (HCC), and to investigate their association with clinicopathological features and survival. Reverse transcription-quantitative polymerase chain reaction analysis was used to investigate miR-638 and SOX2 expression in 78 patients with HCC. Western blot and immunohistochemical analyses were performed in order to determine SOX2 protein expression in HCC samples. Combined with the clinical postoperative follow-up data, the expression of miR-638 and SOX2 and the association between this and the prognostic values of patients with HCC were statistically analyzed. The results of the present study confirmed that miR-638 expression in tumor tissues was significantly downregulated (P<0.001), while SOX2 expression was significantly increased, compared with healthy control tissues (P<0.05). In addition, a significant inverse correlation between miR-638 and SOX2 expression was also observed in the HCC tissues (r=-0.675; P<0.05). Clinicopathological correlation analysis demonstrated that reduced miR-638 and elevated SOX2 expression was significantly associated with the Tumor-Node-Metastasis stage and portal vascular invasion (P<0.05). However, no significant differences were observed in other clinicopathological features, including age, sex, tumor size, tumor differentiation and hepatitis status (P>0.05). Notably, follow-up analysis revealed that patients with HCC with low miR-638 expression and high SOX2 expression tended to have a significantly shorter postoperative survival time (P<0.001). It was concluded that miR-638 may serve a vital role in the occurrence and progression of HCC by regulating SOX2 expression and thus, that miR-638 and SOX2 may be critical as novel diagnostic and prognostic biomarkers for HCC.

Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C.

PubMed

Yamaguchi, Takashi; Matsuzaki, Koichi; Inokuchi, Ryosuke; Kawamura, Rinako; Yoshida, Katsunori; Murata, Miki; Fujisawa, Junichi; Fukushima, Nobuyoshi; Sata, Michio; Kage, Masayoshi; Nakashima, Osamu; Tamori, Akihiro; Kawada, Norifumi; Tsuneyama, Koichi; Dooley, Steven; Seki, Toshihito; Okazaki, Kazuichi

2013-12-01

Insight into hepatic fibrogenesis and carcinogenesis (fibro-carcinogenesis) caused by hepatitis C virus (HCV) infection has come from recent analyses of transforming growth factor (TGF)-β signaling. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. This study aimed to elucidate how HCV infection affected hepatic fibro-carcinogenesis, particularly via phospho-Smad signaling. We first studied phospho-Smad2/3 positivity of 100 patients in different stages of HCV-related chronic liver disease. To examine changes in phospho-Smad2/3 after HCV clearance, we analyzed 32 paired liver biopsy samples obtained before and after sustained virological response (SVR), dividing patients into two groups: 20 patients not developing hepatocellular carcinoma (HCC) after attaining SVR (non-HCC group), and 12 patients who developed HCC despite SVR (HCC group). Hepatocytic tumor-suppressive pSmad3C signaling shifted to carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling as liver diseases progressed. In the non-HCC group, 13 patients (65%) displayed fibrotic regression and inflammation reduction after SVR. Interestingly, SVR restored cytostatic pSmad3C signaling in hepatocytes, while eliminating prior carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling. In the HCC group, seven patients (58%) displayed unchanged or even progressed fibrosis despite smoothened inflammatory activity, reflecting persistently high numbers of hepatocytes with pSmad3L- and pSmad2L/C-signaling and low pSmad3C-signaling. HCV clearance limits fibrosis and reduces HCC incidence by switching inflammation-dependent phospho-Smad signaling from fibro-carcinogenesis to tumor suppression. However, progression to HCC would occur in severely fibrotic livers if an inflammation-independent fibro-carcinogenic process has already begun before HCV clearance. © 2013 The Japan Society of Hepatology.

Hair cortisol concentration (HCC) as a measure for prenatal psychological distress - A systematic review.

PubMed

Mustonen, Paula; Karlsson, Linnea; Scheinin, Noora M; Kortesluoma, Susanna; Coimbra, Bárbara; Rodrigues, Ana João; Karlsson, Hasse

2018-06-01

Prenatal environment reportedly affects the programming of developmental trajectories in offspring and the modification of risks for later morbidity. Among the increasingly studied prenatal exposures are maternal psychological distress (PD) and altered maternal hypothalamus-pituitary-adrenal (HPA) axis functioning. Both prenatal PD and maternal short-term cortisol concentrations as markers for HPA axis activity have been linked to adverse child outcomes and it has been assumed that maternal PD affects the offspring partially via altered cortisol secretion patterns. Yet, the existing literature on the interrelations between these two measures is conflicting. The assessment of cortisol levels by using hair cortisol concentration (HCC) has gained interest, as it offers a way to assess long-term cortisol levels with a single non-invasive sampling. According to our review, 6 studies assessing the associations between maternal HCC during pregnancy and various types of maternal PD have been published so far. Measures of prenatal PD range from maternal symptoms of depression or anxiety to stress related to person's life situation or pregnancy. The aim of this systematic review is to critically evaluate the potential of HCC as a biomarker for maternal PD during pregnancy. We conclude that HCC appears to be inconsistently associated with self-reported symptoms of prenatal PD, especially in the range of mild to moderate symptom levels. Self-reports on PD usually cover short time periods and they seem to depict partly different phenomena than HCC. Thus, methodological aspects are in a key role in future studies evaluating the interconnections across different types of prenatal PD and maternal HPA axis functioning. Further, studies including repetitive measurements of both HCC and PD during the prenatal period are needed, as timing of the assessments is one important source of variation among current studies. The significance of prenatal HCC in the context of offspring outcomes needs to be further investigated. Copyright © 2018 Elsevier Ltd. All rights reserved.

STAT3 activation in monocytes accelerates liver cancer progression.

PubMed

Wu, Wen-Yong; Li, Jun; Wu, Zheng-Sheng; Zhang, Chang-Le; Meng, Xiang-Ling

2011-12-05

Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor ubiquitously expressed in different cell types. STAT3 plays an essential role in cell survival, proliferation, and differentiation. Aberrantly hyper-activated STAT3 signaling in cancer cells and in the tumor microenvironment has been detected in a wide variety of human cancers and is considered an important factor for cancer initiation, development, and progression. However, the role of STAT3 activation in monocytes in the development of HCC has not been well understood. Immunohistochemical analysis of phosphorylated STAT3 was performed on tissue microarray from HCC patients. Using a co-culture system in vivo, HCC cell growth was determined by the MTT assay. In vivo experiments were conducted with mice given diethylinitrosamine (DEN), which induces HCC was used to investigate the role of STAT3 expression in monocytes on tumor growth. Real-time PCR was used to determine the expression of cell proliferation and cell arrest associated genes in the tumor and nontumor tissue from liver. Phosphorylated STAT3 was found in human hepatocellular carcinoma tissue samples and was expressed in tumor cells and also in monocytes. Phosphorylated STAT3 expression in monocyte was significantly correlated to advanced clinical stage of HCC and a poor prognosis. Using a co-culture system in vivo, monocytes promoted HCC cell growth via the IL-6/STAT3 signaling pathway. The STAT3 inhibitor, NSC 74859, significantly suppressed tumor growth in vivo in mice with diethylinitrosamine (DEN)-induced HCC. In this animal model, blockade of STAT3 with NSC 74859 induced tumor cell apoptosis, while inhibiting both tumor cells and monocytes proliferation. Furthermore, NSC 74859 treatment suppressed cancer associated inflammation in DEN-induce HCC. Our data suggest constitutively activated STAT3 monocytes promote liver tumorigenesis in clinical patients and animal experiments. Thus, STAT3 in tumor infiltrating inflammatory cells may an attractive target for liver cancer therapy.

Hair cortisol and self-reported stress in healthy, working adults.

PubMed

Gidlow, Christopher J; Randall, Jason; Gillman, Jamie; Silk, Steven; Jones, Marc V

2016-01-01

Chronic stress can be important in the pathology of chronic disease. Hair cortisol concentrations (HCC) are proposed to reflect long term cortisol secretion from exposure to stress. To date, inconsistencies in the relationship between HCC and self-reported stress have been attributed to variation and limitations of perceived stress measurement. We report data from employees of two large public sector worksites (n=132). Socio-demographic, health, lifestyle, perceived stress scale (PSS), and work-related effort reward imbalance (ERI) were collected at baseline. Participants were asked to respond to mobile text messages every two days, asking them to report current stress levels (Ecological momentary assessment, EMA), and mean stress was determined overall, during work hours, and out of work hours. At 12 weeks, the appraisal of stressful life events scale (ALES) was completed and 3 cm scalp hair samples were taken, from which HCC was determined (to reflect cortisol secretion over the past 12 weeks). Mean response rate to EMA was 81.9 ± 14.9%. Associations between HCC and the various self-reported stress measures (adjusted for use of hair dye) were weak (all<.3). We observed significant associations with HCC for EMA measured stress responses received out of work hours (ρ=.196, p=.013) and ALES Loss subscale (ρ=.241, p=.003), and two individual items from ERI (relating to future work situation). In regression analysis adjusting for other possible confounders, only the HCC-ALES Loss association remained significant (p=.011). Overall, our study confirms that EMA provides a useful measurement tool that can gather perceived stress measures in real-time. But, there was no relationship between self-reported stress collected in this way, and HCC. The modest association between HCC and stress appraisal does however, provide some evidence for the role of cognitive processes in chronic stress. Copyright © 2015 Elsevier Ltd. All rights reserved.

Up-regulation of miR-9 expression predicate advanced clinicopathological features and poor prognosis in patients with hepatocellular carcinoma.

PubMed

Cai, Lizhi; Cai, Xi

2014-12-31

MicroRNAs (miRNAs) are endogenous small (19-24 nt long) noncoding RNAs that regulate gene expression in a sequence specific manner. An increasing association between miRNA and cancer has been recently reported. Hepatocellular carcinoma (HCC), as the fifth most common cancer and the most common cause of death in men, has become the third leading cause of cancer-related deaths globally. In this study, we investigated the miR-9 expression in HCC to evaluate their value in prognosis of this tumor. The expression of miR-9 in matched normal and tumor tissues of HCC was evaluated using a quantitative real-time RT-PCR. A Kaplan-Meier survival curve was generated following a log-rank test. It was observed that miR-9 expression was upregulated in HCC tissues compared with noncancerous liver tissues (7.26 ± 1.30 vs. 3.14 ± 1.08, P < 0.001). The up-regulation of miR-9 in HCC cancer tissues was also significantly correlated with aggressive clinicopathological features. We found that the patients with high miR-9 expression have a higher tumor staging (P = 0.0389) and are in higher risk of venous infiltration (P < 0.0001). Moreover, the results of Kaplan-Meier analyses showed that HCC patients with the high miR-9 expression tend to have shorter overall survival (P < 0.0001). The multivariate analysis clearly indicated that the high miR-9 expression in biopsy samples may be considered as an independent prognostic factor in HCC for decreased survival (4.28; 95%CI, 2.77-7.23, P < 0.001). Our data indicate the potential of miR-9 as a novel prognostic biomarker for HCC. Large well-designed studies with diverse populations and functional evaluations are warranted to confirm and extend our findings. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_228.

Association between chronic hepatitis C infection and hepatocellular carcinoma in a Scottish population.

PubMed Central

Haydon, G H; Jarvis, L M; Simmonds, P; Harrison, D J; Garden, O J; Hayes, P C

1997-01-01

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. The geographical prevalence varies considerably in different countries and Scotland is regarded as an area of low risk for the disease. AIMS: To assess the association between chronic hepatitis C infection (HCV) and HCC in a population of patients presenting to a single hospital. PATIENTS: One hundred and fourteen cases of histologically confirmed liver cancer presenting to the Royal Infirmary of Edinburgh between 1985 and 1994 were examined. METHODS: Of 114 cases of HCC, 80 samples of stored sera were available. Samples positive for HCV Ab were genotyped by restriction fragment length polymorphism analysis of HCV c-DNA. A population of 29 cirrhotic patients (diagnosed between 1985 and 1994) with chronic HCV infection was also genotyped. RESULTS: Chronic HCV infection was a major risk factor (30% of tested HCC patients) identified. HCV genotype 1b was predominant (16 of 20 patients). The time from HCV transmission to development of cancer ranged from 10 to 50 years (median 30). In the cirrhotic patient population, a broader distribution of genotypes was present (genotype 1a: 7; genotype 1b: 8; genotype 2b: 3; genotype 3a: 8 and genotype 4: 2). However, this population was significantly younger. (Mean (SD) 52 (14.5) years) (p = 0.0002) and demonstrated a significantly shorter duration of infection: range 10-40 years (median: 19). CONCLUSION: There is a strong association between chronic HCV infection, cirrhosis, and hepatocarcinogenesis in this Scottish population. The study was unable to distinguish whether the high prevalence of genotype 1b in the HCC population reflected increased oncogenicity in itself, or whether 1b was simply the most prevalent genotype in Scotland when these patients were infected. PMID:9155590

Simplified HCC-ART score for highly sensitive detection of small-sized and early-stage hepatocellular carcinoma in the widely used Okuda, CLIP, and BCLC staging systems.

PubMed

Attallah, Abdelfattah M; Omran, Mohamed M; Attallah, Ahmed A; Abdelrazek, Mohamed A; Farid, Khaled; El-Dosoky, Ibrahim

2017-04-01

Small-sized HCC can be effectively cured by surgery with good clinical outcomes. A highly sensitive HCC α-fetoprotein routine test (HCC-ART) for HCC diagnosis as well as a simplied form of the HCC-ART were reported in the British Journal of Cancer. Here, we verified and studied the applicability of the HCC-ART to the detection of early-stage HCC. 341 cirrhotic patients and 318 HCC patients were included in this study. For each, the HCC-ART score was calculated, and then the sensitivity, specificity, and results of an ROC curve analysis were compared between the HCC-ART and AFP when these biomarkers were used to detect small-sized HCC. Different HCC-ART cutoffs were set for the detection of different tumor sizes. The HCC-ART (AUC = 0.871, 70% sensitivity, 97% specificity) and the simplified HCC-ART (AUC = 0.934, 82% sensitivity, 100% specificity) were found to have high predictive power when attempting to separate cirrhotic patients from those with small-sized HCC. The simplified HCC-ART score was superior to AFP for determining stages according to the early Okuda (0.950 AUC, 84% sensitivity, 99% specificity), CLIP (0.945 AUC, 84% sensitivity, 99% specificity), and BCLC (1.000 AUC, 100% sensitivity, 99% specificity) staging systems. The simplified HCC-ART score was more strongly correlated than AFP and other staging systems with HCC tumor size (P < 0.0001; r = 0.8). The HCC-ART is superior to AFP for diagnosing early-stage HCC. Due to its advantages of minimal variability and a wide continuous scale for assessing HCC severity, the simplified HCC-ART has the potential to be more widely used than the original HCC-ART.

Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: A nationwide nested case-control study.

PubMed

Kim, Gyuri; Jang, Suk-Yong; Han, Eugene; Lee, Yong-Ho; Park, Se-Young; Nam, Chung Mo; Kang, Eun Seok

2017-02-15

Relationship on new statin use and the risk of hepatocellular carcinoma (HCC) in patients with incident type 2 diabetes mellitus (T2DM), who might be at the risk of developing HCC, is uncertained. A nationwide population-based nested case-control study was conducted within the National Health Insurance Service National Sample Cohort 2002-2013 in Korea. Newly prescribed statin after newly diagnosed T2DM was defined as statin use. Controls were matched to case patients on age, sex, follow-up time, and the date of diabetes diagnosis at a five-to-one ratio. Odds ratios (ORs) for associations of statin use with HCC were calculated using conditional logistic regression. After at least a 5-year HCC-free period, there were 229 incident HCC cases and 1,145 matched controls from 47,738 patients with incident diabetes. Of these 229 incident HCC cases, 27 (11.8%) were statin users, whereas 378 (33.0%) were statin users among 1,145 controls. Statin use was associated with a reduced risk of HCC development (adjusted OR [AOR]= 0.36, 95% confidence interval [CI] 0.22-0.60) after adjustment for chronic viral hepatitis, liver cirrhosis, alcoholic liver disease, previous cancer, aspirin use, insulin use, sulfonylurea use, metformin use, thiazolidinedione use, history of chronic obstructive pulmonary disease, Charlson comorbidity score, household income level, and residential area. Risk reduction was accentuated with an increase of cumulative defined daily doses (cDDD) compared with non-users (AORs 0.53, 0.36, 0.32, and 0.26 in ≤60, 60-180, 181-365, and >365cDDD, respectively; P for trend <0.0001). The risk reduction was apparent in the presence of liver disease (AOR = 0.27, 95% CI 0.14-0.50), including heterogeneous groups of clinical diagnosis of liver disease, but not significant in the absence of liver disease (AOR = 0.64, 95% CI 0.32-1.29). Among patients with new onset T2DM, statin use before HCC diagnosis may have a beneficial inhibitory effect on HCC development in a dose-dependent manner, especially in individuals with liver disease. © 2016 UICC.

Protein phosphatase 5 promotes hepatocarcinogenesis through interaction with AMP-activated protein kinase.

PubMed

Chen, Yao-Li; Hung, Man-Hsin; Chu, Pei-Yi; Chao, Tzu-I; Tsai, Ming-Hsien; Chen, Li-Ju; Hsiao, Yung-Jen; Shih, Chih-Ting; Hsieh, Feng-Shu; Chen, Kuen-Feng

2017-08-15

The serine-threonine protein phosphatase family members are known as critical regulators of various cellular functions, such as survival and transformation. Growing evidence suggests that pharmacological manipulation of phosphatase activity exhibits therapeutic benefits. Ser/Thr protein phosphatase 5 (PP5) is known to participate in glucocorticoid receptor (GR) and stress-induced signaling cascades that regulate cell growth and apoptosis, and has been shown to be overexpressed in various human malignant diseases. However, the role of PP5 in hepatocellular carcinoma (HCC) and whether PP5 may be a viable therapeutic target for HCC treatment are unknown. Here, by analyzing HCC clinical samples obtained from 215 patients, we found that overexpression of PP5 is tumor specific and associated with worse clinical outcomes. We further characterized the oncogenic properties of PP5 in HCC cells. Importantly, both silencing of PP5 with lentiviral-mediated short hairpin RNA (shRNA) and chemical inhibition of PP5 phosphatase activity using the natural compound cantharidin/norcantharidin markedly suppressed the growth of HCC cells and tumors in vitro and in vivo. Moreover, we identified AMP-activated protein kinase (AMPK) as a novel downstream target of oncogenic PP5 and demonstrated that the antitumor mechanisms underlying PP5 inhibition involve activation of AMPK signaling. Overall, our results establish a pathological function of PP5 in hepatocarcinogenesis via affecting AMPK signaling and suggest that PP5 inhibition is an attractive therapeutic approach for HCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Hepatitis C virus core protein potentiates proangiogenic activity of hepatocellular carcinoma cells.

PubMed

Shao, Yu-Yun; Hsieh, Min-Shu; Wang, Han-Yu; Li, Yong-Shi; Lin, Hang; Hsu, Hung-Wei; Huang, Chung-Yi; Hsu, Chih-Hung; Cheng, Ann-Lii

2017-10-17

Increased angiogenic activity has been demonstrated in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), but the mechanism was unclear. To study the role of HCV core protein, we used tube formation and Matrigel plug assays to assess the proangiogenic activity of an HCC cell line, HuH7, and 2 of its stable clones-HuH7-core-high and HuH7-core-low, with high and low HCV core protein expression, respectively. In both assays, HuH7-core-high and HuH7-core-low cells dose-dependently induced stronger angiogenesis than control cells. HuH7 cells with HCV core protein expression showed increased mRNA and protein expression of vascular endothelial growth factor (VEGF). VEGF inhibition by bevacizumab reduced the proangiogenic activity of HuH7-core-high cells. The promotor region of VEGF contains the binding site of activator protein-1 (AP-1). Compared with controls, HuH7-core-high cells had an increased AP-1 activity and nuclear localization of phospho-c-jun. AP-1 inhibition using either RNA knockdown or AP-1 inhibitors reduced the VEGF mRNA expression and the proangiogenic activity of HuH7-core-high cells. Among 131 tissue samples from HCC patients, HCV-related HCC revealed stronger VEGF expression than did hepatitis B virus-related HCC. In conclusion, increased VEGF expression through AP-1 activation is a crucial mechanism underlying the proangiogenic activity of the HCV core protein in HCC cells.

Hepatitis C virus core protein potentiates proangiogenic activity of hepatocellular carcinoma cells

PubMed Central

Shao, Yu-Yun; Hsieh, Min-Shu; Wang, Han-Yu; Li, Yong-Shi; Lin, Hang; Hsu, Hung-Wei; Huang, Chung-Yi; Hsu, Chih-Hung; Cheng, Ann-Lii

2017-01-01

Increased angiogenic activity has been demonstrated in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), but the mechanism was unclear. To study the role of HCV core protein, we used tube formation and Matrigel plug assays to assess the proangiogenic activity of an HCC cell line, HuH7, and 2 of its stable clones—HuH7-core-high and HuH7-core-low, with high and low HCV core protein expression, respectively. In both assays, HuH7-core-high and HuH7-core-low cells dose-dependently induced stronger angiogenesis than control cells. HuH7 cells with HCV core protein expression showed increased mRNA and protein expression of vascular endothelial growth factor (VEGF). VEGF inhibition by bevacizumab reduced the proangiogenic activity of HuH7-core-high cells. The promotor region of VEGF contains the binding site of activator protein-1 (AP-1). Compared with controls, HuH7-core-high cells had an increased AP-1 activity and nuclear localization of phospho-c-jun. AP-1 inhibition using either RNA knockdown or AP-1 inhibitors reduced the VEGF mRNA expression and the proangiogenic activity of HuH7-core-high cells. Among 131 tissue samples from HCC patients, HCV-related HCC revealed stronger VEGF expression than did hepatitis B virus-related HCC. In conclusion, increased VEGF expression through AP-1 activation is a crucial mechanism underlying the proangiogenic activity of the HCV core protein in HCC cells. PMID:29156827

The Acyclic Retinoid Peretinoin Inhibits Hepatitis C Virus Replication and Infectious Virus Release in Vitro

NASA Astrophysics Data System (ADS)

Shimakami, Tetsuro; Honda, Masao; Shirasaki, Takayoshi; Takabatake, Riuta; Liu, Fanwei; Murai, Kazuhisa; Shiomoto, Takayuki; Funaki, Masaya; Yamane, Daisuke; Murakami, Seishi; Lemon, Stanley M.; Kaneko, Shuichi

2014-04-01

Clinical studies suggest that the oral acyclic retinoid Peretinoin may reduce the recurrence of hepatocellular carcinoma (HCC) following surgical ablation of primary tumours. Since hepatitis C virus (HCV) infection is a major cause of HCC, we assessed whether Peretinoin and other retinoids have any effect on HCV infection. For this purpose, we measured the effects of several retinoids on the replication of genotype 1a, 1b, and 2a HCV in vitro. Peretinoin inhibited RNA replication for all genotypes and showed the strongest antiviral effect among the retinoids tested. Furthermore, it reduced infectious virus release by 80-90% without affecting virus assembly. These effects could be due to reduced signalling from lipid droplets, triglyceride abundance, and the expression of mature sterol regulatory element-binding protein 1c and fatty acid synthase. These negative effects of Peretinoin on HCV infection may be beneficial in addition to its potential for HCC chemoprevention in HCV-infected patients.

Assessment of the correlation between serum prolidase and alpha-fetoprotein levels in patients with hepatocellular carcinoma

PubMed Central

Uygun Ilikhan, Sevil; Bilici, Muammer; Sahin, Hatice; Demir Akca, Ayşe Semra; Can, Murat; Oz, Ibrahim Ilker; Guven, Berrak; Buyukuysal, M Cagatay; Ustundag, Yucel

2015-01-01

AIM: To determine the predictive value of increased prolidase activity that reflects increased collagen turnover in patients with hepatocellular carcinoma (HCC). METHODS: Sixty-eight patients with HCC (mean age of 69.1 ± 10.1), 31 cirrhosis patients (mean age of 59.3 ± 6.3) and 33 healthy volunteers (mean age of 51.4 ± 12.6) were enrolled in this study. Univariate and multivariate analysis were used to evaluate the association of serum α-fetoprotein (AFP) values with HCC clinicopathological features, such as tumor size, number and presence of vascular and macrovascular invasion. The patients with HCC were divided into groups according to tumor size, number and presence of vascular invasion (diameters; ≤ 3 cm, 3-5 cm and ≥ 5 cm, number; 1, 2 and ≥ 3, macrovascular invasion; yes/no). Barcelona-clinic liver cancer (BCLC) criteria were used to stage HCC patients. Serum samples for measurement of prolidase and alpha-fetoprotein levels were kept at -80 °C until use. Prolidase levels were measured spectrophotometrically and AFP concentrations were determined by a chemiluminescence immunometric commercial diagnostic assay. RESULTS: In patients with HCC, prolidase and AFP values were evaluated according to tumor size, number, presence of macrovascular invasion and BCLC staging classification. Prolidase values were significantly higher in patients with HCC compared with controls (P < 0.001). Prolidase levels were significantly associated with tumor size and number (P < 0.001, P = 0.002, respectively). Prolidase levels also differed in patients in terms of BCLC staging classification (P < 0.001). Furthermore the prolidase levels in HCC patients showed a significant difference compared with patients with cirrhosis (P < 0.001). In HCC patients grouped according to tumor size, number and BCLC staging classification, AFP values differed separately (P = 0.032, P = 0.038, P = 0.015, respectively). In patients with HCC, there was a significant correlation (r = 0.616; P < 0.001) between prolidase and AFP values in terms of tumor size, number and BCLC staging classification, whereas the presence of macrovascular invasion did not show a positive association with serum prolidase and AFP levels. CONCLUSION: Considering the levels of both serum prolidase and AFP could contribute to the early diagnosing of hepatocellular carcinoma. PMID:26078578

Assessment of the correlation between serum prolidase and alpha-fetoprotein levels in patients with hepatocellular carcinoma.

PubMed

Ilikhan, Sevil Uygun; Bilici, Muammer; Sahin, Hatice; Akca, Ayşe Semra Demir; Can, Murat; Oz, Ibrahim Ilker; Guven, Berrak; Buyukuysal, M Cagatay; Ustundag, Yucel

2015-06-14

To determine the predictive value of increased prolidase activity that reflects increased collagen turnover in patients with hepatocellular carcinoma (HCC). Sixty-eight patients with HCC (mean age of 69.1 ± 10.1), 31 cirrhosis patients (mean age of 59.3 ± 6.3) and 33 healthy volunteers (mean age of 51.4 ± 12.6) were enrolled in this study. Univariate and multivariate analysis were used to evaluate the association of serum α-fetoprotein (AFP) values with HCC clinicopathological features, such as tumor size, number and presence of vascular and macrovascular invasion. The patients with HCC were divided into groups according to tumor size, number and presence of vascular invasion (diameters; ≤ 3 cm, 3-5 cm and ≥ 5 cm, number; 1, 2 and ≥ 3, macrovascular invasion; yes/no). Barcelona-clinic liver cancer (BCLC) criteria were used to stage HCC patients. Serum samples for measurement of prolidase and alpha-fetoprotein levels were kept at -80 °C until use. Prolidase levels were measured spectrophotometrically and AFP concentrations were determined by a chemiluminescence immunometric commercial diagnostic assay. In patients with HCC, prolidase and AFP values were evaluated according to tumor size, number, presence of macrovascular invasion and BCLC staging classification. Prolidase values were significantly higher in patients with HCC compared with controls (P < 0.001). Prolidase levels were significantly associated with tumor size and number (P < 0.001, P = 0.002, respectively). Prolidase levels also differed in patients in terms of BCLC staging classification (P < 0.001). Furthermore the prolidase levels in HCC patients showed a significant difference compared with patients with cirrhosis (P < 0.001). In HCC patients grouped according to tumor size, number and BCLC staging classification, AFP values differed separately (P = 0.032, P = 0.038, P = 0.015, respectively). In patients with HCC, there was a significant correlation (r = 0.616; P < 0.001) between prolidase and AFP values in terms of tumor size, number and BCLC staging classification, whereas the presence of macrovascular invasion did not show a positive association with serum prolidase and AFP levels. Considering the levels of both serum prolidase and AFP could contribute to the early diagnosing of hepatocellular carcinoma.

RITA inhibits growth of human hepatocellular carcinoma through induction of apoptosis.

PubMed

Wang, Haihe; Chen, Guofu; Wang, Hongzhi; Liu, Chunbo

2013-01-01

RBP-J-interacting and tubulin-associated (RITA) is a novel RBP-J-interacting protein that downregulates Notch-mediated transcription. The current study focuses on the antitumor effect of RITA in human hepatocellular carcinoma (HCC) and aims to explore its molecular mechanism. Thirty paired HCC and adjacent non-tumoral liver samples were analyzed by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). RITA overexpression was induced by transfection of a pcDNA3.1-Flag-RITA plasmid into HepG2 cells. RITA knockdown was achieved by siRNA transfection. mRNA and protein expression of target genes were quantified by qRT-PCR and Western blotting, respectively. Cell proliferation and apoptosis were measured using MTT assay and flow cytometry. Our results demonstrate that adjacent nontumoral liver samples exhibited increased RITA expression compared to HCC tissues (p < 0.05); RITA levels were associated with tumor differentiation status. Overexpression of RITA suppressed cell proliferation and promoted early apoptosis, while its silencing promoted cell growth dramatically (p < 0.05). RITA overexpression upregulated p53 and reduced cyclin E levels, whereas silencing of RITA had the opposite effect on p53 and cyclin E expression. Our in vitro results represent the first evidence that RITA might suppress tumor growth and induce apoptosis in HCCs, and may be a potent antitumoral agent for HCC treatment that deserves further exploration.

Proinflammatory cytokines cause FAT10 upregulation in cancers of liver and colon.

PubMed

Lukasiak, S; Schiller, C; Oehlschlaeger, P; Schmidtke, G; Krause, P; Legler, D F; Autschbach, F; Schirmacher, P; Breuhahn, K; Groettrup, M

2008-10-09

The mRNA of the ubiquitin-like modifier FAT10 has been reported to be overexpressed in 90% of hepatocellular carcinoma (HCC) and in over 80% of colon, ovary and uterus carcinomas. Elevated FAT10 expression in malignancies was attributed to transcriptional upregulation upon the loss of p53. Moreover, FAT10 induced chromosome instability in long-term in vitro culture, which led to the hypothesis that FAT10 might be involved in carcinogenesis. In this study we show that interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha synergistically upregulated FAT10 expression in liver and colon cancer cells 10- to 100-fold. Real-time RT-PCR revealed that FAT10 mRNA was significantly overexpressed in 37 of 51 (72%) of human HCC samples and in 8 of 15 (53%) of human colon carcinomas. The FAT10 cDNA sequences in HCC samples were not mutated and intact FAT10 protein was detectable. FAT10 expression in both cancer tissues correlated with expression of the IFN-gamma- and TNF-alpha-dependent proteasome subunit LMP2 strongly suggesting that proinflammatory cytokines caused the joint overexpression of FAT10 and LMP2. NIH3T3 transformation assays revealed that FAT10 had no transforming capability. Taken together, FAT10 qualifies as a marker for an interferon response in HCC and colon carcinoma but is not significantly overexpressed in cancers lacking a proinflammatory environment.

DNA methylation, microRNAs, and their crosstalk as potential biomarkers in hepatocellular carcinoma

PubMed Central

Anwar, Sumadi Lukman; Lehmann, Ulrich

2014-01-01

Epigenetic alterations have been identified as a major characteristic in human cancers. Advances in the field of epigenetics have contributed significantly in refining our knowledge of molecular mechanisms underlying malignant transformation. DNA methylation and microRNA expression are epigenetic mechanisms that are widely altered in human cancers including hepatocellular carcinoma (HCC), the third leading cause of cancer related mortality worldwide. Both DNA methylation and microRNA expression patterns are regulated in developmental stage specific-, cell type specific- and tissue-specific manner. The aberrations are inferred in the maintenance of cancer stem cells and in clonal cell evolution during carcinogenesis. The availability of genome-wide technologies for DNA methylation and microRNA profiling has revolutionized the field of epigenetics and led to the discovery of a number of epigenetically silenced microRNAs in cancerous cells and primary tissues. Dysregulation of these microRNAs affects several key signalling pathways in hepatocarcinogenesis suggesting that modulation of DNA methylation and/or microRNA expression can serve as new therapeutic targets for HCC. Accumulative evidence shows that aberrant DNA methylation of certain microRNA genes is an event specifically found in HCC which correlates with unfavorable outcomes. Therefore, it can potentially serve as a biomarker for detection as well as for prognosis, monitoring and predicting therapeutic responses in HCC. PMID:24976726

Hepatocellular carcinoma with both fibrolamellar and classical components: an unusual morphological pattern.

PubMed

Castro-Villabón, Diana; Barrera-Herrera, Luis E; Rodríguez-Urrego, Paula A; Hudacko, Rachel; Vera, Alonso; Álvarez, Johanna; Andrade, Rafael; López, Rocío

2015-01-01

Fibrolamellar carcinoma (FLC) is an uncommon form of primary liver malignancy with unique clinical, histological, and biological characteristics. It is usually seen in young adults without underlying liver disease. Histologically, it shows large cells with abundant eosinophilic cytoplasm, large vesicular nuclei, prominent nucleoli, and lamellar type fibrosis. In contrast, classical hepatocellular carcinoma (HCC) is typically present in elderly male patients with cirrhosis. It is the most common histological subtype, and it is characterized by its resemblance to the normal liver, both in its growth pattern and its cytology. The unusual case of a liver carcinoma that presented with histological features of both FLC and classical HCC is herein reported. This was the case of a 37-year-old female complaining of diffuse abdominal discomfort and epigastric pain for two months. She was referred to us for further management after she was diagnosed with HCC in a noncirrhotic liver. She underwent a left-sided hepatectomy. A yellow nodular mass with well-defined borders and a necrotic center was present in the resection specimen. The morphological features and immunohistochemical studies were consistent with a diagnosis of FLC mixed with classical HCC. The patient was followed up for five months, and no signs of recurrence were evident.

Prognostic value of site-specific extra-hepatic disease in hepatocellular carcinoma: a SEER database analysis.

PubMed

Oweira, Hani; Petrausch, Ulf; Helbling, Daniel; Schmidt, Jan; Mehrabi, Arianeb; Schöb, Othmar; Giryes, Anwar; Abdel-Rahman, Omar

2017-07-01

We the prognostic value of site-specific extra-hepatic disease in hepatocellular carcinoma (HCC) patients registered within the surveillance, epidemiology and end results (SEER) database. SEER database (2010-2013) has been queried through SEER*Stat program to determine the prognosis of advanced HCC patients according to the site of extra-hepatic disease. Survival analysis has been conducted through Kaplan Meier analysis. A total of 4396 patients with stage IV HCC were identified in the period from 2010-2013 and they were included into this analysis. Patients with isolated regional lymph node involvement have better outcomes compared to patients with any other site of extra-hepatic disease (P < 0.0001 for both endpoints). Among patients with distant metastases, patients with bone metastases have better outcomes compared to patients with lung metastases (P < 0.0001 for both endpoints). Multivariate analysis revealed that younger age, normal alpha fetoprotein, single site of extra-hepatic disease, local treatment to the primary tumor and surgery to the metastatic disease were associated with better overall survival and liver cancer-specific survival. Within the limits of the current SEER analysis, HCC patients with isolated lung metastases seem to have worse outcomes compared to patients with isolated bone or regional nodal metastases.​.

miR-133b Regulation of Connective Tissue Growth Factor

PubMed Central

Gjymishka, Altin; Pi, Liya; Oh, Seh-Hoon; Jorgensen, Marda; Liu, Chen; Protopapadakis, Yianni; Patel, Ashnee; Petersen, Bryon E.

2017-01-01

miRNAs are involved in liver regeneration, and their expression is dysregulated in hepatocellular carcinoma (HCC). Connective tissue growth factor (CTGF), a direct target of miR-133b, is crucial in the ductular reaction (DR)/oval cell (OC) response for generating new hepatocyte lineages during liver injury in the context of hepatotoxin-inhibited hepatocyte proliferation. Herein, we investigate whether miR-133b regulation of CTGF influences HCC cell proliferation and migration, and DR/OC response. We analyzed miR-133b expression and found it to be down-regulated in HCC patient samples and induced in the rat DR/OC activation model of 2-acetylaminofluorene with partial hepatectomy. Furthermore, overexpression of miR-133b via adenoviral system in vitro led to decreased CTGF expression and reduced proliferation and Transwell migration of both HepG2 HCC cells and WBF-344 rat OCs. In vivo, overexpression of miR-133b in DR/OC activation models of 2-acetylaminofluorene with partial hepatectomy in rats, and 3,5-diethoxycarbonyl-1,4-dihydrocollidine in mice, led to down-regulation of CTGF expression and OC proliferation. Collectively, these results show that miR-133b regulation of CTGF is a novel mechanism critical for the proliferation and migration of HCC cells and OC response. PMID:26945106

Salivary cortisol reactivity in preschoolers is associated with hair cortisol and behavioral problems.

PubMed

Kao, Katie; Doan, Stacey N; St John, Ashley M; Meyer, Jerrold S; Tarullo, Amanda R

2018-01-01

The interplay between children's cortisol reactivity to challenge and cumulative cortisol exposure is not well understood. Examining the role of cortisol reactivity in early childhood may elucidate biological mechanisms that contribute to children's chronic physiological stress and behavioral dysregulation. In a sample of 65 preschool-aged children, we examined the relation between children's salivary cortisol reactivity to challenging tasks and their hair cortisol concentration (HCC). While both are biomarkers of the hypothalamic-pituitary-adrenal (HPA) axis, salivary cortisol reactivity reflects an acute cortisol response to a stressor and HCC reflects cumulative cortisol exposure. In addition, we examined the relations of these stress biomarkers with internalizing and externalizing problems. Salivary cortisol reactivity was associated with higher HCC and with increased externalizing behaviors. Child HCC also was positively correlated with parent HCC. Results highlight the contributions of salivary cortisol reactivity to children's cumulative cortisol exposure, which may add to their biological risk for health problems later. The observed association between externalizing problems and salivary cortisol reactivity indicates concordances between dysregulated behavioral reactions and dysregulated cortisol responses to challenges. The finding that salivary cortisol reactivity to challenge in early childhood plays a role in children's cumulative cortisol exposure and behavioral development suggests pathways through which cortisol reactivity may influence long-term physical and mental health.

Phase-contrast CT: Qualitative and Quantitative Evaluation of Capillarized Sinusoids and Trabecular Structure in Human Hepatocellular Carcinoma Tissues.

PubMed

Jian, Jianbo; Zhang, Wenxue; Yang, Hao; Zhao, Xinyan; Xuan, Ruijiao; Li, Dongyue; Hu, Chunhong

2017-01-01

Capillarization of sinusoids and change of trabecular thickness are the main histologic features in hepatocellular carcinoma (HCC). Of particular interest are the three-dimensional (3D) visualization and quantitative evaluation of such alterations in the HCC progression. X-ray phase-contrast computed tomography (PCCT) is an emerging imaging method that provides excellent image contrast for soft tissues. This study aimed to explore the potential of in-line PCCT in microstructure imaging of capillarized sinusoids and trabecular structure in human HCC tissues and to quantitatively evaluate the alterations of those fine structures during the development of HCC. This project was designed as an ex vivo experimental study. The study was approved by the institutional review board, and informed consent was obtained from the patients. Eight human resected HCC tissue samples were imaged using in-line PCCT. After histologic processing, PCCT images and histopathologic data were matched. Fine structures in HCC tissues were revealed. Quantitative analyses of capillarized sinusoids (ie, percentage of sinusoidal area [PSA], sinusoidal volume) and trabecular structure (ie, trabecular thickness, surface-area-to-volume ratio [SA/V]) in low-grade (well or moderately differentiated) and high-grade (poorly differentiated) HCC groups were performed. Using PCCT, the alterations of capillarized sinusoids and trabecular structure were clearly observed in 3D geometry, which was confirmed by the corresponding histologic sections. The 3D qualitative analyses of sinusoids in the high-grade HCC group were significantly different (P < 0.05) in PSA (7.8 ± 2.5%) and sinusoidal volume (2.9 ± 0.6 × 10 7  µm 3 ) from those in the low-grade HCC group (PSA, 12.9 ± 2.2%; sinusoidal volume, 2.4 ± 0.3 × 10 7  µm 3 ). Moreover, the 3D quantitative evaluation of the trabecular structure in the high-grade HCC group showed a significant change (P < 0.05) in the trabecular thickness (87.8 ± 15.6 µm) and SA/V (2.2 ± 1.3 × 10 3  µm - 1 ) compared to the low-grade HCC group (trabecular thickness, 75.9 ± 7.1 µm; SA/V, 7.5 ± 1.3 × 10 3  µm - 1 ). This study provides insights into the 3D alterations of microstructures such as capillarized sinusoids and the trabecular structure at a micrometer level, which might allow for an improved understanding of the development of HCC. Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Pesticide exposure and liver cancer: a review

PubMed Central

VoPham, Trang; Bertrand, Kimberly A.; Hart, Jaime E.; Laden, Francine; Brooks, Maria M.; Yuan, Jian-Min; Talbott, Evelyn O.; Ruddell, Darren; Chang, Chung-Chou H.; Weissfeld, Joel L.

2017-01-01

Purpose To review the epidemiologic literature examining pesticide exposure and liver cancer incidence. Methods A search of the MEDLINE and Embase databases was conducted in October 2015. Eligibility criteria included examining hepatocellular carcinoma (HCC) or primary liver cancer, pesticides as an exposure of interest, and individual-level incidence. The review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Forty-eight papers were assessed for eligibility and 15 studies were included in the review. The majority of studies were conducted in China and Egypt (n=8), used a case-control design (n=14), and examined HCC (n=14). Most studies showed no association between self-reported and/or occupational exposure to pesticides and liver cancer risk. Six studies demonstrated statistically significant positive associations, including three biomarker-based studies (two using pre-diagnostic sera) that reported higher serum levels of dichlorodiphenyltrichloroethane (DDT) were associated with increased HCC risk. Studies indirectly measuring pesticide exposure using self-reported exposure, occupation, job-exposure matrices, or geographic residence demonstrated inconsistent results. These studies were limited by exposure assessment methods, lack of confounder information, minimal case confirmation, selection bias, and/or over-adjustment. Conclusions There is mixed evidence suggesting a possible association between specific pesticides and HCC risk, with the strongest evidence observed in biomarker-based studies. In particular, organochlorine pesticides, including DDT, may increase HCC risk. Future research should focus on improved pesticide exposure assessment methods, potentially incorporating multiple approaches including biomonitoring while considering the chemicals of interest, historical exposure to address latency periods, and examining specific chemicals and exposure pathways. PMID:28194594

Functional polymorphisms of circadian negative feedback regulation genes are associated with clinical outcome in hepatocellular carcinoma patients receiving radical resection.

PubMed

Zhang, Zhaohui; Ma, Fei; Zhou, Feng; Chen, Yibing; Wang, Xiaoyan; Zhang, Hongxin; Zhu, Yong; Bi, Jianwei; Zhang, Yiguan

2014-12-01

Previous studies have demonstrated that circadian negative feedback loop genes play an important role in the development and progression of many cancers. However, the associations between single-nucleotide polymorphisms (SNPs) in these genes and the clinical outcomes of hepatocellular carcinoma (HCC) after surgical resection have not been studied so far. Thirteen functional SNPs in circadian genes were genotyped using the Sequenom iPLEX genotyping system in a cohort of 489 Chinese HCC patients who received radical resection. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis. Cumulative effect analysis and survival tree analysis were used for the multiple SNPs analysis. Four individual SNPs, including rs3027178 in PER1, rs228669 and rs2640908 in PER3 and rs3809236 in CRY1, were significantly associated with overall survival (OS) of HCC patients, and three SNPs, including rs3027178 in PER1, rs228729 in PER3 and rs3809236 in CRY1, were significantly associated with recurrence-free survival (RFS). Moreover, we observed a cumulative effect of significant SNPs on OS and RFS (P for trend < 0.001 for both). Survival tree analysis indicated that wild genotype of rs228729 in PER3 was the primary risk factor contributing to HCC patients' RFS. Our study suggests that the polymorphisms in circadian negative feedback loop genes may serve as independent prognostic biomarkers in predicting clinical outcomes for HCC patients who received radical resection. Further studies with different ethnicities are needed to validate our findings and generalize its clinical utility.

A nomogram incorporating six easily obtained parameters to discriminate intrahepatic cholangiocarcinoma and hepatocellular carcinoma.

PubMed

Wang, Mengmeng; Gao, Yuzhen; Feng, Huijuan; Warner, Elisa; An, Mingrui; Jia, Jian'an; Chen, Shipeng; Fang, Meng; Ji, Jun; Gu, Xing; Gao, Chunfang

2018-03-01

Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are the most prevalent histologic types of primary liver cancer (PLC). Although ICC and HCC share similar risk factors and clinical manifestations, ICC usually bears poorer prognosis than HCC. Confidently discriminating ICC and HCC before surgery is beneficial to both treatment and prognosis. Given the lack of effective differential diagnosis biomarkers and methods, construction of models based on available clinicopathological characteristics is in need. Nomograms present a simple and efficient way to make a discrimination. A total of 2894 patients who underwent surgery for PLC were collected. Of these, 1614 patients formed the training cohort for nomogram construction, and thereafter, 1280 patients formed the validation cohort to confirm the model's performance. Histopathologically confirmed ICC was diagnosed in 401 (24.8%) and 296 (23.1%) patients in these two cohorts, respectively. A nomogram integrating six easily obtained variables (Gender, Hepatitis B surface antigen, Aspartate aminotransferase, Alpha-fetoprotein, Carcinoembryonic antigen, Carbohydrate antigen 19-9) is proposed in accordance with Akaike's Information Criterion (AIC). A score of 15 was determined as the cut-off value, and the corresponding discrimination efficacy was sufficient. Additionally, patients who scored higher than 15 suffered poorer prognosis than those with lower scores, regardless of the subtype of PLC. A nomogram for clinical discrimination of ICC and HCC has been established, where a higher score indicates ICC and poor prognosis. Further application of this nomogram in multicenter investigations may confirm the practicality of this tool for future clinical use. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Temporal Trends of Non-alcoholic Fatty Liver Disease-related Hepatocellular Carcinoma in the Veteran Affairs Population

PubMed Central

Mittal, Sahil; Sada, Yvonne H.; El-Serag, Hashem B.; Kanwal, Fasiha; Duan, Zhigang; Temple, Sarah; May, Sarah B.; Kramer, Jennifer R.; Richardson, Peter A.; Davila, Jessica A.

2014-01-01

Background & Aims Non-alcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC). However, no systemic studies from the United States have examined temporal trends, HCC surveillance practices, and outcomes of NAFLD-related HCC. Methods We identified a national cohort of 1500 patients who developed HCC from 2005 through 2010 from Veterans Administration (VA) hospitals. We reviewed patients’ full VA medical records; NAFLD was diagnosed based on histologic evidence for, or the presence of, metabolic syndrome in the absence of hepatitis C virus (HCV) infection, hepatitis B, or alcoholic liver disease. We compared annual prevalence values for the main risk factors (NAFLD, alcohol abuse, HCV), as well HCC surveillance and outcomes, among HCC patients. Results NAFLD was the underlying risk factor for HCC in 120 patients (8.0%); the annual proportion of NAFLD-related HCC remained relatively stable (7.5%–12.0%). In contrast, the proportion of HCC cases associated with HCV increased from 61.0% in 2005 (95% confidence interval, 53.1%–68.9%) to 74.9% in 2010 (95% confidence interval, 69.0%–80.7%). The proportion of HCC cases associated with only alcohol abuse decreased from 21.9% in 2005 to 15.7% in 2010, and the annual proportion of HCC cases associated with hepatitis B remained relatively stable (1.4%–3.5%). A significantly lower proportion of patients with NAFLD-related HCC had cirrhosis (58.3%) compared to patients with alcohol- or HCV-related HCC (72.4% and 85.6%, respectively; P<.05). A significantly higher percentage of patients with NAFLD-related HCC did not receive HCC surveillance in the 3 years before their HCC diagnosis, compared to patients with alcohol- or HCV-associated HCC. A lower proportion of patients with NAFLD-related HCC received HCC-specific treatment (61.5%) than of patients with HCV-related HCC (77.5%; P<.01). However, 1-year survival did not differ among patients with HCC related to different risk factors. Conclusions NAFLD is the third most common risk factor for HCC in the VA. The proportion of NAFLD-related HCC was relatively stable from 2005 through 2010. Although patients with NAFLD-related HCC receive less HCC surveillance and treatment, a similar proportion survive for 1 year, compared to patients with alcohol- or HCV-related HCC. PMID:25148760

miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis.

PubMed

Van Renne, Nicolaas; Roca Suarez, Armando Andres; Duong, Francois H T; Gondeau, Claire; Calabrese, Diego; Fontaine, Nelly; Ababsa, Amina; Bandiera, Simonetta; Croonenborghs, Tom; Pochet, Nathalie; De Blasi, Vito; Pessaux, Patrick; Piardi, Tullio; Sommacale, Daniele; Ono, Atsushi; Chayama, Kazuaki; Fujita, Masashi; Nakagawa, Hidewaki; Hoshida, Yujin; Zeisel, Mirjam B; Heim, Markus H; Baumert, Thomas F; Lupberger, Joachim

2018-05-01

HCV infection is a leading risk factor of hepatocellular carcinoma (HCC). However, even after viral clearance, HCC risk remains elevated. HCV perturbs host cell signalling to maintain infection, and derailed signalling circuitry is a key driver of carcinogenesis. Since protein phosphatases are regulators of signalling events, we aimed to identify phosphatases that respond to HCV infection with relevance for hepatocarcinogenesis. We assessed mRNA and microRNA (miRNA) expression profiles in primary human hepatocytes, liver biopsies and resections of patients with HCC, and analysed microarray and RNA-seq data from paired liver biopsies of patients with HCC. We revealed changes in transcriptional networks through gene set enrichment analysis and correlated phosphatase expression levels to patient survival and tumour recurrence. We demonstrate that tumour suppressor protein tyrosine phosphatase receptor delta (PTPRD) is impaired by HCV infection in vivo and in HCC lesions of paired liver biopsies independent from tissue inflammation or fibrosis. In liver tissue adjacent to tumour, high PTPRD levels are associated with a dampened transcriptional activity of STAT3, an increase of patient survival from HCC and reduced tumour recurrence after surgical resection. We identified miR-135a-5p as a mechanistic regulator of hepatic PTPRD expression in patients with HCV. We previously demonstrated that STAT3 is required for HCV infection. We conclude that HCV promotes a STAT3 transcriptional programme in the liver of patients by suppressing its regulator PTPRD via upregulation of miR-135a-5p. Our results show the existence of a perturbed PTPRD-STAT3 axis potentially driving malignant progression of HCV-associated liver disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Microfluidic chip for isolation of viable circulating tumor cells of hepatocellular carcinoma for their culture and drug sensitivity assay.

PubMed

Zhang, Yu; Zhang, Xiaofeng; Zhang, Jinling; Sun, Bin; Zheng, Lulu; Li, Jun; Liu, Sixiu; Sui, Guodong; Yin, Zhengfeng

2016-11-01

Circulating tumor cells (CTCs) have been proposed to be an active source of metastasis or recurrence of hepatocellular carcinoma (HCC). The enumeration and characterization of CTCs has important clinical significance in recurrence prediction and treatment monitoring in HCC patients. We previously developed a unique method to separate HCC CTCs based on the interaction of the asialoglycoprotein receptor (ASGPR) expressed on their membranes with its ligand. The current study applied the ligand-receptor binding assay to a CTC-chip in a microfluidic device. Efficient capture of HCC CTCs originates from the small dimensions of microfluidic channels and enhanced local topographic interactions between the microfluidic channel and extracellular extensions. With the optimized conditions, a capture yield reached > 85% for artificial CTC blood samples. Clinical utility of the system was further validated. CTCs were detected in all the examined 36 patients with HCC, with an average of 14 ± 10/2 mL. On the contrary, no CTCs were detected in healthy, benign liver disease or non-HCC cancer subjects. The current study also successfully demonstrated that the captured CTCs on our CTC-chip were readily released with ethylene diamine tetraacetic acid (EDTA); released CTCs remained alive and could be expanded to form a spheroid-like structure in a 3-dimensional cell culture assay; furthermore, sensitivity of released CTCs to chemotherapeutic agents (sorafenib or oxaliplatin) could be effectively tested utilizing this culture assay. In conclusion, the methodologies presented here offer great promise for accurate enumeration and easy release of captured CTCs, and released CTCs could be cultured for further functional studies.

Serum metabolome profiles characterized by patients with hepatocellular carcinoma associated with hepatitis B and C.

PubMed

Saito, Takafumi; Sugimoto, Masahiro; Okumoto, Kazuo; Haga, Hiroaki; Katsumi, Tomohiro; Mizuno, Kei; Nishina, Taketo; Sato, Sonoko; Igarashi, Kaori; Maki, Hiroko; Tomita, Masaru; Ueno, Yoshiyuki; Soga, Tomoyoshi

2016-07-21

To clarify the characteristics of metabolite profiles in virus-related hepatocellular carcinoma (HCC) patients using serum metabolome analysis. The serum levels of low-molecular-weight metabolites in 68 patients with HCC were quantified using capillary electrophoresis chromatography and mass spectrometry. Thirty and 38 of the patients suffered from hepatitis B virus-related HCC (HCC-B) and hepatitis C virus-related HCC (HCC-C), respectively. The main metabolites characteristic of HCC were those associated with glutathione metabolism, notably 13 γ-glutamyl peptides, which are by-products of glutathione induction. Two major profiles, i.e., concentration patterns, of metabolites were identified in HCC patients, and these were classified into two groups: an HCC-B group and an HCC-C group including some of the HCC-B cases. The receiver operating characteristic curve for the multiple logistic regression model discriminating HCC-B from HCC-C incorporating the concentrations of glutamic acid, methionine and γ-glutamyl-glycine-glycine showed a highly significant area under the curve value of 0.94 (95%CI: 0.89-1.0, P < 0.0001). The serum levels of γ-glutamyl peptides, as well as their concentration patterns, contribute to the development of potential biomarkers for virus-related HCC. The difference in metabolite profiles between HCC-B and HCC-C may reflect the respective metabolic reactions that underlie the different pathogeneses of these two types of HCC.

Infection with hepatitis C virus depends on TACSTD2, a regulator of claudin-1 and occludin highly downregulated in hepatocellular carcinoma

PubMed Central

Alayli, Farah; Melis, Marta; Kabat, Juraj; Pomerenke, Anna; Altan-Bonnet, Nihal; Zamboni, Fausto; Emerson, Suzanne U.

2018-01-01

Entry of hepatitis C virus (HCV) into hepatocytes is a complex process that involves numerous cellular factors, including the scavenger receptor class B type 1 (SR-B1), the tetraspanin CD81, and the tight junction (TJ) proteins claudin-1 (CLDN1) and occludin (OCLN). Despite expression of all known HCV-entry factors, in vitro models based on hepatoma cell lines do not fully reproduce the in vivo susceptibility of liver cells to primary HCV isolates, implying the existence of additional host factors which are critical for HCV entry and/or replication. Likewise, HCV replication is severely impaired within hepatocellular carcinoma (HCC) tissue in vivo, but the mechanisms responsible for this restriction are presently unknown. Here, we identify tumor-associated calcium signal transducer 2 (TACSTD2), one of the most downregulated genes in primary HCC tissue, as a host factor that interacts with CLDN1 and OCLN and regulates their cellular localization. TACSTD2 gene silencing disrupts the typical linear distribution of CLDN1 and OCLN along the cellular membrane in both hepatoma cells and primary human hepatocytes, recapitulating the pattern observed in vivo in primary HCC tissue. Mechanistic studies suggest that TACSTD2 is involved in the phosphorylation of CLDN1 and OCLN, which is required for their proper cellular localization. Silencing of TACSTD2 dramatically inhibits HCV infection with a pan-genotype effect that occurs at the level of viral entry. Our study identifies TACSTD2 as a novel regulator of two major HCV-entry factors, CLDN1 and OCLN, which is strongly downregulated in malignant hepatocytes. These results provide new insights into the complex process of HCV entry into hepatocytes and may assist in the development of more efficient cellular systems for HCV propagation in vitro. PMID:29538454

HBX Protein-Induced Downregulation of microRNA-18a is Responsible for Upregulation of Connective Tissue Growth Factor in HBV Infection-Associated Hepatocarcinoma.

PubMed

Liu, Xiaomin; Zhang, Yingjian; Wang, Ping; Wang, Hongyun; Su, Huanhuan; Zhou, Xin; Zhang, Lamei

2016-07-16

BACKGROUND This study was designed to improve our understanding of the role of miR-18a and its target (connective tissue growth factor (CTGF), which are mediators in HBX-induced hepatocellular carcinoma (HCC). MATERIAL AND METHODS We first investigated the expression of several candidate microRNAs (miRNAs) reported to have been aberrantly expressed between HepG2 and HepG2.2.15, which is characterized by stable HBV infection, while the CTGF is identified as a target of miR-18a. Furthermore, the expression of CTGF evaluated in HepG2 was transfected with HBX, while the HepG2.2.15 was transfected with miR-18a and CTGF siRNA. We examined the cell cycle at the same time. RESULTS We found that the expression of miR-18a was abnormally reduced in the HBV-positive HCC tissue samples compared with HBV-negative HCC samples. Through the use of a luciferase reporter system, we also identified CTGF 3'UTR (1046-1052 bp) as the exact binding site for miR-18a. We also observed a clear increase in CTGF mRNA and protein expression levels in HBV-positive HCC human tissue samples in comparison with the HBV-negative controls, indicating a possible negatively associated relationship between miR-18a and CTGF. Furthermore, we investigated the effect of HBX overexpression on miR-18a and CTGF, as well as the viability and cell cycle status of HepG2 cells. In addition, we found that HBX introduction downregulated miR-18a, upregulated CTGF, elevated the viability, and promoted cell cycle progression. We transfected HepG2.2.15 with miR-18a mimics and CTGF siRNA, finding that upregulated miR-18a and downregulated CTGF suppress the viability and cause cell cycle arrest. CONCLUSIONS Our study shows the role of the CTGF gene as a target of miR-18a, and identifies the function of HBV/HBX/miR-18a/CTGF as a key signaling pathway mediating HBV infection-induced HCC.

Studies on piston bowl geometries using single blend ratio of various non-edible oils.

PubMed

Viswanathan, Karthickeyan; Pasupathy, Balamurugan

2017-07-01

The depletion of fossil fuels and hike in crude oil prices were some of the main reasons to explore new alternatives from renewable source of energy. This work presents the impact of various bowl geometries on diesel engine with diesel and biodiesel samples. Three non-edible oils were selected, namely pumpkin seed oil, orange oil and neem oil. These oils were converted into respective biodiesel using transesterification process in the presence of catalyst and alcohol. After transesterification process, the oils were termed as pumpkin seed oil methyl ester (PSOME), orange oil methyl ester (OME) and neem oil methyl ester (NOME), respectively. The engine used for experimentation was a single-cylinder four-stroke water-cooled direct-injection diesel engine and loads were applied to the engine using eddy current dynamometer. Two bowl geometries were developed, namely toroidal combustion chamber (TCC) and trapezoidal combustion chamber (TRCC). Also, the engine was inbuilt with hemispherical combustion chamber (HCC). The base line readings were recorded using neat diesel fuel with HCC for various loads. Followed by 20% of biodiesel mixed with 80% neat diesel for all prepared methyl esters and termed as B1 (20% PSOME with 80% diesel), B2 (20% OME with 80% diesel) and B3 (20% NOME with 80% diesel). All fuel samples were tested in HCC, TCC and TRCC bowl geometries under standard injection timing and with compression ratio of 18. Increased brake thermal efficiency and reduced brake specific fuel consumption were observed with diesel in TCC geometry. Also, higher heat release and cylinder pressures with lower ignition delay were recorded with TCC bowl geometry. TCC bowl geometry showed lower CO, HC and smoke emissions with B2 fuel sample than diesel and other biodiesel samples. But, higher NOx emission was observed in HCC and TCC than that in TRCC bowl geometry. Graphical abstract ᅟ.

MicroRNA-124-3p expression and its prospective functional pathways in hepatocellular carcinoma: A quantitative polymerase chain reaction, gene expression omnibus and bioinformatics study.

PubMed

He, Rong-Quan; Yang, Xia; Liang, Liang; Chen, Gang; Ma, Jie

2018-04-01

The present study aimed to explore the potential clinical significance of microRNA (miR)-124-3p expression in the hepatocarcinogenesis and development of hepatocellular carcinoma (HCC), as well as the potential target genes of functional HCC pathways. Reverse transcription-quantitative polymerase chain reaction was performed to evaluate the expression of miR-124-3p in 101 HCC and adjacent non-cancerous tissue samples. Additionally, the association between miR-124-3p expression and clinical parameters was also analyzed. Differentially expressed genes identified following miR-124-3p transfection, the prospective target genes predicted in silico and the key genes of HCC obtained from Natural Language Processing (NLP) were integrated to obtain potential target genes of miR-124-3p in HCC. Relevant signaling pathways were assessed with protein-protein interaction (PPI) networks, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein Annotation Through Evolutionary Relationships (PANTHER) pathway enrichment analysis. miR-124-3p expression was significantly reduced in HCC tissues compared with expression in adjacent non-cancerous liver tissues. In HCC, miR-124-3p was demonstrated to be associated with clinical stage. The mean survival time of the low miR-124-3p expression group was reduced compared with that of the high expression group. A total of 132 genes overlapped from differentially expressed genes, miR-124-3p predicted target genes and NLP identified genes. PPI network construction revealed a total of 109 nodes and 386 edges, and 20 key genes were identified. The major enriched terms of three GO categories included regulation of cell proliferation, positive regulation of cellular biosynthetic processes, cell leading edge, cytosol and cell projection, protein kinase activity, transcription activator activity and enzyme binding. KEGG analysis revealed pancreatic cancer, prostate cancer and non-small cell lung cancer as the top three terms. Angiogenesis, the endothelial growth factor receptor signaling pathway and the fibroblast growth factor signaling pathway were identified as the most significant terms in the PANTHER pathway analysis. The present study confirmed that miR-124-3p acts as a tumor suppressor in HCC. miR-124-3p may target multiple genes, exerting its effect spatiotemporally, or in combination with a diverse range of processes in HCC. Functional characterization of miR-124-3p targets will offer novel insight into the molecular changes that occur in HCC progression.

Perioperative plasma glypican-3 level may enable prediction of the risk of recurrence after surgery in patients with stage I hepatocellular carcinoma.

PubMed

Ofuji, Kazuya; Saito, Keigo; Suzuki, Shiro; Shimomura, Manami; Shirakawa, Hirofumi; Nobuoka, Daisuke; Sawada, Yu; Yoshimura, Mayuko; Tsuchiya, Nobuhiro; Takahashi, Mari; Yoshikawa, Toshiaki; Tada, Yoshitaka; Konishi, Masaru; Takahashi, Shinichiro; Gotohda, Naoto; Nakamoto, Yasunari; Nakatsura, Tetsuya

2017-06-06

Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored cell surface protein overexpressed in hepatocellular carcinoma(HCC), and its overexpression is associated with poor prognosis. The diagnostic potential of GPC3 as a serum marker has been reported. In the present study, we evaluated the usefulness of plasma GPC3 as a predictor for recurrence after surgical resection in stage I HCC patients by newly developed an enzyme-linked immunosorbent assay (ELISA) system. Current study demonstrated that high levels of preoperative plasma GPC3 patients tended to experience postoperative recurrence. On the other hand, pre- and postoperative plasma GPC3 positivity of non-recurrence patients was very low. Moreover, even after surgery, approximately half of patients who experienced recurrence were positive for plasma GPC3. Postoperative plasma GPC3 positivity was significantly correlated with worse recurrence-free survival. Immuohistochemical analysis also showed positive rate of GPC3-expression in HCC was higher in recurrence patients than in non-recurrence patients. These results suggested that both pre- and postoperative plasma GPC3 levels may be accurate predictors for recurrence after curative resection of early-stage HCC. It should be noted that the current study only examined a small number of cases; thus, a larger sample size is necessary to validate GPC3 as a predictor for HCC recurrence.

CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma.

PubMed

Gao, Qiang; Zhao, Ying-Jun; Wang, Xiao-Ying; Qiu, Shuang-Jian; Shi, Ying-Hong; Sun, Jian; Yi, Yong; Shi, Jie-Yi; Shi, Guo-Ming; Ding, Zhen-Bin; Xiao, Yong-Sheng; Zhao, Zhong-Hua; Zhou, Jian; He, Xiang-Huo; Fan, Jia

2012-07-15

CXC chemokines and their cognate receptors have been implicated widely in cancer pathogenesis. In this study, we report a critical causal relationship between CXCR6 expression and tumorigenesis in the setting of human hepatocellular carcinoma (HCC). Among the CXC chemokine receptors, only CXCR6 was detected in all the hepatoma cell lines studied. Moreover, in HCC tissue, CXCR6 expression was significantly higher than in noncancerous liver tissues. Reduction of CXCR6 or its ligand CXCL16 in cancer cells reduced cell invasion in vitro and tumor growth, angiogenesis, and metastases in vivo. Importantly, loss of CXCR6 led to reduced Gr-1+ neutrophil infiltration and decreased neoangiogenesis in hepatoma xenografts via inhibition of proinflammatory cytokine production. Clinically, high expression of CXCR6 was an independent predictor of increased recurrence and poor survival in HCCs. Human HCC samples expressing high levels of CXCR6 also contained an increased number of CD66b+ neutrophils and microvessels, and the combination of CXCR6 and neutrophils was a superior predictor of recurrence and survival than either marker used alone. Together, our findings suggest that elevated expression of CXCR6 promotes HCC invasiveness and a protumor inflammatory environment and is associated with poor patient outcome. These results support the concept that inhibition of the CXCR6-CXCL16 pathway may improve prognosis after HCC treatment.

Quantitative proteome analysis reveals the correlation between endocytosis-associated proteins and hepatocellular carcinoma dedifferentiation.

PubMed

Naboulsi, Wael; Bracht, Thilo; Megger, Dominik A; Reis, Henning; Ahrens, Maike; Turewicz, Michael; Eisenacher, Martin; Tautges, Stephanie; Canbay, Ali E; Meyer, Helmut E; Weber, Frank; Baba, Hideo A; Sitek, Barbara

2016-11-01

The majority of poorly differentiated hepatocellular carcinomas (HCCs) develop from well-differentiated tumors. Endocytosis is a cellular function which is likely to take part in this development due to its important role in regulating the abundances of vital signaling receptors. Here, we aimed to investigate the abundance of endocytosis-associated proteins in HCCs with various differentiation grades. Therefore, we analyzed 36 tissue specimens from HCC patients via LC-MS/MS-based label-free quantitative proteomics including 19 HCC tissue samples with different degrees of histological grades and corresponding non-tumorous tissue controls. As a result, 277 proteins were differentially regulated between well-differentiated tumors and controls. In moderately and poorly differentiated tumors, 278 and 1181 proteins, respectively, were significantly differentially regulated compared to non-tumorous tissue. We explored the regulated proteins based on their functions and identified thirty endocytosis-associated proteins, mostly overexpressed in poorly differentiated tumors. These included proteins that have been shown to be up-regulated in HCC like clathrin heavy chain-1 (CLTC) as well as unknown proteins, such as secretory carrier-associated membrane protein 3 (SCAMP3). The abundances of SCAMP3 and CLTC were immunohistochemically examined in tissue sections of 84 HCC patients. We demonstrate the novel association of several endocytosis-associated proteins, in particular, SCAMP3 with HCC progression. Copyright © 2016 Elsevier B.V. All rights reserved.

Chemotherapy for hepatocellular carcinoma: The present and the future

PubMed Central

Le Grazie, Marco; Biagini, Maria Rosa; Tarocchi, Mirko; Polvani, Simone; Galli, Andrea

2017-01-01

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it’s still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatin- and gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC. PMID:28824742

Hippo Cascade Controls Lineage Commitment of Liver Tumors in Mice and Humans.

PubMed

Zhang, Shanshan; Wang, Jingxiao; Wang, Haichuan; Fan, Lingling; Fan, Biao; Zeng, Billy; Tao, Junyan; Li, Xiaolei; Che, Li; Cigliano, Antonio; Ribback, Silvia; Dombrowski, Frank; Chen, Bin; Cong, Wenming; Wei, Lixin; Calvisi, Diego F; Chen, Xin

2018-04-01

Primary liver cancer consists mainly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A subset of human HCCs expresses a ICC-like gene signature and is classified as ICC-like HCC. The Hippo pathway is a critical regulator of normal and malignant liver development. However, the precise function(s) of the Hippo cascade along liver carcinogenesis remain to be fully delineated. The role of the Hippo pathway in a murine mixed HCC/ICC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated. The authors demonstrated the inactivation of Hippo in AKT/Ras liver tumors leading to nuclear localization of Yap and TAZ. Coexpression of AKT/Ras with Lats2, which activates Hippo, or the dominant negative form of TEAD2 (dnTEAD2), which blocks Yap/TAZ activity, resulted in delayed hepatocarcinogenesis and elimination of ICC-like lesions in the liver. Mechanistically, Notch2 expression was found to be down-regulated by the Hippo pathway in liver tumors. Overexpression of Lats2 or dnTEAD2 in human HCC cell lines inhibited their growth and led to the decreased expression of ICC-like markers, as well as Notch2 expression. Altogether, this study supports the key role of the Hippo cascade in regulating the differentiation status of liver tumors. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

A comparative study of sorafenib and metronomic chemotherapy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma with poor liver function.

PubMed

Yang, Hyun; Woo, Hyun Young; Lee, Soon Kyu; Han, Ji Won; Jang, Bohyun; Nam, Hee Chul; Lee, Hae Lim; Lee, Sung Won; Song, Do Seon; Song, Myeong Jun; Oh, Jung Suk; Chun, Ho Jong; Jang, Jeong Won; Lozada, Angelo; Bae, Si Hyun; Choi, Jong Young; Yoon, Seung Kew

2017-06-01

Metronomic chemotherapy (MET) is frequently administered in comparatively low doses as a continuous chemotherapeutic agent. The aim of this study was to evaluate the feasibility and overall survival (OS) of MET compared to sorafenib for advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). A total of 54 patients with advanced HCC and PVTT who had undergone MET were analyzed between 2005 and 2013. A total of 53 patients who had undergone sorafenib therapy were analyzed as the control group. The primary endpoint of this study was OS. The median number of MET cycles was two (1-15). The OS values for the MET group and sorafenib group were 158 days (132-184) and 117 days (92-142), respectively ( P =0.029). The Cox proportional-hazard model showed that a higher risk of death was correlated with higher serum alpha fetoprotein level (≥400 mg/dL, hazard ratio [HR]=1.680, P =0.014) and Child-Pugh class B (HR=1.856, P =0.008). MET was associated with more favorable outcomes in terms of overall survival than was sorafenib in patients with advanced HCC with PVTT, especially in patients with poor liver function. Therefore, MET can be considered as a treatment option in patients with advanced HCC with PVTT and poor liver function.

Chemotherapy for hepatocellular carcinoma: The present and the future.

PubMed

Le Grazie, Marco; Biagini, Maria Rosa; Tarocchi, Mirko; Polvani, Simone; Galli, Andrea

2017-07-28

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it's still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatin- and gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

Interaction of S100A1 with LATS1 promotes cell growth through regulation of the Hippo pathway in hepatocellular carcinoma.

PubMed

Guo, Qingping; Wang, Jiale; Cao, Zeyu; Tang, Yongchang; Feng, Chao; Huang, Feizhou

2018-06-05

Despite advances in surgery and chemotherapy, the prognosis of patients with hepatocellular carcinoma (HCC) remains poor. In the present study, the role of S100A1 in the progression of HCC was investigated. Immunohistochemical staining was used to measure the expression of S100A1 in HCC tissues. S100A1 was knocked down by siRNA. A battery of experiments was used to evaluate the biology functions of S100A1. It was found that S100A1 was upregulated in HCC tissues, and its upregulation was associated with a large tumor size, low differentiation and shorter survival time. The biological experiments demonstrated that S100A1 functions as an oncogene in HCC. It was also found that S100A1 knockdown enhanced the inhibitory effects of cisplatin on HCC cells. The results showed that the downregulation of S100A1 induced the phosphorylation of yes‑associated protein (YAP), and treatment with CHX demonstrated that the downregulation of S100A1 accelerated YAP protein degradation. The downregulation of S100A1 did not alter the expression of mammalian sterile 20‑like kinase (MST)1/2 or phosphorylated MST1/2, but upregulated the phosphorylation of large tumor suppressor kinase 1 (LATS1). It was further confirmed that S100A1 interacted with LATS1. LATS1 depletion significantly reduced the effects of S100A1 on cell growth rate and apoptosis, and there was a positive correlation between phosphorylated LATS1 and S100A1 in clinical samples, indicating that LATS1 was responsible for the S100A1-induced changes in cancer cell growth and Hippo signaling. In conclusion, the results of the present study indicated that S100A1 functions as an oncogene and may be a biomarker for the prognosis of patients with HCC. S100A1 exerted its oncogenic function by interacting with LATS1 and activating YAP. S100A1 may serve as a target for novel therapies in HCC.

Aldo-Keto Reductases as Early Biomarkers of Hepatocellular Carcinoma: A Comparison Between Animal Models and Human HCC.

PubMed

Torres-Mena, Julia Esperanza; Salazar-Villegas, Karla Noemí; Sánchez-Rodríguez, Ricardo; López-Gabiño, Belém; Del Pozo-Yauner, Luis; Arellanes-Robledo, Jaime; Villa-Treviño, Saúl; Gutiérrez-Nava, María Angélica; Pérez-Carreón, Julio Isael

2018-04-01

The intrinsic heterogeneity of hepatocellular carcinoma (HCC) represents a great challenge for its molecular classification and for detecting predictive biomarkers. Aldo-keto reductase (Akr) family members have shown differential expression in human HCC, while AKR1B10 overexpression is considered a biomarker; AKR7A3 expression is frequently reduced in HCC. To investigate the time-course expression of Akr members in the experimental hepatocarcinogenesis. Using DNA-microarray data, we analyzed the time-course gene expression profile from nodules to tumors (4-17 months) of 17 Akr members induced by the resistant hepatocyte carcinogenesis model in the rat. The expression of six members (Akr1c19, Akr1b10, Akr7a3, Akr1b1, Akr1cl1, and Akr1b8) was increased, comparable to that of Ggt and Gstp1, two well-known liver cancer markers. In particular, Akr7a3 and Akr1b10 expression also showed a time-dependent increment at mRNA and protein levels in a second hepatocarcinogenesis model induced with diethylnitrosamine. We confirmed that aldo-keto reductases 7A3 and 1B10 were co-expressed in nine biopsies of human HCC, independently from the presence of glypican-3 and cytokeratin-19, two well-known HCC biomarkers. Because it has been suggested that expression of Akr members is regulated through NRF2 activity at the antioxidant response element (ARE) sequences, we searched and identified at least two ARE sites in Akr1b1, Akr1b10, and Akr7a3 from rat and human gene sequences. Moreover, we observed higher NRF2 nuclear translocation in tumors as compared with non-tumor tissues. Our results demonstrate that Akr7a3 mRNA and protein levels are consistently co-expressed along with Akr1b10, in both experimental liver carcinogenesis and some human HCC samples. These results highlight the presence of AKR7A3 and AKR1B10 from early stages of the experimental HCC and introduce them as a potential application for early diagnosis, staging, and prognosis in human cancer.

Surgery for Intermediate and Advanced Hepatocellular Carcinoma: A Consensus Report from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014).

PubMed

Ho, Ming-Chih; Hasegawa, Kiyoshi; Chen, Xiao-Ping; Nagano, Hiroaki; Lee, Young-Joo; Chau, Gar-Yang; Zhou, Jian; Wang, Chih-Chi; Choi, Young Rok; Poon, Ronnie Tung-Ping; Kokudo, Norihiro

2016-10-01

The Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy does not recommended surgery for treating BCLC stage B and C hepatocellular carcinoma (HCC). However, numerous Asia-Pacific institutes still perform surgery for this patient group. This consensus report from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting aimed to share opinions and experiences pertaining to liver resection for intermediate and advanced HCCs and to provide evidence to issue recommendations for surgery in this patient group. Thirteen experts from five Asia-Pacific regions were invited to the meeting; 10 of them (Japan: 2, Taiwan: 3, South Korea: 2, Hong Kong: 1, and China: 2) voted for the final consensus. The discussion focused on evaluating the preoperative liver functional reserve and surgery for large tumors, multiple tumors, HCCs with vascular invasion, and HCCs with distant metastasis. The feasibility of future prospective randomized trials comparing surgery with transarterial chemoembolization for intermediate HCC and with sorafenib for advanced HCC was also discussed. The Child-Pugh score (9/10 experts) and indocyanine green retention rate at 15 min (8/10) were the most widely accepted methods for evaluating the preoperative liver functional reserve. All (10/10) experts agreed that portal hypertension, tumor size >5 cm, portal venous invasion, hepatic venous invasion, and extrahepatic metastasis are not absolute contraindications for the surgical resection of HCC. Furthermore, 9 of the 10 experts agreed that tumor resection may be performed for patients with >3 tumors. The limitations of surgery are associated with a poor liver functional reserve, incomplete tumor resection, and a high probability of recurrence. Surgery provides significant survival benefits for Asian-Pacific patients with intermediate and advanced HCCs, particularly when the liver functional reserve is favorable. However, prospective randomized controlled trials are difficult to conduct because of technical and ethical considerations.

A phase II, randomized, controlled trial of S-adenosylmethionine in reducing serum alpha-fetoprotein (AFP) in patients with hepatitis C cirrhosis and elevated AFP

PubMed Central

Morgan, Timothy R.; Osann, Kathryn; Bottiglieri, Teodoro; Pimstone, Neville; Hoefs, John C.; Hu, Ke-Qin; Hassanein, Tarek; Boyer, Thomas D.; Kong, Lorene; Chen, Wen-Pin; Richmond, Ellen; Gonzalez, Rachel; Rodriguez, Luz M.; Meyskens, Frank L.

2015-01-01

In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC while administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum AFP level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 grams/day, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. 110 subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury, or markers of oxidative stress or antioxidant potential. PMID:26130251

Epidemiology, disease burden and outcomes of cirrhosis in a large secondary care hospital in South Auckland, New Zealand.

PubMed

Hsiang, J C; Bai, W W; Raos, Z; Stableforth, W; Upton, A; Selvaratnam, S; Gane, E J; Gerred, S J

2015-02-01

Liver cirrhosis is an important cause of morbidity and mortality; however, little is known about its impact in New Zealand. We aim to determine the disease burden, epidemiology and outcomes of cirrhotic patients. This is a retrospective study of cirrhosis patients under secondary public hospital care in a geographically defined region, between the years 2000 and 2011. Cirrhosis complications and mortality was recorded. Poisson log-linear regression analysis was performed for incidence rate ratio (IRR) and Cox regression analysis was used to analyse time-related events. Seven hundred and forty-six cirrhotic patients were analysed; most were European/Other (39.9%), Pacific islanders (21.6%), Southeast Asian/Chinese (17.8%) and Maori (12.3%). 68.4% were male. The common primary aetiologies for cirrhosis were chronic hepatitis B (CHB) cirrhosis (37.3%), alcoholic liver disease (ALD) cirrhosis (24.1%), chronic hepatitis C (CHC) cirrhosis (22.3%) and non-alcoholic fatty liver disease (NAFLD) cirrhosis (16.4%). The hepatocellular carcinoma (HCC) mortality rates were highest in NAFLD and CHB cirrhosis groups (3.0 and 3.1 per 100 patient-year respectively), compared with ALD and CHC groups (2.2 and 1.4 per 100 patient-year, all P < 0.05 respectively). Patients with ALD and NAFLD cirrhosis had the highest all-cause and non-HCC mortality rate compared with viral hepatitis cirrhosis groups. The IRR for HCC incidence, liver-related mortality and HCC mortality were 1.087, 1.098 and 1.114, respectively (all P < 0.001), suggesting increasing incidence and disease burden over the study period. The number of cirrhotic patients in secondary care is increasing steadily. Cirrhosis complications and mortality rates are also rising, particularly the incidence and mortality of HCC. © 2014 Royal Australasian College of Physicians.

Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer.

PubMed

Philip, Philip A; Mahoney, Michelle R; Allmer, Cristine; Thomas, James; Pitot, Henry C; Kim, George; Donehower, Ross C; Fitch, Tom; Picus, Joel; Erlichman, Charles

2005-09-20

Epidermal growth factor receptor/human epidermal growth factor receptor 1 (EGFR/HER1) and ligand expression is frequently seen in hepatocellular cancers (HCCs). Erlotinib (Tarceva, OSI-774; OSI Pharmaceuticals, Melville, NY) is a receptor tyrosine kinase inhibitor with specificity for the EGFR/HER1. The primary objective of this study was to determine the proportion of patients with advanced HCC who were progression-free at 6 months. Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was given continuously at a dose of 150 mg per day orally. Thirty-eight patients with HCC were enrolled. Median age of the patients was 69 years (range, 27 to 83 years). A majority of patients (63%) had an Eastern Cooperative Oncology Group performance status of 1. Forty-seven percent of patients had received prior chemotherapy for advanced HCC. EGFR/HER1 expression was detected in 88% of the patients. Median number of cycles per patient was two (range, 1 to 26). Twelve (32%; CI 95%, 18 to 49) of the 38 patients with HCC were progression-free at 6 months. Three patients had partial radiologic responses of duration of 2, 10, and 11 months, respectively. Disease control was seen in 59% of the patients. Median overall survival time was 13 months. Ten patients (26%) had toxicity-related dose reductions of erlotinib. Grade 3/4 skin toxicity or diarrhea was encountered in five and three patients, respectively. Results of this trial suggest a benefit for EGFR/HER1 blockade with erlotinib in patients with HCC manifested by disease control. Additional studies with erlotinib as a single agent or in combination with other agents are warranted.

Living donor liver transplantation for hepatocellular carcinoma achieves better outcomes.

PubMed

Lin, Chih-Che; Chen, Chao-Long

2016-10-01

Liver transplantation (LT) for hepatocellular carcinoma (HCC) at Kaohsiung Chang Gung Memorial Hospital mainly relies on live donor LT (LDLT). Owing to taking the risk of LD, we are obligated to adopt strict selection criteria for HCC patients and optimize the pre-transplant conditions to ensure a high disease-free survival similar to those without HCC, even better than deceased donor LT (DDLT). Better outcomes are attributed to excellent surgical results and optimal patient selection. The hospital mortality of primary and salvage LDLT are lower than 2% in our center. Although Taiwan Health Insurance Policy extended the Milan to University of California, San Francisco (UCSF) criteria in 2006, selection criteria will not be consolidated to take into account only by the morphologic size/number of tumors but also by their biology. The criteria are divided into modifiable image morphology, alpha fetoprotein (AFP), and positron emission tomography (PET) scan with standard uptake value (SUV) and unmodifiable unfavorable pathology such as HCC combined with cholangiocarcinoma (CC), sarcomatoid type, and poor differentiation. Downstaging therapy is necessary for HCC patients beyond criteria to fit all modifiable standards. The upper limit of downstaging treatment seems to be extended by more effective drug eluting transarterial chemoembolization in cases without absolute contraindications. In contrast, the pitfall of unmodifiable tumor pathology should be excluded by the findings of pretransplant core biopsy/resection if possible. More recently, achieving complete tumor necrosis in explanted liver could almost predict no recurrence after transplant. Necrotizing therapy is advised if possible before transplant even the tumor status within criteria to minimize the possibility of tumor recurrence. LDLT with low surgical mortality in experienced centers provides the opportunities of optimizing the pre-transplant tumor conditions and timing of transplant to achieve better outcomes.

Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis.

PubMed

Zhu, Ze-Xin; Wang, Xiao-Xue; Yuan, Ke-Fei; Huang, Ji-Wei; Zeng, Yong

2018-05-17

Hepatocellular carcinoma (HCC) is the most common malignancy in liver. Transarterial chemoembolization (TACE) is recommended as an effective treatment in advanced HCC patients. Recent studies showed iodine-125 seed (a low-energy radionuclide) can provide long-term local control and increase survival for HCC patients. The aim of the study was to evaluate the outcome of TACE plus iodine-125 seed in comparison with TACE alone for HCC. A comprehensive search of studies among PubMed, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews was conducted with published date from the earliest to January 10th, 2018. No language restrictions were applied, while only prospective randomized controlled trials (RCTs) or non-randomized controlled trials (non-RCTs) were eligible for a full-text review. The primary outcome was overall survival (OS), response rate (the rate of partial atrophy or complete clearance of the tumor lesion) and adverse events (AEs). The odds ratios (ORs) were combined using either fixed-effects model or random-effects model. All statistical analyses were performed using the Stata 12.0 software. 9 studies were included, involving 894 patients. Among them, 473 patients received combined therapy of TACE plus iodine-125 implantation, compared with 421 patients with TACE alone. Patients receiving combined therapy of TACE plus iodine-125 showed significantly improvement in 1-year OS (OR = 4.47, 95% confidence intervals (CI): 2.97-6.73; P < 0.001), 2-year OS (OR = 4.72, 95% CI: 2.63-8.47; P < 0.001). No significant publication bias was observed in any of the measured outcomes. Based on these findings, TACE plus iodine-125 implantation achieves better clinical efficacy compared with TACE alone in the treatment of HCC. Copyright © 2018. Published by Elsevier Ltd.

Microvessel density and angiogenesis in primary hepatic malignancies: Differential expression of CD31 and VEGFR-2 in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

PubMed

Bösmüller, Hans; Pfefferle, Vanessa; Bittar, Zeid; Scheble, Veit; Horger, Marius; Sipos, Bence; Fend, Falko

2018-06-19

Microvessel density is an indicator of tumor-driven neoangiogenesis. Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have distinct vascular patterns, which are also reflected in their imaging characteristics. Since a significant proportion of HCC are treated without biopsy confirmation, it is essential to discriminate HCC and ICC radiologically. The aim of our study was therefore to compare microvessel density and expression of VEGFR-2 in HCC and ICC, since these data may ultimately help us to better understand their imaging characteristics. Whereas CD31 documents vessel density, VEGFR-2 expression is an indicator of tumor-related neoangiogenesis. CD31 and VEGFR-2 expressing microvessels were quantified on tissue microarrays of 95 resection specimens of HCC and 47 cases of ICC. Microvessel density was evaluated by counting immuno-reactive vascular structures both within the tumor and adjacent liver control tissue, respectively. Further 16 cases of ICC were immunostained for CD31 and VEGFR-2 on full sections. The frequency of VEGFR-2 (46.2/HPF; range 0-150) and CD31 (61.2/HPF; range 2.6-140) expressing vascular structures was significantly increased in HCC compared to adjacent liver parenchyma (VEGFR-2 33.3/HPF, range 0-87, CD31 21.4/HPF, range 0-78, both p < 0,001). ICC revealed significantly less VEGFR2-positive microvessels (15.4/HPF; range 2-77) compared to matched control tissue (42.3/HPF; range 4.6-109), whereas microvessel density with CD31 was comparable between ICC and adjacent liver (32.1/HPF; range 5.3-78 versus 28.0/HPF; range 5.3-57; p = 0.89). In ICC, the tumor-to-normal microvessel density ratio was 0.38 for VEGFR-2 and 1.24 for CD31. These ratios were nearly identical (VEGFR: 0.38; CD31: 0,97) for the 16 cases of ICC studied on whole sections, confirming the validity of the TMA approach. In contrast, ratios of VEGFR-2 and CD31 in HCC vs. adjacent liver were significantly higher (VEGFR: 2.23; CD31: 6.57). Expression of VEGFR-2 by tumor cells was not observed in any of the cases. HCC and ICC differ significantly in their microvessel density, confirming the hypovascular nature of ICC as compared to the hypervascularity of HCC. Of note, inverse tumor-to-normal ratios of microvascular VEGFR-2 expression between the two neoplasms indicate distinct features of neoangiogenesis. Whether these differences can be exploited for improvements in imaging of hepatic tumors and may play a role for anti-angiogenic treatment strategies requires further studies. Copyright © 2018 Elsevier GmbH. All rights reserved.

The lncRNA CASC9 and RNA binding protein HNRNPL form a complex and co-regulate genes linked to AKT signaling.

PubMed

Klingenberg, Marcel; Groß, Matthias; Goyal, Ashish; Polycarpou-Schwarz, Maria; Miersch, Thilo; Ernst, Anne-Sophie; Leupold, Jörg; Patil, Nitin; Warnken, Uwe; Allgayer, Heike; Longerich, Thomas; Schirmacher, Peter; Boutros, Michael; Diederichs, Sven

2018-05-23

The identification of viability-associated long non-coding RNAs (lncRNA) might be a promising rationale for new therapeutic approaches in liver cancer. Here, we applied the first RNAi screening approach in hepatocellular carcinoma (HCC) cell lines to find viability-associated lncRNAs. Among the multiple identified lncRNAs with a significant impact on HCC cell viability, we selected CASC9 (Cancer Susceptibility 9) due to the strength of its phenotype, expression, and upregulation in HCC versus normal liver. CASC9 regulated viability across multiple HCC cell lines as shown by CRISPR interference, single siRNA- and siPOOL-mediated depletion of CASC9. Further, CASC9 depletion caused an increase in apoptosis and decrease of proliferation. We identified the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL) as a CASC9 interacting protein by RNA affinity purification (RAP) and validated it by native RNA immunoprecipitation (RIP). Knockdown of HNRNPL mimicked the loss-of-viability phenotype observed upon CASC9 depletion. Analysis of the proteome (SILAC) of CASC9- and HNRNPL-depleted cells revealed a set of co-regulated genes which implied a role of the CASC9:HNRNPL complex in AKT-signaling and DNA damage sensing. CASC9 expression levels were elevated in patient-derived tumor samples compared to normal control tissue and had a significant association with overall survival of HCC patients. In a xenograft chicken chorioallantoic membrane model, we measured a decreased tumor size after knockdown of CASC9. Taken together, we provide a comprehensive list of viability-associated lncRNAs in HCC. We identified the CASC9:HNRNPL complex as a clinically relevant viability-associated lncRNA/protein complex which affects AKT-signaling and DNA damage sensing in HCC. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Role of contrast-enhanced ultrasonography with Sonazoid for hepatocellular carcinoma: evidence from a 10-year experience.

PubMed

Maruyama, Hitoshi; Sekimoto, Tadashi; Yokosuka, Osamu

2016-05-01

Hepatocellular carcinoma (HCC) represents primary liver cancer. Because the development of HCC limits the prognosis as well as the quality of life of the patients, its management should be properly conducted based on an accurate diagnosis. The liver is the major target organ of ultrasound (US), which is the simple, non-invasive, and real-time imaging method available worldwide. Microbubble-based contrast agents are safe and reliable and have become popular, which has resulted in the improvement of diagnostic performances of US due to the increased detectability of the peripheral blood flow. Sonazoid (GE Healthcare, Waukesha, WI, USA), a second-generation contrast agent, shows the unique property of accumulation in the liver and spleen. Contrast-enhanced US with Sonazoid is now one of the most frequently used modalities in the practical management of liver tumors, including the detection and characterization of the nodule, evaluation of the effects of non-surgical treatment, intraoperative support, and post-treatment surveillance. This article reviews the 10-year evidence for contrast-enhanced US with Sonazoid in the practical management of HCC.

MicroRNA-199 suppresses cell proliferation, migration and invasion by downregulating RGS17 in hepatocellular carcinoma.

PubMed

Zhang, Wei; Qian, Sheng; Yang, Guowei; Zhu, Liang; Zhou, Bo; Wang, Jianhua; Liu, Rong; Yan, Zhiping; Qu, Xudong

2018-06-15

Hepatocellular carcinoma (HCC), the most common primary tumor of the liver, has a poor prognosis and shows rapid progression. MicroRNAs (miRNAs) play important roles in carcinogenesis and tumor progression. Regulators of G-protein signaling (RGS) are critical for defining G-protein-dependent signal fidelity. RGS17 plays an important role in the regulation of cancer cell proliferation, migration and invasion. Here, we showed that miR-199 was downregulated in a hepatocarcinoma cell line. Overexpression of miR-199 significantly suppressed HCC cell proliferation, migration, and invasion in vitro. RGS17 overexpression promoted HCC cell proliferation, migration, and invasion, and reversed the miR-199 mediated inhibition of proliferation, migration, and invasion. Dual-fluorescence reporter experiments confirmed that miR-199 downregulated RGS17 by direct interaction with the 3'-UTR of RGS17 mRNA. In vivo studies showed that miR-199 overexpression significantly inhibited the growth of tumors. Taken together, the results suggested that miR-199 inhibited tumor growth and metastasis by targeting RGS17. Published by Elsevier B.V.

Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes

PubMed Central

Kwon, Young-Chan; Bose, Sandip K.; Steele, Robert; Meyer, Keith; Di Bisceglie, Adrian M.; Ray, Ratna B.

2015-01-01

ABSTRACT We have previously reported that hepatitis C virus (HCV) infection of primary human hepatocytes (PHH) induces the epithelial mesenchymal transition (EMT) state and extends hepatocyte life span (S. K. Bose, K. Meyer, A. M. Di Bisceglie, R. B. Ray, and R. Ray, J Virol 86:13621–13628, 2012, http://dx.doi.org/10.1128/JVI.02016-12). These hepatocytes displayed sphere formation on ultralow binding plates and survived for more than 12 weeks. The sphere-forming hepatocytes expressed a number of cancer stem-like cell (CSC) markers, including high levels of the stem cell factor receptor c-Kit. The c-Kit receptor is regarded as one of the CSC markers in hepatocellular carcinoma (HCC). Analysis of c-Kit mRNA displayed a significant increase in the liver biopsy specimens of chronically HCV-infected patients. We also found c-Kit is highly expressed in transformed human hepatocytes (THH) infected in vitro with cell culture-grown HCV genotype 2a. Further studies suggested that HCV core protein significantly upregulates c-Kit expression at the transcriptional level. HCV infection of THH led to a significant increase in the number of spheres displayed on ultralow binding plates and in enhanced EMT and CSC markers and tumor growth in immunodeficient mice. The use of imatinib or dasatinib as a c-Kit inhibitor reduced the level of sphere-forming cells in culture. The sphere-forming cells were sensitive to treatment with sorafenib, a multikinase inhibitor, that is used for HCC treatment. Further, stattic, an inhibitor of the Stat3 molecule, induced sphere-forming cell death. A combination of sorafenib and stattic had a significantly stronger effect, leading to cell death. These results suggested that HCV infection potentiates CSC generation, and selected drugs can be targeted to efficiently inhibit cell growth. IMPORTANCE HCV infection may develop into HCC as an end-stage liver disease. We focused on understanding the mechanism for the risk of HCC from chronic HCV infection and identified targets for treatment. HCV-infected primary and transformed human hepatocytes (PHH or THH) generated CSC. HCV-induced spheres were highly sensitive to cell death from sorafenib and stattic treatment. Thus, our study is highly significant for HCV-associated HCC, with the potential for developing a target-specific strategy for improved therapies. PMID:26355082

PIVKA-II is a useful tool for diagnostic characterization of ultrasound-detected liver nodules in cirrhotic patients

PubMed Central

Saitta, Carlo; Raffa, Giuseppina; Alibrandi, Angela; Brancatelli, Santa; Lombardo, Daniele; Tripodi, Gianluca; Raimondo, Giovanni; Pollicino, Teresa

2017-01-01

Abstract Protein induced by vitamin K absence-II (PIVKA-II) is a potential screening marker for hepatocellular carcinoma (HCC). Limited data are available about its utility in discriminating neoplastic from regenerative nodules at ultrasonography (US) evaluation in cirrhotic patients. Aim of this study was to investigate the diagnostic utility of PIVKA-II in cases showing liver nodules of uncertain diagnosis at US. Ninety cirrhotics with US evidence of liver nodule(s) were enrolled. All patients underwent blood sampling within 1 week of US and were thereafter followed up. HCC was confirmed in 40/90 cases, and in all cases it was in a very early/early stage. All sera were tested for PIVKA-II and alpha-fetoprotein (AFP) at the end of follow-up. PIVKA-II at a cut off of 60 mAU/mL was significantly associated with HCC at both univariate and multivariate analysis (P = .016 and P = .032, respectively). AFP at a cut off of 6.5 ng/mL was not associated with HCC at univariate analysis (P = .246). ROC curves showed that PIVKA-II had 60% sensitivity, 88% specificity, 80% positive predictive value (PPV), and 73% negative predictive value (NPV), whereas AFP had 67% sensitivity, 68% specificity, 63% PPV, and 72% NPV. AUROC curves showed that the combination of both biomarkers increased the diagnostic accuracy for HCC (AUC 0.76; sensitivity 70%, specificity 94%, PPV 91%, and NPV 79%). In conclusion, PIVKA-II is a useful tool for the diagnostic definition of US-detected liver nodules in cirrhotic patients, and it provides high diagnostic accuracy for HCC when combined with AFP. PMID:28658121

Hair cortisol concentrations and cortisol stress reactivity predict PTSD symptom increase after trauma exposure during military deployment.

PubMed

Steudte-Schmiedgen, Susann; Stalder, Tobias; Schönfeld, Sabine; Wittchen, Hans-Ulrich; Trautmann, Sebastian; Alexander, Nina; Miller, Robert; Kirschbaum, Clemens

2015-09-01

Previous evidence on endocrine risk markers for posttraumatic stress disorder (PTSD) has been inconclusive. Here, we report results of the first prospective study to investigate whether long-term hair cortisol levels and experimentally-induced cortisol stress reactivity are predictive of the development of PTSD symptomatology in response to trauma during military deployment. Male soldiers were examined before deployment to Afghanistan and at a 12-month post-deployment follow-up using dimensional measures for psychopathological symptoms. The predictive value of baseline (i) hair cortisol concentrations (HCC, N=90) and (ii) salivary cortisol stress reactivity (measured by the Trier Social Stress Test, N=80) for the development of PTSD symptomatology after being exposed to new-onset traumatic events was analyzed. Baseline cortisol activity significantly predicted PTSD symptom change from baseline to follow-up upon trauma exposure. Specifically, our results consistently revealed that lower HCC and lower cortisol stress reactivity were predictive of a greater increase in PTSD symptomatology in soldiers who had experienced new-onset traumatic events (explaining 5% and 10.3% of variance, respectively). Longitudinal analyses revealed an increase in HCC from baseline to follow-up and a trend for a negative relationship between HCC changes and the number of new-onset traumatic events. Additional pre-deployment analyses revealed that trauma history was reflected in lower HCC (at trend level) and that HCC were negatively related to stressful load. Our data indicate that attenuated cortisol secretion is a risk marker for subsequent development of PTSD symptomatology upon trauma exposure. Future studies are needed to confirm our findings in other samples. Copyright © 2015 Elsevier Ltd. All rights reserved.

Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma.

PubMed

Yoo, Byoung Kwon; Santhekadur, Prasanna K; Gredler, Rachel; Chen, Dong; Emdad, Luni; Bhutia, Sujit; Pannell, Lewis; Fisher, Paul B; Sarkar, Devanand

2011-05-01

There is virtually no effective treatment for advanced hepatocellular carcinoma (HCC) and novel targets need to be identified to develop effective treatment. We recently documented that the oncogene Astrocyte elevated gene-1 (AEG-1) plays a seminal role in hepatocarcinogenesis. Employing yeast two-hybrid assay and coimmunoprecipitation followed by mass spectrometry, we identified staphylococcal nuclease domain containing 1 (SND1), a nuclease in the RNA-induced silencing complex (RISC) facilitating RNAi-mediated gene silencing, as an AEG-1 interacting protein. Coimmunoprecipitation and colocalization studies confirmed that AEG-1 is also a component of RISC and both AEG-1 and SND1 are required for optimum RISC activity facilitating small interfering RNA (siRNA) and micro RNA (miRNA)-mediated silencing of luciferase reporter gene. In 109 human HCC samples SND1 was overexpressed in ≈74% cases compared to normal liver. Correspondingly, significantly higher RISC activity was observed in human HCC cells compared to immortal normal hepatocytes. Increased RISC activity, conferred by AEG-1 or SND1, resulted in increased degradation of tumor suppressor messenger RNAs (mRNAs) that are target of oncomiRs. Inhibition of enzymatic activity of SND1 significantly inhibited proliferation of human HCC cells. As a corollary, stable overexpression of SND1 augmented and siRNA-mediated inhibition of SND1 abrogated growth of human HCC cells in vitro and in vivo, thus revealing a potential role of SND1 in hepatocarcinogenesis. We unravel a novel mechanism that overexpression of AEG-1 and SND1 leading to increased RISC activity might contribute to hepatocarcinogenesis. Targeted inhibition of SND1 enzymatic activity might be developed as an effective therapy for HCC. Copyright © 2011 American Association for the Study of Liver Diseases.

Soluble Axl is an accurate biomarker of cirrhosis and hepatocellular carcinoma development: results from a large scale multicenter analysis

PubMed Central

Dengler, Mirko; Staufer, Katharina; Huber, Heidemarie; Stauber, Rudolf; Bantel, Heike; Weiss, Karl Heinz; Starlinger, Patrick; Pock, Hannelore; Klöters-Plachky, Petra; Gotthardt, Daniel N.; Rauch, Peter; Lackner, Carolin; Stift, Judith; Brostjan, Christine; Gruenberger, Thomas; Kumada, Takashi; Toyoda, Hidenori; Tada, Toshifumi; Weiss, Thomas S.; Trauner, Michael; Mikulits, Wolfgang

2017-01-01

Patients with chronic liver disease (CLD) and cirrhosis are at high risk for hepatocellular carcinoma (HCC). Current diagnostic tools for HCC detection include imaging techniques and serum biomarkers such as α-fetoprotein (AFP). Yet, these methods are limited in sensitivity and specificity to accurately detect early HCC. Here we focused on the potential of soluble Axl (sAxl) as a biomarker in CLD patients by analyzing serum samples of 1067 patients and healthy controls from centers in Europe and Asia. We show that serum concentrations of sAxl were significantly increased at early (82.57 ng/mL) and later stages of HCC (114.50 ng/mL) as compared to healthy controls (40.15 ng/mL). Notably, no elevated sAxl levels were detected in patients with CLD including chronic viral hepatitis, autoimmune hepatitis, cholestatic liver disease, or non-alcoholic fatty liver disease versus healthy controls. Furthermore, sAxl did not rise in liver adenomas or cholangiocarcinoma (CCA). Yet, patients with advanced fibrosis (F3) or cirrhosis (F4) showed enhanced sAxl concentrations (F3: 54.67 ng/mL; F4: 94.74 ng/mL). Hepatic myofibroblasts exhibited an increased release of sAxl, suggesting that elevated sAxl levels arise from these cells during fibrosis. Receiver operating characteristic curve analysis of sAxl displayed a strongly increased sensitivity and specificity to detect both cirrhosis (80.8%/92.0%) and HCC (83.3%/86.7%) with an area under the curve of 0.935/0.903 as compared to AFP. In conclusion, sAxl shows high diagnostic accuracy at early stage HCC as well as cirrhosis, thereby outperforming AFP. Importantly, sAxl remains normal in most common CLDs, liver adenomas and CCA. PMID:28526812

Hepatitis B core protein promotes liver cancer metastasis through miR-382-5p/DLC-1 axis.

PubMed

Du, Juan; Bai, Fuxiang; Zhao, Peiqing; Li, Xiaoyan; Li, Xueen; Gao, Lifen; Ma, Chunhong; Liang, Xiaohong

2018-01-01

The hepatitis B virus core protein (HBc), also named core antigen, is well-known for its key role in viral capsid formation and virus replication. Recently, studies showed that HBc has the potential to control cell biology activity by regulating host gene expression. Here, we utilized miRNA microarray to identify 24 upregulated miRNAs and 21 downregulated miRNAs in HBc-expressed HCC cells, which were involved in multiple biological processes, including cell motility. Consistently, the in vitro transwell assay and the in vivo tail-vein injection model showed HBc promotion on HCC metastasis. Further, the miRNA-target gene network analysis displayed that the deleted in liver cancer (DLC-1) gene, an important negative regulator for cell motility, was potentially targeted by several differentially expressed miRNAs in HBc-introduced cells. Introduction of miRNAs mimics or inhibitors and 3'UTR luciferase activity assay proved that miR-382-5p efficiently suppressed DLC-1 expression and its 3'-UTR luciferase reporter activity. Importantly, cotransfection of miR-382-5p mimics/inhibitors and the DLC-1 expression vector almost abrogated HBc promotion on cell motility, indicating that the miR-382-5p/DLC-1 axis is important for mediating HBc-enhanced HCC motility. Clinical HCC samples also showed a negative correlation between miR-382-5p and DLC-1 expression level. Furthermore, HBc-positive HCC tissues showed high miR-382-5p level and reduced DLC-1 expression. In conclusion, our findings revealed that HBc promoted HCC motility by regulating the miR-382-5p/DLC-1 axis, which might provide a novel target for clinical diagnosis and treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Increased RNA-Induced Silencing Complex (RISC) Activity Contributes to Hepatocellular Carcinoma

PubMed Central

Yoo, Byoung Kwon; Santhekadur, Prasanna K.; Gredler, Rachel; Chen, Dong; Emdad, Luni; Bhutia, Sujit; Pannell, Lewis; Fisher, Paul B.; Sarkar, Devanand

2011-01-01

There is virtually no effective treatment for advanced hepatocellular carcinoma (HCC) and novel targets need to be identified to develop effective treatment. We recently documented that the oncogene Astrocyte elevated gene-1 (AEG-1) plays a seminal role in hepatocarcinogenesis. Employing yeast two-hybrid assay and co-immunoprecipitation followed by mass spectrometry we identified Staphylococcal nuclease domain containing 1 (SND1), a nuclease in the RNA-induced silencing complex (RISC) facilitating RNAi-mediated gene silencing, as an AEG-1 interacting protein. Co-immunoprecipitation and co-localization studies confirmed that AEG-1 is also a component of RISC and both AEG-1 and SND1 are required for optimum RISC activity facilitating siRNA and miRNA-mediated silencing of luciferase reporter gene. In 109 human HCC samples SND1 was overexpressed in ∼74% cases compared to normal liver. Correspondingly, significantly higher RISC activity was observed in human HCC cells compared to immortal normal hepatocytes. Increased RISC activity, conferred by AEG-1 or SND1, resulted in increased degradation of tumor suppressor mRNAs that are target of oncomiRs. Inhibition of enzymatic activity of SND1 significantly inhibited proliferation of human HCC cells. As a corollary, stable overexpression of SND1 augmented and siRNA-mediated inhibition of SND1 abrogated growth of human HCC cells in vitro and in vivo thus revealing a potential role of SND1 in hepatocarcinogenesis. Conclusion We unravel a novel mechanism that overexpression of AEG-1 and SND1 leading to increased RISC activity might contribute to hepatocarcinogenesis. Targeted inhibition of SND1 enzymatic activity might be developed as an effective therapy for HCC. PMID:21520169

Identification of GRB2 and GAB1 Coexpression as an Unfavorable Prognostic Factor for Hepatocellular Carcinoma by a Combination of Expression Profile and Network Analysis

PubMed Central

Yang, Mei; Wang, Danhua; Yu, Lingxiang; Guo, Chaonan; Guo, Xiaodong; Lin, Na

2013-01-01

Aim To screen novel markers for hepatocellular carcinoma (HCC) by a combination of expression profile, interaction network analysis and clinical validation. Methods HCC significant molecules which are differentially expressed or had genetic variations in HCC tissues were obtained from five existing HCC related databases (OncoDB.HCC, HCC.net, dbHCCvar, EHCO and Liverome). Then, the protein-protein interaction (PPI) network of these molecules was constructed. Three topological features of the network ('Degree', 'Betweenness', and 'Closeness') and the k-core algorithm were used to screen candidate HCC markers which play crucial roles in tumorigenesis of HCC. Furthermore, the clinical significance of two candidate HCC markers growth factor receptor-bound 2 (GRB2) and GRB2-associated-binding protein 1 (GAB1) was validated. Results In total, 6179 HCC significant genes and 977 HCC significant proteins were collected from existing HCC related databases. After network analysis, 331 candidate HCC markers were identified. Especially, GAB1 has the highest k-coreness suggesting its central localization in HCC related network, and the interaction between GRB2 and GAB1 has the largest edge-betweenness implying it may be biologically important to the function of HCC related network. As the results of clinical validation, the expression levels of both GRB2 and GAB1 proteins were significantly higher in HCC tissues than those in their adjacent nonneoplastic tissues. More importantly, the combined GRB2 and GAB1 protein expression was significantly associated with aggressive tumor progression and poor prognosis in patients with HCC. Conclusion This study provided an integrative analysis by combining expression profile and interaction network analysis to identify a list of biologically significant HCC related markers and pathways. Further experimental validation indicated that the aberrant expression of GRB2 and GAB1 proteins may be strongly related to tumor progression and prognosis in patients with HCC. The overexpression of GRB2 in combination with upregulation of GAB1 may be an unfavorable prognostic factor for HCC. PMID:24391994

Validity of registration of ICD codes and prescriptions in a research database in Swedish primary care: a cross-sectional study in Skaraborg primary care database

PubMed Central

2010-01-01

Background In recent years, several primary care databases recording information from computerized medical records have been established and used for quality assessment of medical care and research. However, to be useful for research purposes, the data generated routinely from every day practice require registration of high quality. In this study we aimed to investigate (i) the frequency and validity of ICD code and drug prescription registration in the new Skaraborg primary care database (SPCD) and (ii) to investigate the sources of variation in this registration. Methods SPCD contains anonymous electronic medical records (ProfDoc III) automatically retrieved from all 24 public health care centres (HCC) in Skaraborg, Sweden. The frequencies of ICD code registration for the selected diagnoses diabetes mellitus, hypertension and chronic cardiovascular disease and the relevant drug prescriptions in the time period between May 2002 and October 2003 were analysed. The validity of data registration in the SPCD was assessed in a random sample of 50 medical records from each HCC (n = 1200 records) using the medical record text as gold standard. The variance of ICD code registration was studied with multi-level logistic regression analysis and expressed as median odds ratio (MOR). Results For diabetes mellitus and hypertension ICD codes were registered in 80-90% of cases, while for congestive heart failure and ischemic heart disease ICD codes were registered more seldom (60-70%). Drug prescription registration was overall high (88%). A correlation between the frequency of ICD coded visits and the sensitivity of the ICD code registration was found for hypertension and congestive heart failure but not for diabetes or ischemic heart disease. The frequency of ICD code registration varied from 42 to 90% between HCCs, and the greatest variation was found at the physician level (MORPHYSICIAN = 4.2 and MORHCC = 2.3). Conclusions Since the frequency of ICD code registration varies between different diagnoses, each diagnosis must be separately validated. Improved frequency and quality of ICD code registration might be achieved by interventions directed towards the physicians where the greatest amount of variation was found. PMID:20416069

Validity of registration of ICD codes and prescriptions in a research database in Swedish primary care: a cross-sectional study in Skaraborg primary care database.

PubMed

Hjerpe, Per; Merlo, Juan; Ohlsson, Henrik; Bengtsson Boström, Kristina; Lindblad, Ulf

2010-04-23

In recent years, several primary care databases recording information from computerized medical records have been established and used for quality assessment of medical care and research. However, to be useful for research purposes, the data generated routinely from every day practice require registration of high quality. In this study we aimed to investigate (i) the frequency and validity of ICD code and drug prescription registration in the new Skaraborg primary care database (SPCD) and (ii) to investigate the sources of variation in this registration. SPCD contains anonymous electronic medical records (ProfDoc III) automatically retrieved from all 24 public health care centres (HCC) in Skaraborg, Sweden. The frequencies of ICD code registration for the selected diagnoses diabetes mellitus, hypertension and chronic cardiovascular disease and the relevant drug prescriptions in the time period between May 2002 and October 2003 were analysed. The validity of data registration in the SPCD was assessed in a random sample of 50 medical records from each HCC (n = 1200 records) using the medical record text as gold standard. The variance of ICD code registration was studied with multi-level logistic regression analysis and expressed as median odds ratio (MOR). For diabetes mellitus and hypertension ICD codes were registered in 80-90% of cases, while for congestive heart failure and ischemic heart disease ICD codes were registered more seldom (60-70%). Drug prescription registration was overall high (88%). A correlation between the frequency of ICD coded visits and the sensitivity of the ICD code registration was found for hypertension and congestive heart failure but not for diabetes or ischemic heart disease.The frequency of ICD code registration varied from 42 to 90% between HCCs, and the greatest variation was found at the physician level (MORPHYSICIAN = 4.2 and MORHCC = 2.3). Since the frequency of ICD code registration varies between different diagnoses, each diagnosis must be separately validated. Improved frequency and quality of ICD code registration might be achieved by interventions directed towards the physicians where the greatest amount of variation was found.

Influence of higher BMI for hepatitis B- and C-related hepatocellular carcinomas.

PubMed

Hashimoto, Masakazu; Tashiro, Hirotaka; Kobayashi, Tsuyoshi; Kuroda, Shintaro; Hamaoka, Michinori; Ohdan, Hideki

2017-08-01

Although obesity is associated with hepatocellular carcinoma (HCC) development, its impact on the surgical outcomes of patients with hepatitis B virus (HBV)-and hepatitis C virus (HCV)-related HCC remains unclear. We retrospectively analyzed 714 patients with HCC who underwent curative hepatectomy. Among them, the HBV-related HCC group (n = 125) and HCV-related HCC group (n = 426) were subdivided according to the presence of body mass index (BMI) ≥ 25 kg/m 2 . The surgical outcomes were compared. The 5-year overall survival rate after hepatectomy in the HBV-related HCC group was significantly better than that in the HCV-related HCC group. The 5-year overall survival rates of the HBV-related HCC with and without BMI ≥ 25 kg/m 2 groups were 65 and 85%, respectively. The 5-year overall survival rates in the HCV-related HCC with and without BMI ≥ 25 kg/m 2 groups were 75 and 65%, respectively. The HBV-related HCC with BMI ≥ 25 kg/m 2 groups had a significantly worse prognosis than the HBV-related HCC without BMI ≥ 25 kg/m 2 groups, while the HCV-related HCC with BMI ≥ 25 kg/m 2 groups had a significantly better prognosis than the HCV-related HCC without BMI ≥ 25 kg/m 2 groups. Multivariate analysis revealed that BMI ≥ 25 kg/m 2 was the positive and negative prognostic factor for the surgical outcomes of patients with HBV- and HCV-related HCC, respectively. BMI ≥ 25 kg/m 2 negatively affected the surgical outcomes of patients with HBV-related HCC and positively affected those of patients with HCV-related HCC.

Differences in antiproliferative effect of STAT3 inhibition in HCC cells with versus without HBV expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Yun; Zhou, Lin; Xie, Haiyang

2015-06-05

Chronic infection with hepatitis B virus (HBV) plays an important role in the etiology of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 3 (STAT3) inactivation could inhibit the tumor growth of HCC. In this study, differential antiproliferative effect of STAT3 inhibition was observed with HBV-related HCC cells being more resistant than non-HBV-related HCC cells. Resistance of HBV-related HCC cells to STAT3 inhibition was positively correlated to the expression of HBV. Enhanced ERK activation after STAT3 blockade was detected in HBV-related HCC cells but not in non-HBV-related HCC cells. Combined ERK and STAT3 inhibition eliminates the discrepancy between themore » two types of HCC cells. Moderate reduced HBV expression was found after STAT3 inhibition. These findings disclose a discrepancy in cellular response to STAT3 inhibition between non-HBV-related and HBV-related HCC cells and underscore the complexity of antiproliferative effect of STAT3 inactivation in HBV-related HCC cells. - Highlights: • HBV endows HCC cells with resistance to STAT3 inactivation on proliferation. • Abnormal ERK activation after STAT3 inhibition in HBV-related HCC cells. • Combined ERK and STAT3 inhibition eliminates the discrepancy. • STAT3 inhibition moderately reduces HBV expression.« less

Clinical analysis of patients with hepatocellular carcinoma recurrence after living-donor liver transplantation

PubMed Central

Na, Gun Hyung; Hong, Tae Ho; You, Young Kyoung; Kim, Dong Goo

2016-01-01

AIM: To evaluated patterns and outcomes of hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT). METHODS: From 2001 to 2014, 293 patients underwent LDLT for HCC at our transplant center. We retrospectively reviewed 54 (18.4%) patients with HCC recurrence after LDLT. We evaluated patterns and outcomes of HCC recurrence after LDLT, with particular attention to the Milan criteria at transplantation, treatments for HCC-recurrent patients, and factors related to survival after HCC recurrence. Furthermore, we evaluated the efficacy of combination treatment of sorafenib and an mTOR inhibitor. RESULTS: The 1-, 2-, and 3-year overall survival rates after HCC recurrence were 41.1%, 20.5%, and 15.4%, respectively. The median time interval between LDLT and HCC recurrence was 6.5 mo. Although recurrence rates according to the Milan criteria at LDLT were significantly different, HCC recurrence patterns and survival rates after HCC recurrence were not significantly different between the two groups. Time to recurrence < 12 mo (P = 0.048), multiple recurrences at HCC recurrence (P = 0.038), and palliative treatment for recurrent tumors (P = 0.003) were significant independent prognostic factors for poor survival after HCC recurrence in a multivariate analysis. The combination treatment of sorafenib and sirolimus showed survival benefits in the palliative treatment group (P = 0.005). CONCLUSION: Curative treatment for recurrent HCC after LDLT is the most important factor in survival rates after HCC recurrence and combination treatments of sorafenib and an mTOR inhibitor could have survival benefits in patients with HCC recurrence after LT in the palliative treatment group. PMID:27433092

Clinical analysis of patients with hepatocellular carcinoma recurrence after living-donor liver transplantation.

PubMed

Na, Gun Hyung; Hong, Tae Ho; You, Young Kyoung; Kim, Dong Goo

2016-07-07

To evaluated patterns and outcomes of hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT). From 2001 to 2014, 293 patients underwent LDLT for HCC at our transplant center. We retrospectively reviewed 54 (18.4%) patients with HCC recurrence after LDLT. We evaluated patterns and outcomes of HCC recurrence after LDLT, with particular attention to the Milan criteria at transplantation, treatments for HCC-recurrent patients, and factors related to survival after HCC recurrence. Furthermore, we evaluated the efficacy of combination treatment of sorafenib and an mTOR inhibitor. The 1-, 2-, and 3-year overall survival rates after HCC recurrence were 41.1%, 20.5%, and 15.4%, respectively. The median time interval between LDLT and HCC recurrence was 6.5 mo. Although recurrence rates according to the Milan criteria at LDLT were significantly different, HCC recurrence patterns and survival rates after HCC recurrence were not significantly different between the two groups. Time to recurrence < 12 mo (P = 0.048), multiple recurrences at HCC recurrence (P = 0.038), and palliative treatment for recurrent tumors (P = 0.003) were significant independent prognostic factors for poor survival after HCC recurrence in a multivariate analysis. The combination treatment of sorafenib and sirolimus showed survival benefits in the palliative treatment group (P = 0.005). Curative treatment for recurrent HCC after LDLT is the most important factor in survival rates after HCC recurrence and combination treatments of sorafenib and an mTOR inhibitor could have survival benefits in patients with HCC recurrence after LT in the palliative treatment group.

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

PubMed Central

Kubo, Shoji; Takemura, Shigekazu; Tanaka, Shogo; Shinkawa, Hiroji; Nishioka, Takayoshi; Nozawa, Akinori; Kinoshita, Masahiko; Hamano, Genya; Ito, Tokuji; Urata, Yorihisa

2015-01-01

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC. PMID:26217076

Investigation of Pokemon-regulated proteins in hepatocellular carcinoma using mass spectrometry-based multiplex quantitative proteomics.

PubMed

Bi, Xin; Jin, Yibao; Gao, Xiang; Liu, Feng; Gao, Dan; Jiang, Yuyang; Liu, Hongxia

2013-01-01

Pokemon is a transcription regulator involved in embryonic development, cellular differentiation and oncogenesis. It is aberrantly overexpressed in multiple human cancers including Hepatocellular carcinoma (HCC) and is considered as a promising biomarker for HCC. In this work, the isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics strategy was used to investigate the proteomic profile associated with Pokemon in human HCC cell line QGY7703 and human hepatocyte line HL7702. Samples were labeled with four-plex iTRAQ reagents followed by two-dimensional liquid chromatography coupled with tandem mass spectrometry analysis. A total of 24 differentially expressed proteins were selected as significant. Nine proteins were potentially up-regulated by Pokemon while 15 proteins were potentially down-regulated and many proteins were previously identified as potential biomarkers for HCC. Gene ontology (GO) term enrichment revealed that the listed proteins were mainly involved in DNA metabolism and biosynthesis process. The changes of glucose-6-phosphate 1-dehydrogenase (G6PD, up-regulated) and ribonucleoside-diphosphate reductase large sub-unit (RIM1, down-regulated) were validated by Western blotting analysis and denoted as Pokemon's function of oncogenesis. We also found that Pokemon potentially repressed the expression of highly clustered proteins (MCM3, MCM5, MCM6, MCM7) which played key roles in promoting DNA replication. Altogether, our results may help better understand the role of Pokemon in HCC and promote the clinical applications.

Midkine Increases Diagnostic Yield in AFP Negative and NASH-Related Hepatocellular Carcinoma

PubMed Central

Vongsuvanh, Roslyn; van der Poorten, David; Iseli, Tristan; Strasser, Simone I.; McCaughan, Geoffrey W.; George, Jacob

2016-01-01

Robust biomarkers for population-level hepatocellular carcinoma (HCC) surveillance are lacking. We compared serum midkine (MDK), dickkopf-1 (DKK1), osteopontin (OPN) and AFP for HCC diagnosis in 86 HCC patients matched to 86 cirrhotics, 86 with chronic liver disease (CLD) and 86 healthy controls (HC). Based on the performance of each biomarker, we assessed a separate longitudinal cohort of 28 HCC patients, at and before cancer diagnosis. Serum levels of MDK and OPN were higher in HCC patients compared to cirrhosis, CLD and HC groups. DKK1 was not different between cases and controls. More than half of HCC patients had normal AFP. In this AFP-negative HCC cohort, 59.18% (n = 29/49) had elevated MDK, applying the optimal cut-off of 0.44 ng/ml. Using AFP ≥ 20 IU/ml or MDK ≥ 0.44 ng/ml, a significantly greater number (76.7%; n = 66/86) of HCC cases were detected. The area under the receiver operating curve for MDK was superior to AFP and OPN in NASH-HCC diagnosis. In the longitudinal cohort, MDK was elevated in 15/28 (54%) of HCC patients at diagnosis, of whom 67% had elevated MDK 6 months prior. Conclusion: AFP and MDK have a complementary role in HCC detection. MDK increases the diagnostic yield in AFP-negative HCC and has greater diagnostic performance than AFP, OPN and DKK-1 in the diagnosis of NASH-HCC. Additionally, MDK has a promising role in the pre-clinical diagnosis of HCC. PMID:27219517

A Targetable Molecular Chaperone Hsp27 Confers Aggressiveness in Hepatocellular Carcinoma.

PubMed

Zhang, Yurong; Tao, Xuemei; Jin, Guangzhi; Jin, Haojie; Wang, Ning; Hu, Fangyuan; Luo, Qin; Shu, Huiqun; Zhao, Fangyu; Yao, Ming; Fang, Jingyuan; Cong, Wenming; Qin, Wenxin; Wang, Cun

2016-01-01

Heat shock protein 27 (Hsp27) is an ATP-independent molecular chaperone and confers survival advantages and resistance to cancer cells under stress conditions. The effects and molecular mechanisms of Hsp27 in HCC invasion and metastasis are still unclear. In this study, hepatocellular carcinoma (HCC) tissue array (n = 167) was used to investigate the expression and prognostic relevance of Hsp27 in HCC patients. HCC patients with high expression of Hsp27 exhibited poor prognosis. Overexpression of Hsp27 led to the forced invasion of HCC cells, whereas silencing Hsp27 attenuated invasion and metastasis of HCC cells in vitro and in vivo. We revealed that Hsp27 activated Akt signaling, which in turn promoted MMP2 and ITGA7 expression and HCC metastasis. We further observed that targeting Hsp27 using OGX-427 obviously suppressed HCC metastasis in two metastatic models. These findings indicate that Hsp27 is a useful predictive factor for prognosis of HCC and it facilitates HCC metastasis through Akt signaling. Targeting Hsp27 with OGX-427 may represent an attractive therapeutic option for suppressing HCC metastasis.

A Targetable Molecular Chaperone Hsp27 Confers Aggressiveness in Hepatocellular Carcinoma

PubMed Central

Zhang, Yurong; Tao, Xuemei; Jin, Guangzhi; Jin, Haojie; Wang, Ning; Hu, Fangyuan; Luo, Qin; Shu, Huiqun; Zhao, Fangyu; Yao, Ming; Fang, Jingyuan; Cong, Wenming; Qin, Wenxin; Wang, Cun

2016-01-01

Heat shock protein 27 (Hsp27) is an ATP-independent molecular chaperone and confers survival advantages and resistance to cancer cells under stress conditions. The effects and molecular mechanisms of Hsp27 in HCC invasion and metastasis are still unclear. In this study, hepatocellular carcinoma (HCC) tissue array (n = 167) was used to investigate the expression and prognostic relevance of Hsp27 in HCC patients. HCC patients with high expression of Hsp27 exhibited poor prognosis. Overexpression of Hsp27 led to the forced invasion of HCC cells, whereas silencing Hsp27 attenuated invasion and metastasis of HCC cells in vitro and in vivo. We revealed that Hsp27 activated Akt signaling, which in turn promoted MMP2 and ITGA7 expression and HCC metastasis. We further observed that targeting Hsp27 using OGX-427 obviously suppressed HCC metastasis in two metastatic models. These findings indicate that Hsp27 is a useful predictive factor for prognosis of HCC and it facilitates HCC metastasis through Akt signaling. Targeting Hsp27 with OGX-427 may represent an attractive therapeutic option for suppressing HCC metastasis. PMID:26941848

Triterpenoids principle of Wedelia calendulacea attenuated diethynitrosamine-induced hepatocellular carcinoma via down-regulating oxidative stress, inflammation and pathology via NF-kB pathway.

PubMed

Verma, Amita; Singh, Deepika; Anwar, Firoz; Bhatt, Prakash Chandra; Al-Abbasi, Fahad; Kumar, Vikas

2018-02-01

The aerial part of Wedelia calendulacea have been used in Ayurveda, Unani, Tibetan, Siddha and other folk medicine systems to protect the liver and renal tissue. Liver is considered as primary metabolizing site of body, which is prone to damage by endogenous and exogenous toxicants. A reason for liver toxicity, and major causes of the hepatocellular carcinoma (HCC). 19-α-Hydroxyurs-12(13)-ene-28 oic acid-3-O-β-D-glucopyranoside (HEG), a triterpenoids found in the higher plants, has been known to possess protective effect against various toxicants. The aim of the current study was to scrutinize the hepatoprotective mechanism of HEG against DEN-induced oxidative stress, hyperproliferation, inflammation and apoptosis tissue injury in Wistar rats. Invitro cell lines study of HEG scrutinized against the Hep-G2 and HuH-7 cells. A single dose of DEN (200 mg/kg) and double dose of phenobarbitol were administered to induce the liver damage in rats; the dose treatment of HEG was terminated at the end of 22 weeks. Macroscopical study was performed for the confirmation of hepatic nodules. The serum and hepatic samples were collected for further biochemical and histopathological analysis. Hepatic; non-hepatic; Phase I and II antioxidant enzymes were also examined. Additionally, we also scrutinized the inflammatory cytokines viz., tumor necrosis factor-α, interlukin-6, interlukin-1β, and Nuclear factor kappa beta (NF-kB), respectively. Histopathological study was also performed for analyzing the changes during the HCC. HEG confirmed the reduction of growth and deoxyribonucleic acid synthesis of both cell lines. DEN successfully induced the HCC in all group, which was significantly (p < 0.001) altered by the HEG in a dose-dependent manner. The decreased level of pro-inflammatory cytokines and altered membrane-bound enzyme activity were also observed. HEG inhibits the phase I, II and antioxidant enzymes at the effective dose-dependent manner, which were considered as the precursor of the HCC. The alteration of phase I, II and antioxidant enzymes confirmed the inhibition of inflammatory reaction and oxidative stress, which directly or indirectly inhibited the NF-kB expression. Collectively, we can conclude that the HEG inhibited the growth of Hepatocellular carcinoma via attenuating the NF-kB pathway.

HBx drives alpha fetoprotein expression to promote initiation of liver cancer stem cells through activating PI3K/AKT signal pathway.

PubMed

Zhu, Mingyue; Li, Wei; Lu, Yan; Dong, Xu; Lin, Bo; Chen, Yi; Zhang, Xueer; Guo, Junli; Li, Mengsen

2017-03-15

Hepatitis B virus (HBV)-X protein (HBx) plays critical role in inducing the malignant transformation of liver cells. Alpha fetoprotein (AFP) expression is closely related to hepatocarcinogenesis. We report that Oct4, Klf4, Sox2 and c-myc expression positively associated with AFP(+)/HBV(+) hepatocellular carcinoma(HCC) tissues, and the expression of the stemness markers CD44, CD133 and EpCAM was significantly higher in AFP(+)/HBV(+) HCC tissues compared to normal liver tissues or AFP (-)/HBV(-) HCC tissues. AFP expression turned on prior to expression of Oct4, Klf4, Sox2 and c-myc, and the stemness markers CD44, CD133 and EpCAM in the normal human liver L-02 cell line or CHL cell lines upon transfection with MCV-HBx vectors. Stem-like cells generated more tumour colonies compared to primary cells, and xenografts induced tumourigenesis in nude mice. Expression of reprogramming-related proteins was significantly enhanced in HLE cells while transfected with pcDNA3.1-afp vectors. The specific PI3K inhibitor Ly294002 inhibited the effects of pcDNA3.1-afp vectors. AFP-siRNA vectors were able to inhibit tumour colony formation and reprogramming-related gene expression. Altogether, HBx stimulates AFP expression to induce natural reprogramming of liver cells, and AFP plays a critical role in promoting the initiation of HCC progenitor/stem cells. AFP may be a potential novel biotarget for combating HBV-induced hepatocarcinogenesis. © 2016 UICC.

Administration of interleukin-12 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines in mouse hepatocellular carcinoma.

PubMed

Tatsumi, T; Takehara, T; Kanto, T; Miyagi, T; Kuzushita, N; Sugimoto, Y; Jinushi, M; Kasahara, A; Sasaki, Y; Hori, M; Hayashi, N

2001-10-15

Dendritic cells (DCs) are potent antigen-presenting cells that are capable of priming systemic antitumor immune response. Here, we evaluated the combined effectiveness of tumor lysate-pulsed DC immunization and interleukin (IL)-12 administration on the induction of antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. Mouse DCs were pulsed with lysate of BNL 1ME A.7R.1 (BNL), a BALB/c-derived HCC cell line, and then injected into syngeneic mice in combination with systemic administration of IL-12. Lymphocytes from mice treated with BNL lysate-pulsed DCs and IL-12 showed stronger cytolytic activity and produced higher amounts of IFN-gamma than those from mice treated with BNL lysate-pulsed DCs alone. Although immunization with BNL lysate-pulsed DCs alone did not lead to complete regression of established tumors, it significantly inhibited tumor growth compared with vehicle injection. Importantly, the combined therapy of BNL lysate-pulsed DCs and IL-12 resulted in tumor rejection or significant inhibition of tumor growth compared with mice treated with BNL lysate-pulsed DCs alone. In vivo lymphocyte depletion experiments demonstrated that this combination was dependent on both CD8+ and CD4+ T cells, but not natural killer cells. These results demonstrated that IL-12 administration enhanced the therapeutic effect of immunization of tumor lysate-pulsed DCs against HCC in mice. This combination of IL-12 and DCs may be useful for suppressing the growth of residual tumor after primary therapy of human HCC.

Tumour seeding after percutaneous cryoablation for hepatocellular carcinoma

PubMed Central

Wang, Chun-Ping; Wang, Hong; Qu, Jian-Hui; Lu, Yin-Ying; Bai, Wen-Lin; Dong, Zheng; Gao, Xu-Dong; Rong, Guang-Hua; Zeng, Zhen; Yang, Yong-Ping

2012-01-01

AIM: To assess the rate and risk factors for tumour seeding in a large cohort of patients. METHODS: Over an 8-year period, 1436 hepatocellular carcinoma (HCC) patients with 2423 tumour nodules underwent 3015 image-guided percutaneous cryoablation sessions [1215 guided by ultrasonography and 221 by spiral computed tomography (CT)]. Follow-up CT or magnetic resonance imaging was performed every 3 mo. The detailed clinical data were recorded to analyse the risk factors for seeding. RESULTS: The median follow-up time was 18 (range 1-90) mo. Seeding was detected in 11 patients (0.76%) at 1-24 (median 6.0) mo after cryoablation. Seeding occurred along the needle tract in 10 patients and at a distant location in 1 patient. Seeded tumours usually showed similar imaging and histopathological features to the primary HCCs. Univariate analyses identified subcapsular tumour location and direct subcapsular needle insertion as risk factors for seeding. Multivariate analysis showed that only direct subcapsular needle insertion was an independent risk factor for seeding (P = 0.017; odds ratio 2.57; 95%CI: 1.47-3.65). Seeding after cryoablation occurred earlier in patients with poorly differentiated HCC than those with well or moderately differentiated HCC [1.33 ± 0.577 mo vs 11.12 ± 6.896 mo; P = 0.042; 95%CI: (-19.115)-(-0.468)]. CONCLUSION: The risk of seeding after cryoablation for HCC is small. Direct puncture of subcapsular tumours should be avoided to minimise seeding. PMID:23236233

The liver tissue bank and clinical database in China.

PubMed

Yang, Yuan; Liu, Yi-Min; Wei, Ming-Yue; Wu, Yi-Fei; Gao, Jun-Hui; Liu, Lei; Zhou, Wei-Ping; Wang, Hong-Yang; Wu, Meng-Chao

2010-12-01

To develop a standardized and well-rounded material available for hepatology research, the National Liver Tissue Bank (NLTB) Project began in 2008 in China to make well-characterized and optimally preserved liver tumor tissue and clinical database. From Dec 2008 to Jun 2010, over 3000 individuals have been enrolled as liver tumor donors to the NLTB, including 2317 cases of newly diagnosed hepatocellular carcinoma (HCC) and about 1000 cases of diagnosed benign or malignant liver tumors. The clinical database and sample store can be managed easily and correctly with the data management platform used. We believe that the high-quality samples with detailed information database will become the cornerstone of hepatology research especially in studies exploring the diagnosis and new treatments for HCC and other liver diseases.

Pokemon promotes the invasiveness of hepatocellular carcinoma by enhancing MEF2D transcription.

PubMed

Kong, Jing; Liu, Xiaoping; Li, Xiangqian; Wu, Jinsheng; Wu, Ning; Chen, Jun; Fang, Fang

2016-05-01

Pokemon, a master oncogene crucial for the tumorigenicity and progression of a variety of cancers, has been demonstrated to enhance the proliferation and survival of hepatocellular carcinoma (HCC). However, the contribution of Pokemon to the invasiveness of HCC has not yet been studied. In this study, we employed HCC cells to investigate the role of Pokemon in the invasion of HCC with multidisciplinary approaches. Pokemon overexpression was found to be closely associated with invasion and intrahepatic metastasis of HCC in clinical specimens. Suppression of Pokemon attenuated the invasion of HCC cells by in vitro transwell and wound-healing assays. Myocyte enhancer factor 2D (MEF2D), an oncogene that can promote the invasiveness of HCC, was found to be underexpressed during Pokemon silencing in HCC cells. Restoration of MEF2D abolished the effect of Pokemon downregulation on the migration of HCC cells. Further experiments verified that Pokemon binds two putative recognition sites located within the upstream region of the MEF2D promoter and enhances its transcription. The association between Pokemon and MEF2D was further confirmed in HCC specimens. Animal experiments further confirmed that Pokemon downregulation attenuated the metastasis of HCC cells in mice. Collectively, Pokemon was found to enhance the migration and invasion of HCC by increasing MEF2D expression. Thus, targeting Pokemon and MEF2D may be an effective strategy to suppress the metastasis of HCC.

A novel chemotherapeutic sensitivity-testing system based on collagen gel droplet embedded 3D-culture methods for hepatocellular carcinoma.

PubMed

Hou, Jun; Hong, Zhixian; Feng, Fan; Chai, Yantao; Zhang, Yunkai; Jiang, Qiyu; Hu, Yan; Wu, Shunquan; Wu, Yingsong; Gao, Xunian; Chen, Qiong; Wan, Yong; Bi, Jingfeng; Zhang, Zheng

2017-11-08

Patients suffering from advanced stage hepatocellular carcinoma (HCC) often exhibit a poor prognosis or dismal clinical outcomes due to ineffective chemotherapy or a multi-drug resistance (MDR) process. Thus, it is urgent to develop a new chemotherapeutic sensitivity testing system for HCC treatment. The presence study investigated the potential application of a novel chemotherapeutic sensitivity-testing system based on a collagen gel droplet embedded 3D-culture system (CD-DST). Primary cells were separating from surgical resection specimens and then tested by CD-DST. To identify whether HCC cell lines or cells separating from clinical specimens contain MDR features, the cells were treated with an IC 50 (half maximal inhibitory concentration) or IC max (maximal inhibitory concentration) concentration of antitumor agents, e.g., 5-furuolouracil (5-FU), paclitaxel (PAC), cisplatin (CDDP), epirubicin (EPI), or oxaliplatin (L-OHP), and the inhibitory rates (IRs) were calculated. HepG2 cells were sensitive to 5-FU, PAC, CDDP, EPI, or L-OHP; the IC 50 value is 0.83 ± 0.45 μg/ml, 0.03 ± 0.02 μg/ml, 1.15 ± 0.75 μg/ml, 0.09 ± 0.03 μg/ml, or 1.76 ± 0.44 μg/ml, respectively. Only eight (8/26), nine (9/26), or five (5/26) patients were sensitive to the IC max concentration of CDDP, EPI, or L-OHP; whereas only three (3/26), four (4/26), or two (2/26) patients were sensitive to the IC 50 concentration of CDDP, EPI, or L-OHP. No patients were sensitive to 5-FU or PAC. The in vitro drug sensitivity exanimation revealed the MDR features of HCC and examined the sensitivity of HCC cells from clinical specimens to anti-tumor agents. CD-DST may be a useful method to predict the potential clinical benefits of anticancer agents for HCC patients.

Blocking and reversing hepatic fibrosis in patients with chronic hepatitis B treated by traditional Chinese medicine (tablets of biejia ruangan or RGT): study protocol for a randomized controlled trial.

PubMed

Qu, Jianhui; Yu, Zujiang; Li, Qin; Chen, Yongping; Xiang, Dedong; Tan, Lin; Lei, Chunliang; Bai, Wenlin; Li, Hongyan; Shang, Qinghua; Chen, Liang; Hu, Xiaoyu; Lu, Wei; Li, Zhiqin; Chen, Da; Wang, Xiaodong; Zhang, Changjiang; Xiao, Guangming; Qi, Xun; Chen, Jing; Zhou, Li; Chen, Guofeng; Li, Yonggang; Zeng, Zhen; Rong, Guanghua; Dong, Zheng; Chen, Yan; Lou, Min; Wang, Chunping; Lu, Yinying; Zhang, Cuihong; Yang, Yongping

2014-11-10

Chronic hepatitis B (CHB) can progress to cirrhosis, hepatocellular carcinoma (HCC) and ultimately liver-related death. Although oral antiviral therapy for patients with CHB reduces the risk of such complications, once cirrhosis is established, the benefits of antiviral therapy are not robustly demonstrated. According to traditional Chinese medicine (TCM), some Chinese herbal medicines promote blood circulation and soften hard masses, and therefore they may block and reverse hepatic fibrosis. The aim of this study is to evaluate the effects of TCM tablets of the compound biejia ruangan (RGT) administered for fibrosis, and entecavir (ETV), on the development of HCC in patients with CHB or hepatitis B virus (HBV)-related compensated cirrhosis. This multicenter, centrally randomized, double-blind, placebo-controlled, parallel-group study is planned to complete within 5 years. For the study, 1,000 with CHB or HBV-related compensated cirrhosis are randomly assigned in a 1:1 ratio to a treatment group (0.5 mg ETV once daily; 2 g RGT three times daily) or a control group (0.5 mg ETV once daily; 2 g RGT dummy agent three times daily). The primary end points are the development of HCC and liver-related death. Secondary end points include disease progression and overall survival. Although antiviral therapy can achieve sustained suppression of HBV replication, thereby preventing cirrhosis, patients with CHB treated with nucleos(t)ide analogs (NUCs) retain a higher risk for HCC compared with patients with inactive disease. Although previous clinical trials with RGT have confirmed the efficacy of blocking and reversing hepatic fibrosis in patients with CHB or compensated cirrhosis, the long-term risk for HCC or disease progression in these patients treated with combination of RGT and NUCs compared with NUCs alone is unclear. Therefore, it is necessary to investigate the effects of the RGT blockade and reversal of hepatic fibrosis on the development of HCC in patients with CHB or HBV-related compensated cirrhosis in large, prospective, multicenter, double-blind, randomized, controlled trials in China. ClinicalTrials.gov Identifier: NCT01965418. Date registered: 17 October 2013.

The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus.

PubMed

Ueyama, Misuzu; Nishida, Nao; Korenaga, Masaaki; Korenaga, Keiko; Kumagai, Erina; Yanai, Hidekatsu; Adachi, Hiroki; Katsuyama, Hisayuki; Moriyama, Sumie; Hamasaki, Hidetaka; Sako, Akahito; Sugiyama, Masaya; Aoki, Yoshihiko; Imamura, Masatoshi; Murata, Kazumoto; Masaki, Naohiko; Kawaguchi, Takumi; Torimura, Takuji; Hyogo, Hideyuki; Aikata, Hiroshi; Ito, Kiyoaki; Sumida, Yoshio; Kanazawa, Akio; Watada, Hirotaka; Okamoto, Koji; Honda, Kenjiro; Kon, Kazuyoshi; Kanto, Tatsuya; Mizokami, Masashi; Watanabe, Sumio

2016-04-01

Type 2 diabetes mellitus (T2DM) is an established independent risk factor for hepatocellular carcinoma (HCC). T2DM is associated with non-alcoholic steatohepatitis (NASH), which is a major cause of non-HBV and non-HCV-related HCC; nevertheless, it has been difficult to identify those patients with T2DM who have a high risk of developing HCC. The aim of this study was to identify genetic determinants that predispose T2DM patients to HCC by genotyping T2DM susceptibility loci and PNPLA3. We recruited 389 patients with T2DM who satisfied the following three criteria: negative for HBs-Ag and anti-HCV Ab, alcohol intake <60 g/day, and history of T2DM >10 years. These patients were divided into two groups: T2DM patients with HCC (DM-HCC, n = 59) or those without HCC (DM-non-HCC, n = 330). We genotyped 51 single-nucleotide polymorphisms (SNPs) previously reported as T2DM or NASH susceptibility loci (PNPLA3) compared between the DM-HCC and DM-non-HCC groups with regard to allele frequencies at each SNP. The SNP rs738409 located in PNPLA3 was the greatest risk factor associated with HCC. The frequency of the PNPLA3 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 2.53, p = 1.05 × 10(-5)). Among individuals homozygous for the PNPLA3 G allele (n = 115), the frequency of the JAZF1 rs864745 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 3.44, p = 0.0002). PNPLA3 and JAZF1 were associated with non-HBV and non-HCV-related HCC development among Japanese patients with T2DM.

Synergistic effects of family history of hepatocellular carcinoma and hepatitis B virus infection on risk for incident hepatocellular carcinoma.

PubMed

Loomba, Rohit; Liu, Jessica; Yang, Hwai-I; Lee, Mei-Hsuan; Lu, Sheng-Nan; Wang, Li-Yu; Iloeje, Uchenna H; You, San-Lin; Brenner, David; Chen, Chien-Jen

2013-12-01

Little is known about the effects of family history of hepatocellular carcinoma (HCC) on hepatitis B progression or risk of HCC. We examined how family HCC history and presence or stage of hepatitis B virus (HBV) infection affect risk for HCC. We performed a population-based cohort study of 22,472 participants from 7 townships in Taiwan who underwent evaluation for liver disease from 1991 through 1992. Those who received a first diagnosis of HCC from January 1, 1991, to December 31, 2008, were identified from the Taiwanese cancer registry. There were 374 cases of incident HCC over 362,268 person-years of follow-up evaluation. The cumulative risk of HCC in hepatitis B surface antigen (HBsAg)-seronegative patients without a family history of HCC was 0.62%, in those with a family history of HCC the cumulative risk was 0.65%, in HBsAg-seropositive patients without a family history of HCC the cumulative risk was 7.5%, and in HBsAg-seropositive patients with a family history of HCC the cumulative risk was 15.8% (P < .001). The multivariate-adjusted hazard ratio for HBsAg-seropositive individuals with family history, compared with HBsAg-seronegative individuals without a family history of HCC, was 32.33 (95% confidence interval, 20.8-50.3; P < .001). The relative excess risk owing to interaction was 19, the attributable proportion was 0.59, and the synergy index value was 2.54. These findings indicate synergy between family HCC history and HBsAg serostatus. The synergy between these factors remained significant in stratification analyses by HBeAg serostatus and serum level of HBV DNA. Family history of HCC multiplies the risk of HCC at each stage of HBV infection. Patients with a family history of HCC require more intensive management of HBV infection and surveillance for liver cancer. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Differential Expression of Glypican-3 and Insulin–Like Growth Factor-II mRNAs and Alpha-Fetoprotein and Ki-67 Markers in HCV Related Hepatocellular Carcinomas In Egyptian Patients

PubMed

Saber, Mohamed A; MM AbdelHafiz, Samah; Khorshed, Fatma E; Aboushousha, Tarek S; Hamdy, Hussam EM; Seleem, Mohamed I; Soliman, Amira H

2017-01-01

Background: Increasing evidence indicates that in hepatocellular carcinomas (HCCs) abnormal gene expression, for example of glypican-3 (GPC-3) and insulin-like growth factor-II (IGF-II), are associated with the occurrence and progression of HCC. The objective of this study was to evaluate the differential expression of GPC-3 and IGF-II mRNAs in HCC tissues with a background of chronic hepatitis C virus (HCV) genotype 4 cirrhosis, in relation to Ki-67 and alpha-feto protein (AFP) tissue markers. Methods: One hundred and five patients with HCCs who had undergone hepatectomy, were included, after obtaining informed consent. Total RNA was extracted from malignant and corresponding peri-malignant liver tissues, and GPC-3 and IGF-II mRNAs in addition to beta-actin mRNA as an internal control, were evaluated in all samples by reverse transcriptase-polymerase chain reactions (RT-PCR). Routine histopathological diagnosis as well as immunohistochemical (IHC) staining using monoclonal antibodies for Ki-67 and AFP were also performed. Result: Expression of GPC-3 mRNA was positive in all HCC malignant tissue, with overexpression in 86/105 (81.9%); in respect to the grade of the tumor (1-3 grades), while in peri-malignant tissue it was over expressed only in 20/105 (19%). The IGF-II mRNA was over expressed in only 10/105 (9.5%) malignant and peri-malignant samples. AFP was expressed in 33.3% of malignant samples but absent in peri-malignant tissues. Ki-67 expression was significantly increased in malignant compared to peri-malignant tissue. Conclusion: GPC-3 and IGF II mRNAs may be good molecular markers for HCC, especially with a background of cirrhosis due to chronic HCV infection. Significant correlations were noted with the pattern of AFP and Ki-67 expression. Creative Commons Attribution License

[Clinical safety audits for primary care centers. A pilot study].

PubMed

Ruiz Sánchez, Míriam; Borrell-Carrió, Francisco; Ortodó Parra, Cristina; Fernàndez I Danés, Neus; Fité Gallego, Anna

2013-01-01

To identify organizational processes, violations of rules, or professional performances that pose clinical levels of insecurity. Descriptive cross-sectional survey with customized externally-behavioral verification and comparison of sources, conducted from June 2008 to February 2010. Thirteen of the 53 primary care teams (PCT) of the Catalonian Health Institute (ICS Costa de Ponent, Barcelona). Employees of 13 PCT classified into: director, nurse director, customer care administrators, and general practitioners. Non-random selection, teaching (TC)/non-teaching, urban (UC)/rural and small/large (LC) health care centers (HCC). A total of 33 indicators were evaluated; 15 of procedures, 9 of attitude, 3 of training, and 6 of communication. Level of uncertainty: <50% positive answers for each indicator. no collaboration. A total of 55 professionals participated (84.6% UC, 46.2% LC and 76.9% TC). Rank distribution: 13 customer care administrators, 13 nurse directors, 13 HCC directors, and 16 general practitioners. Levels of insecurity emerged from the following areas: reception of new medical professionals, injections administration, nursing weekend home calls, urgent consultations to specialists, aggressive patients, critical incidents over the agenda of the doctors, communication barriers with patients about treatment plans, and with immigrants. Clinical safety is on the agenda of the health centers. Identified areas of uncertainty are easily approachable, and are considered in the future system of accreditation of the Catalonian Government. General practitioners are more critical than directors, and teaching health care centers, rural and small HCC had a better sense of security. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Potential for Dietary ω-3 Fatty Acids to Prevent Nonalcoholic Fatty Liver Disease and Reduce the Risk of Primary Liver Cancer123

PubMed Central

Jump, Donald B; Depner, Christopher M; Tripathy, Sasmita; Lytle, Kelli A

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity, and its prevalence is anticipated to increase as the obesity epidemic remains unabated. NAFLD is now the most common cause of chronic liver disease in developed countries and is defined as excessive lipid accumulation in the liver, that is, hepatosteatosis. NAFLD ranges in severity from benign fatty liver to nonalcoholic steatohepatitis (NASH), and NASH is characterized by hepatic injury, inflammation, oxidative stress, and fibrosis. NASH can progress to cirrhosis, and cirrhosis is a risk factor for primary hepatocellular carcinoma (HCC). The prevention of NASH will lower the risk of cirrhosis and NASH-associated HCC. Our studies have focused on NASH prevention. We developed a model of NASH by using mice with the LDL cholesterol receptor gene ablated fed the Western diet (WD). The WD induces a NASH phenotype in these mice that is similar to that seen in humans and includes robust induction of hepatic steatosis, inflammation, oxidative stress, and fibrosis. With the use of transcriptomic, lipidomic, and metabolomic approaches, we examined the capacity of 2 dietary ω-3 (n–3) polyunsaturated fatty acids, eicosapentaenoic acid (20:5ω-3; EPA) and docosahexaenoic acid (22:6ω-3; DHA), to prevent WD-induced NASH. Dietary DHA was superior to EPA at attenuating WD-induced changes in plasma lipids and hepatic injury and at reversing WD effects on hepatic metabolism, oxidative stress, and fibrosis. The outcome of these studies suggests that DHA may be useful in preventing NASH and reducing the risk of HCC. PMID:26567194

Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Lijie; Dong, Pingping; Liu, Longzi

Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstratedmore » that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. - Highlights: • Pofut1 overexpression in HCC was correlated with aggressive tumor behaviors. • Pofut1 overexpression in HCC was associated with poor prognosis. • Pofut1 promoted cell proliferation, migration and invasion in hepatoma cells. • Pofut1 activated Notch signaling pathway in hepatoma cells.« less

Inhibition of connective tissue growth factor overexpression decreases growth of hepatocellular carcinoma cells in vitro and in vivo.

PubMed

Jia, Xiao-Qin; Cheng, Hai-Qing; Li, Hong; Zhu, Yan; Li, Yu-Hua; Feng, Zhen-Qing; Zhang, Jian-Ping

2011-11-01

We have previously found that connective tissue growth factor (CTGF) is highly expressed in a rat model of liver cancer. Here, we examined expression of CTGF in human hepatocellular carcinoma (HCC) cells and its effect on cell growth. Real-time PCR was used to observe expression of CTGF in human HCC cell lines HepG2, SMMC-7721, MHCC-97H and LO2. siRNA for the CTGF gene was designed, synthesized and cloned into a Plk0.1-GFP-SP6 vector to construct a lentivirus-mediated shRNA/CTGF. CTGF mRNA and protein expression in HepG2 cells treated by CTGF-specific shRNA was evaluated by real-time PCR and Western blotting. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was utilized to evaluate the growth effect, and a colony formation assay was used for observing clonogenic growth. In vivo, tumor cell proliferation was evaluated in a nude mouse model of xenotransplantation. Statistical significance was determined by t test for comparison between two groups, or analysis of variance (ANOVA) for multiple groups. Immunohistochemical staining of CTGF was seen in 35 of 40 HCC samples (87.5%). CTGF was overexpressed 5-fold in 20 HCC tissues, compared with surrounding non-tumor liver tissue. CTGF mRNA level was 5 - 8-fold higher in HepG2, SMMC-7721 and MHCC-97H than in LO2 cells. This indicated that the inhibition rate of cell growth was 43% after knockdown of CTGF expression (P < 0.05). Soft agar colony formation assay showed that siRNA mediated knockdown of CTGF inhibited colony formation in soft agar of HepG2 cells (P < 0.05). The volume of tumors from CTGF-shRNA-expressing cells only accounted for 35% of the tumors from the scrambled control-infected HepG2 cells (P < 0.05). CTGF was overexpressed in human HCC cells and downregulation of CTGF inhibited HCC growth in vitro and in vivo. Knockdown of CTGF may be a potential therapeutic strategy for treatment of HCC.

Redox proteomics screening cellular factors associated with oxidative stress in hepatocarcinogenesis.

PubMed

Zhou, Li; Wen, Ji; Huang, Zhao; Nice, Edouard C; Huang, Canhua; Zhang, Haiyuan; Li, Qifu

2017-03-01

Liver cancer is a major global health problem being the sixth most common cancer and the third cause of cancer-related death, with hepatocellular carcinoma (HCC) representing more than 90% of primary liver cancers. Mounting evidence suggests that, compared with their normal counterparts, many types of cancer cell have increased levels of ROS. Therefore, cancer cells need to combat high levels of ROS, especially at early stages of tumor development. Recent studies have revealed that ROS-mediated regulation of redox-sensitive proteins (redox sensors) is involved in the pathogenesis and/or progression of many human diseases, including cancer. Unraveling the altered functions of redox sensors and the underlying mechanisms in hepatocarcinogenesis is critical for the development of novel cancer therapeutics. For this reason, redox proteomics has been developed for the high-throughput screening of redox sensors, which will benefit the development of novel therapeutic strategies for the treatment of HCC. In this review, we will briefly introduce several novel redox proteomics techniques that are currently available to study various oxidative modifications in hepatocarcinogenesis and summarize the most important discoveries in the study of redox processes related to the development and progression of HCC. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Targeting c-Met in Cancer by MicroRNAs: Potential Therapeutic Applications in Hepatocellular Carcinoma.

PubMed

Karagonlar, Zeynep F; Korhan, Peyda; Atabey, Neşe

2015-11-01

Preclinical Research Cancer is one of the world's deadliest diseases, with very low survival rates and increased occurrence in the future. Successfully developed target-based therapies have significantly changed cancer treatment. However, primary and/or acquired resistance in the tumor is a major challenge in current therapies and novel combinational therapies are required. RNA interference-mediated gene inactivation, alone or in combination with other current therapies, provides novel promising therapeutics that can improve cure rate and overcome resistance mechanisms to conventional therapeutics. Hepatocyte Growth Factor/c-Met signaling is one of the most frequently dysregulated pathways in human cancers and abnormal c-Met activation is correlated with poor clinical outcomes and drug resistance in hepatocellular carcinoma (HCC). In recent years, a growing number of studies have identified several inhibitors and microRNAs (miRNAs), specifically targeting c-Met in various cancers, including HCC. In this review, we discuss current knowledge regarding miRNAs, focusing on their involvement in cancer and their potential as research tools and therapeutics. Then, we focus on the potential use of c-Met targeting miRNAs for suppressing aberrant c-Met signaling in HCC treatment. © 2015 Wiley Periodicals, Inc.

Glypican-3 induces oncogenicity by preventing IGF-1R degradation, a process that can be blocked by Grb10

PubMed Central

Cheng, Wei; Huang, Po-Chun; Chao, Hsiao-Mei; Jeng, Yung-Ming; Hsu, Hey-Chi; Pan, Hung-Wei; Hwu, Wuh-Liang; Lee, Yu-May

2017-01-01

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a major cause of cancer-related death worldwide. Previously, we demonstrated that glypican-3 (GPC3) is highly expressed in HCC, and that GPC3 induces oncogenicity and promotes the growth of cancer cells through IGF-1 receptor (IGF-1R). In the present study, we investigated the mechanisms of GPC3-mediated enhancement of IGF-1R signaling. We demonstrated that GPC3 decreased IGF-1-induced IGF-1R ubiquitination and degradation and increased c-Myc protein levels. GPC3 bound to Grb10, a mediator of ligand-induced receptor ubiquitination, and the overexpression of Grb10 blocked GPC3-enhanced IGF-1-induced ERK phosphorylation. GPC3 promoted the growth of NIH3T3 and PLC-PRF-5 cells in serum-free medium but did not promote the growth of IGF-1R negative R- cells. Grb10 overexpression decreased GPC3-promoted cell growth. Therefore, the present study elucidates the mechanisms of GPC3-induced oncogenicity, which may highlight new strategies for the treatment of HCC. PMID:29113314

BCORL1 is an independent prognostic marker and contributes to cell migration and invasion in human hepatocellular carcinoma.

PubMed

Yin, Guozhi; Liu, Zhikui; Wang, Yufeng; Dou, Changwei; Li, Chao; Yang, Wei; Yao, Yingmin; Liu, Qingguang; Tu, Kangsheng

2016-02-15

The deregulation of E-cadherin has been considered as a leading cause of hepatocellular carcinoma (HCC) metastasis. BCL6 corepressor-like 1 (BCORL1) is a transcriptional corepressor and contributes to the repression of E-cadherin. However, the clinical significance of BCORL1 and its role in the metastasis of HCC remain unknown. Differentially expressed BCORL1 between HCC and matched tumor-adjacent tissues, HCC cell lines and normal hepatic cell line were detected by Western blot. The expression of BCORL1 was altered by siRNAs or lentivirus-mediated vectors. Transwell assays were performed to determine HCC cell invasion and migration. Increased expression of BCORL1 protein was detected in HCC specimens and cell lines. Clinical association analysis showed that BCORL1 protein was expressed at significant higher levels in HCC patients with multiple tumor nodes, venous infiltration and advanced TNM tumor stage. Survival analysis indicated that high expression of BCORL1 protein conferred shorter overall survival (OS) and recurrence-free survival (RFS) of HCC patients. Multivariate Cox regression analysis disclosed that BCORL1 expression was an independent prognostic marker for predicting survival of HCC patients. Our in vitro studies demonstrated that BCORL1 prominently promoted HCC cell migration and invasion. Otherwise, an inverse correlation between BCORL1 and E-cadherin expression was observed in HCC tissues. BCORL1 inversely regulated E-cadherin abundance and subsequently facilitated epithelial-mesenchymal transition (EMT) in HCC cells. Notably, the effect of BCORL1 knockdown on HCC cells was abrogated by E-cadherin silencing. BCORL1 may be a novel prognostic factor and promotes cell migration and invasion through E-cadherin repression-induced EMT in HCC.

Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy.

PubMed

Saraiya, N; Yopp, A C; Rich, N E; Odewole, M; Parikh, N D; Singal, A G

2018-05-30

Although studies suggest decreased incident hepatocellular carcinoma (HCC) after direct-acting antivirals (DAA), data are conflicting regarding HCC recurrence and aggressiveness in patients who have a history of HCC with complete response. Characterize HCC recurrence patterns after DAA therapy. Two reviewers searched MEDLINE and SCOPUS from January 2015 to December 2017 and identified studies evaluating HCC recurrence patterns following DAA therapy. A pooled estimate was calculated using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with PRISMA guidelines. Among 24 studies (n = 1820 patients), the proportion of patients with HCC recurrence following DAA therapy ranged from 0% to 59% (pooled estimate 24.4%; 95% CI: 18.4%-30.4%). Among 11 full text manuscripts, pooled HCC recurrence was 21.9% (95% CI: 16.2%-28.3%). Factors associated with recurrence included history of prior HCC recurrence and a shorter interval between HCC complete response and DAA initiation. Nine studies comparing DAA-treated and interferon-treated or untreated patients found similar recurrence among DAA-treated patients. Most (77.8%) patients with HCC recurrence were detected at an early tumour stage, of whom 64.7% received curative treatment. Study limitations included heterogeneous cohorts, potential misclassification of HCC absence prior to DAA, ascertainment bias for recurrence, and short durations of follow-up. Current data suggest acceptable HCC recurrence rates after DAA therapy, particularly if DAA therapy is delayed at least 6 months after HCC complete response. However, data characterising HCC recurrence after DAA therapy are of limited quality, highlighting the need for high quality prospective studies. © 2018 John Wiley & Sons Ltd.

Primary Seronegative but Molecularly Evident Hepadnaviral Infection Engages Liver and Induces Hepatocarcinoma in the Woodchuck Model of Hepatitis B

PubMed Central

Mulrooney-Cousins, Patricia M.; Chauhan, Ranjit; Churchill, Norma D.; Michalak, Tomasz I.

2014-01-01

Hepadnavirus at very low doses establishes in woodchucks asymptomatic, serologically undetectable but molecularly evident persistent infection. This primary occult infection (POI) preferentially engages the immune system and initiates virus-specific T cell response in the absence of antiviral antibody induction. The current study aimed to determine whether POI with time may culminate in serologically identifiable infection and hepatitis, and what are, if any, its pathological consequences. Juvenile woodchucks were intravenously injected with inocula containing 10 or 100 virions of woodchuck hepatitis virus (WHV) to induce POI and followed for life or up to 5.5 years thereafter. All 10 animals established molecularly detectable infection with virus DNA in serum (<100–200 copies/mL) and in circulating lymphoid cells, but serum WHV surface antigen and antibodies to WHV core antigen remained undetectable for life. By approximately 2.5–3.5 years post-infection, circulating virus transiently increased to 103 copies/mL and virus replication became detectable in the livers, but serological markers of infection and biochemical or histological evidence of hepatitis remained undetectable. Nonetheless, typical hepatocellular carcinoma (HCC) developed in 2/10 animals. WHV DNA integration into hepatic and lymphatic system genomes was identified in 9/10 animals. Virus recovered from the liver virus-negative or virus-positive phases of POI displayed the wild-type sequence and transmitted infection to healthy woodchucks causing hepatitis and HCC. In summary, for the first time, our data demonstrate that an asymptomatic hepadnaviral persistence initiated by very small amounts of otherwise pathogenic virus, advancing in the absence of traditional serological markers of infection and hepatitis, coincides with virus DNA integration into the host's hepatic and immune system genomes, retains liver pro-oncogenic potency and is capable of transmitting liver pathogenic infection. This emphasizes the role for primary occult hepatitis B virus infection in the development of seemingly cyptogenic HCC in seronegative but virus DNA reactive patients. PMID:25165821

Imaging findings of mimickers of hepatocellular carcinoma

PubMed Central

Lee, Eunchae; Jang, Hyun-Jung

2015-01-01

Radiological imaging plays a crucial role in the diagnosis of hepatocellular carcinoma (HCC) as the noninvasive diagnosis of HCC in high-risk patients by typical imaging findings alone is widely adopted in major practice guidelines for HCC. While imaging techniques have markedly improved in detecting small liver lesions, they often detect incidental benign liver lesions and non-hepatocellular malignancy that can be misdiagnosed as HCC. The most common mimicker of HCC in cirrhotic liver is nontumorous arterioportal shunts that are seen as focal hypervascular liver lesions on dynamic contrast-enhanced cross-sectional imaging. Rapidly enhancing hemangiomas can be easily misdiagnosed as HCC especially on MR imaging with liver-specific contrast agent. Focal inflammatory liver lesions mimic HCC by demonstrating arterial-phase hypervascularity and subsequent washout on dynamic contrast-enhanced imaging. It is important to recognize the suggestive imaging findings for intrahepatic cholangiocarcinoma (CC) as the management of CC is largely different from that of HCC. There are other benign mimickers of HCC such as angiomyolipomas and focal nodular hyperplasia-like nodules. Recognition of their typical imaging findings can reduce false-positive HCC diagnosis. PMID:26770920

Contrast ultrasound LI-RADS LR-5 identifies hepatocellular carcinoma in cirrhosis in a multicenter restropective study of 1,006 nodules.

PubMed

Terzi, Eleonora; Iavarone, Massimo; Pompili, Maurizio; Veronese, Letizia; Cabibbo, Giuseppe; Fraquelli, Mirella; Riccardi, Laura; De Bonis, Ludovico; Sangiovanni, Angelo; Leoni, Simona; Zocco, Maria Assunta; Rossi, Sandro; Alessi, Nicola; Wilson, Stephanie R; Piscaglia, Fabio

2018-03-01

The use of contrast enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis was questioned because of the risk of a false positive diagnosis in cases of cholangiocarcinoma. The American College of Radiology has recently released a scheme (CEUS Liver Imaging Reporting and Data System [LI-RADS®]) to classify lesions at risk of HCC investigated by CEUS. The aim of the present study was to validate this LI-RADS scheme for the diagnosis of HCC. A total of 1,006 nodules from 848 patients with chronic liver disease at risk of HCC were collected in five Italian centers and retrospectively analyzed. Nodules were classified as LR-5, (HCC) if ≥1 cm with arterial phase hyperenhancement, and late washout (onset ≥60 s after contrast injection) of mild degree. Rim enhancement and/or early and/or marked washout qualified lesions as LR-M (malignant, but not specific for HCC). Other combinations qualified lesions at intermediate risk for HCC (LR-3) or probable HCC (LR-4). Diagnostic reference standard was CT/MRI diagnosis of HCC (n = 506) or histology (n = 500). The median nodule size was 2 cm. Of 1,006 nodules, 820 (81%) were HCC, 40 (4%) were cholangiocarcinoma, 116 (11%) regenerative nodules (±dysplastic). The LR-5 category (52% of all nodules) was 98.5% predictive of HCC, with no risk of misdiagnosis for pure cholangiocarcinoma. Sensitivity for HCC was 62%. All LR-M nodules were malignant and the majority of non-hepatocellular origin. Over 75% of cholangiocarcinomas were LR-M. The LR-3 category included 203 lesions (HCC 96 [47%]) and the LR-4 202 (HCC 173 [87%]). The CEUS LI-RADS class LR-5 is highly specific for HCC, enabling its use for a confident non-invasive diagnosis. This is a retrospective study of approximately 1,000 focal lesions at risk for hepatocellular carcinoma (HCC). Herein, we demonstrate that the refined definition of the typical contrast enhanced ultrasound pattern of HCC introduced by the Liver Imaging Reporting and Data System (LI-RADS®) practically abolishes the risk of misdiagnosis of other malignant entities (e.g. cholangiocarcinoma) for HCC with negligible reduction in sensitivity. These data support the use of contrast enhanced ultrasound to diagnose HCC in cirrhosis. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Antibiotic tigecycline enhances cisplatin activity against human hepatocellular carcinoma through inducing mitochondrial dysfunction and oxidative damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Jun; Song, Meijun; Zhou, Mi

Targeting mitochondrial metabolism has been recently demonstrated to be a promising therapeutic strategy for the treatment of various cancer. In this work, we demonstrate that antibiotic tigecycline is selectively against hepatocellular carcinoma (HCC) through inducing mitochondrial dysfunction and oxidative damage. Tigecycline is more effective in inhibiting proliferation and inducing apoptosis of HCC than normal liver cells. Importantly, tigecycline significantly enhances the inhibitory effects of chemotherapeutic drug cisplatin in HCC in vitro and in vivo. Mechanistically, tigecycline specifically inhibits mitochondrial translation as shown by the decreased protein levels of Cox-1 and -2 but not Cox-4 or Grp78, and increased mRNA levels of Cox-1more » and -2 but not Cox-4 in HCC cells exposed to tigecycline. In addition, tigecycline significantly induces mitochondrial dysfunction in HCC cells via decreasing mitochondrial membrane potential, complex I and IV activities, mitochondrial respiration and ATP levels. Tigecycline also increases levels of mitochondrial superoxide, hydrogen peroxide and ROS levels. Consistent with oxidative stress, oxidative damage on DNA, protein and lipid are also observed in tigecycline-treated cells. Importantly, antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of tigecycline, suggesting that oxidative stress is required for the action of tigecycline in HCC cells. We further show that HCC cells have higher level of mitochondrial biogenesis than normal liver cells which might explain the different sensitivity to tigecycline between HCC and normal liver cells. Our work is the first to demonstrate that tigecycline is a promising candidate for HCC treatment and highlight the therapeutic value of targeting mitochondrial metabolism in HCC. - Highlights: • Tigecycline selectively targets HCC in vitro and in vivo. • Tigecycline enhances HCC cell response to chemotherapeutic drug. • Tigecycline inhibits mitochondrial translation and functions in HCC cells. • Tigecycline induces oxidative stress and damage in HCC cells. • Mitochondrial biogenesis and respiration is higher in HCC than normal liver cells.« less

Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features.

PubMed

Kopanja, Dragana; Pandey, Akshay; Kiefer, Megan; Wang, Zebin; Chandan, Neha; Carr, Janai R; Franks, Roberta; Yu, Dae-Yeul; Guzman, Grace; Maker, Ajay; Raychaudhuri, Pradip

2015-08-01

Overexpression of FoxM1 correlates with poor prognosis in hepatocellular carcinoma (HCC). Moreover, the Ras-signaling pathway is found to be ubiquitously activated in HCC through epigenetic silencing of the Ras-regulators. We investigated the roles of FoxM1 in Ras-driven HCC, and on HCC cells with stem-like features. We employed a transgenic mouse model that expresses the oncogenic Ras in the liver. That strain was crossed with a strain that harbor floxed alleles of FoxM1 and the MxCre gene that allows conditional deletion of FoxM1. FoxM1 alleles were deleted after development of HCC, and the effects on the tumors were analyzed. Also, FoxM1 siRNA was used in human HCC cell lines to determine its role in the survival of the HCC cells with stem cell features. Ras-driven tumors overexpress FoxM1. Deletion of FoxM1 inhibits HCC progression. There was increased accumulation of reactive oxygen species (ROS) in the FoxM1 deleted HCC cells. Moreover, FoxM1 deletion caused a disproportionate loss of the CD44+ and EpCAM+ HCC cells in the tumors. We show that FoxM1 directly activates expression of CD44 in human HCC cells. Moreover, the human HCC cells with stem cell features are addicted to FoxM1 for ROS-regulation and survival. Our results provide genetic evidence for an essential role of FoxM1 in the progression of Ras-driven HCC. In addition, FoxM1 is required for the expression of CD44 in HCC cells. Moreover, FoxM1 plays a critical role in the survival of the HCC cells with stem cell features by regulating ROS. Published by Elsevier B.V.

Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis

PubMed Central

Kawai, Hirokazu; Nomoto, Minoru; Suda, Takeshi; Kamimura, Kenya; Tsuchiya, Atsunori; Tamura, Yasushi; Yano, Masahiko; Takamura, Masaaki; Igarashi, Masato; Wakai, Toshifumi; Yamagiwa, Satoshi; Matsuda, Yasunobu; Ohkoshi, Shogo; Kurosaki, Isao; Shirai, Yoshio; Okada, Masahiko; Aoyagi, Yutaka

2011-01-01

AIM: To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis (NASH) focusing on multicentric occurrence (MO) of HCC. METHODS: We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background. The clinical features were implicated with reference to the literature available. RESULTS: MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC (2 males and 2 females). One patient had synchronous MO; an advanced HCC, two well-differentiated HCCs and a dysplastic nodule, followed by the development of metachronous MO of HCC. The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule. Of these three patients, one had synchronous MO, one had metachronous MO and the other had both synchronous and metachronous MO. There were no obvious differences between the patients with or without MO in terms of liver function tests, tumor markers and anatomical extent of HCC. On the other hand, all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity, type 2 diabetes mellitus (T2DM), hypertension and cirrhosis. Although these conditions were not limited to MO of HCC, all the conditions were met in only one of eight patients without MO of HCC. Thus, concurrence of these conditions may be a predisposing situation to synchronous MO of HCC. In particular, old age, T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature. CONCLUSION: The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study. Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic improvement in NASH. PMID:21307983

Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians.

PubMed

Arends, Pauline; Sonneveld, Milan J; Zoutendijk, Roeland; Carey, Ivana; Brown, Ashley; Fasano, Massimo; Mutimer, David; Deterding, Katja; Reijnders, Jurriën G P; Oo, Ye; Petersen, Jörg; van Bömmel, Florian; de Knegt, Robert J; Santantonio, Teresa; Berg, Thomas; Welzel, Tania M; Wedemeyer, Heiner; Buti, Maria; Pradat, Pierre; Zoulim, Fabien; Hansen, Bettina; Janssen, Harry L A

2015-08-01

Hepatocellular carcinoma (HCC) risk-scores may predict HCC in Asian entecavir (ETV)-treated patients. We aimed to study risk factors and performance of risk scores during ETV treatment in an ethnically diverse Western population. We studied all HBV monoinfected patients treated with ETV from 11 European referral centres within the VIRGIL Network. A total of 744 patients were included; 42% Caucasian, 29% Asian, 19% other, 10% unknown. At baseline, 164 patients (22%) had cirrhosis. During a median follow-up of 167 (IQR 82-212) weeks, 14 patients developed HCC of whom nine (64%) had cirrhosis at baseline. The 5-year cumulative incidence rate of HCC was 2.1% for non-cirrhotic and 10.9% for cirrhotic patients (p<0.001). HCC incidence was higher in older patients (p<0.001) and patients with lower baseline platelet counts (p=0.02). Twelve patients who developed HCC achieved virologic response (HBV DNA <80 IU/mL) before HCC. At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with development of HCC. Discriminatory performance of HCC risk scores was low, with sensitivity ranging from 18% to 73%, and c-statistics from 0.71 to 0.85. Performance was further reduced in Caucasians with c-statistics from 0.54 to 0.74. Predicted risk of HCC based on risk-scores declined during ETV therapy (all p<0.001), but predictive performances after 1 year were comparable to those at baseline. Cumulative incidence of HCC is low in patients treated with ETV, but ETV does not eliminate the risk of HCC. Discriminatory performance of HCC risk scores was limited, particularly in Caucasians, at baseline and during therapy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Molecular mechanisms of nano-selenium in mitigating hepatocellular carcinoma induced by N-nitrosodiethylamine (NDEA) in rats.

PubMed

Ahmed, Hanaa H; Khalil, Wagdy K B; Hamza, Amal H

2014-12-01

The possible molecular mechanisms of Nano-selenium (nano-se) in attenuating hepatocellular carcinoma (HCC) was investigated in this study. To achieve this target, the apoptotic/necrotic rate in hepatic cells was investigated morphologically by double staining with acridine orange/ethidium bromide to address the type of cell death induced by nano-Se in HCC-bearing rats. To predict the oxidative stress and DNA damage, the generation of 8-hydroxy-2-deoxyguanosine (8-OHdG) and 2-deoxyguanosine (2-dG) was examined. Moreover, the expression of some HCC-related genes was investigated such as aldo-keto reductase 1B10 (Akr1b10), ING3 and Foxp1 genes. As well as the histopathological study of liver tissue sections was performed. The results obtained from this study revealed that (HCC+Nano Se) group shows the highest number of damaged cancerous cells. Furthermore, the necrotic/apoptotic rate was significantly higher in (nano-Se+HCC), (HCC+Doxo) and (HCC+Doxo+nano-se) compared to that in the untreated HCC group. Treatment of HCC group with nano-se decreased the ratio of 8-OHdG/2-dG generation significantly with respect to the untreated HCC group. The opposite was observed regarding the gene expression of AKr1b10 and ING3. The treatment of HCC group with nano-se elicited significant increase in the expression of Akr1b10 and ING3 genes compared with untreated HCC group. On the other hand, the expression of Foxp1 gene was significantly decreased in HCC group treated with nano-se in comparison with the untreated HCC group. The histopathological study provided a supportive evidence for the molecular genetics study. Our data shed light on the molecular mechanisms of nano-se in attenuating HCC in the experimental model.

Aldehyde dehydrogenase 2 polymorphism for development to hepatocellular carcinoma in East Asian alcoholic liver cirrhosis.

PubMed

Abe, Hiroshi; Aida, Yuta; Seki, Nobuyoshi; Sugita, Tomonori; Tomita, Yoichi; Nagano, Tomohisa; Itagaki, Munenori; Sutoh, Satoshi; Nagatsuma, Keisuke; Itoh, Kyoko; Matsuura, Tomokazu; Aizawa, Yoshio

2015-09-01

We aimed to clarify the influences of aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 1B (ADH1B) polymorphisms, and ethanol consumption profile to hepatocellular carcinoma (HCC) development in alcoholic liver cirrhosis without chronic hepatitis B and C virus infection (non-B non-C). Of 236 freshly diagnosed non-B non-C alcoholic liver cirrhosis patients, 67 were diagnosed as HCC and the remaining 169 as not having HCC. The relationship between the genetic polymorphisms and development to HCC were evaluated in well-matched patients with HCC (HCC group, n = 67) and without HCC (non-HCC group, n = 67) using propensity scores in age, sex, and prevalence of diabetes mellitus. Daily amount of ethanol consumption was significantly lower (P = 0.005), and consumptive period was significantly longer (P = 0.003) in HCC group than non-HCC group. Of 134 well-matched patients, 113 (84.3%) had ALDH2*1/*1 genotype and 21 (15.7%) had ALDH2*1/*2 genotype. In HCC development, consumptive long period (P = 0.007) and carrying ALDH2*1/*2 genotype (P = 0.026) were identified as significant factors independently participated, while there was no relation to ADH1B polymorphism. In addition, consumptive period was significantly longer in HCC group than non-HCC group in ALDH2*1/*1 genotype patients (P = 0.0005), while there was no difference in profile of ethanol consumption in ALDH2*1/*2 genotype patients. Among HCC group, daily (P = 3.78 × 10(-6) ) and cumulative amount (P = 4.89 × 10(-6) ) of ethanol consumption were significantly higher in ALDH2*1/*1 genotype patients than ALDH2*1/*2 genotype patients. In alcoholic liver cirrhosis, investigations of ALDH2 polymorphism and ethanol consumption profile are useful for prediction of HCC development. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Osteoactivin expressed during cirrhosis development in rats fed a choline-deficient, L-amino acid-defined diet, accelerates motility of hepatoma cells.

PubMed

Onaga, Masaaki; Ido, Akio; Hasuike, Satoru; Uto, Hirofumi; Moriuchi, Akihiro; Nagata, Kenji; Hori, Takeshi; Hayash, Katsuhiro; Tsubouchi, Hirohito

2003-11-01

Hepatocellular carcinoma (HCC) is closely associated with chronic liver diseases, particularly cirrhosis. However, the genes involved in hepatocarcinogenesis in the context of developing cirrhosis remain unknown. This study aims to identify genes associated with early cirrhosis-associated hepatocarcinogenesis. We examined genes differentially expressed between the livers of normal rats and rats fed a choline-deficient, L-amino acid-defined (CDAA) diet using suppression subtractive hybridization. We examined both the expression in the liver and HCC tissues of osteoactivin (OA), isolated in this screen, and its effect on invasiveness and metastasis. OA mRNA was strongly expressed in the livers of rats fed the CDAA diet for 1-3 months. Moderate expression was sustained for 18 months. OA overexpression increased the invasiveness and metastasis of rat hepatoma cells in vitro and in vivo. In humans, OA expression was not detectable in normal liver tissues. While OA transcripts were detectable in cirrhotic nontumorous liver tissues surrounding HCCs, the majority of HCC tissue samples exhibited higher levels of OA expression than the surrounding normal tissue. These results indicate that OA is a novel factor involved in the progression of HCC via stimulation of tumor invasiveness and metastatic potential.

Identification and characterization of a prevalent hepatitis B virus X protein mutant in Taiwanese patients with hepatocellular carcinoma.

PubMed

Yeh, C T; Shen, C H; Tai, D I; Chu, C M; Liaw, Y F

2000-11-02

The aim of this study was to investigate whether there was a particular hepatitis B virus (HBV) X protein (HBx) mutant associated with Taiwanese patients with hepatocellular carcinoma (HCC). Initially, the entire coding region of HBx gene from the serum samples of 14 Taiwanese patients were sequenced. A novel mutant, HBx-A31, was preferentially found in patients with HCC. Sera from 67 patients with HCC and 100 patients with chronic hepatitis B were thus subjected for codon 31 analysis using a dual amplification created restriction site method. HBx-A31 was detected more frequently in patients with HCC (52% versus 12%; P<0.001) and in patients with liver cirrhosis (44% versus 6%; P<0.001). Site directed mutagenesis experiment revealed that HBx-A31 was less effective in transactivating HBV enhancer I-X promoter complex, less efficient in supporting HBV replication, and less potent in enhancing TNF-alpha induced increment of CPP32/caspase 3 activities in HepG2 cells. In conclusion, a prevalent HBx mutant was identified in Taiwanese patients with hepatocellular carcinoma. Development of this mutant might represent a strategy of the virus to escape immune surveillance and thus contribute to the process of multiple-step hepatocarcinogenesis.

Etiology and Viral Genotype in Patients with End-Stage Liver Diseases admitted to a Hepatology Unit in Colombia

PubMed Central

Cortes-Mancera, Fabian; Loureiro, Carmen Luisa; Hoyos, Sergio; Restrepo, Juan-Carlos; Correa, Gonzalo; Jaramillo, Sergio; Norder, Helene; Pujol, Flor Helene; Navas, Maria-Cristina

2011-01-01

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the principal risk factor associated to end-stage liver diseases in the world. A study was carried out on end-stage liver disease cases admitted to an important hepatology unit in Medellin, the second largest city in Colombia. From 131 patients recruited in this prospective study, 71% of cases were diagnosed as cirrhosis, 12.2% as HCC, and 16.8% as cirrhosis and HCC. Regarding the risk factors of these patients, alcohol consumption was the most frequent (37.4%), followed by viral etiology (17.6%). Blood and/or hepatic tissue samples from patients with serological markers for HCV or HBV infection were characterized; on the basis of the phylogenetic analysis of HCV 5′ UTR and HBV S gene, isolates belonged to HCV/1 and HBV/F3, respectively. These results confirm the presence of strains associated with poor clinical outcome, in patients with liver disease in Colombia; additionally, HBV basal core promoter double mutant was identified in HCC cases. Here we show the first study of cirrhosis and/or HCC in Colombian and HBV and HCV molecular characterization of these patients. Viral aetiology was not the main risk factor in this cohort but alcohol consumption. PMID:21941645

Long non-coding RNA NEAT1-modulated abnormal lipolysis via ATGL drives hepatocellular carcinoma proliferation.

PubMed

Liu, Xirui; Liang, Yingjian; Song, Ruipeng; Yang, Guangchao; Han, Jihua; Lan, Yaliang; Pan, Shangha; Zhu, Mingxi; Liu, Yao; Wang, Yan; Meng, Fanzheng; Cui, Yifeng; Wang, Jiabei; Zhang, Bo; Song, Xuan; Lu, Zhaoyang; Zheng, Tongsen; Liu, Lianxin

2018-05-15

Abnormal metabolism, including abnormal lipid metabolism, is a hallmark of cancer cells. Some studies have demonstrated that the lipogenic pathway might promote the development of hepatocellular carcinoma (HCC). However, the role of the lipolytic pathway in HCC has not been elucidated. We compared levels of adipose triglyceride lipase (ATGL) in human HCC and healthy liver tissues by real time PCR, western blot and immunohistochemistry. We measured diacylglycerol(DAG) and free fatty acid (FFA) levels in HCC cells driven by the NEAT1-ATGL axis and in HCC tissues. We also assessed the effects of ATGL, DAG, FFA, and NEAT1 on HCC cells proliferation in vitro and in an orthotopic xenograft HCC mouse model. We also performed a luciferase reporter assay to investigate the interaction between NEAT1/ATGL and miR-124-3p. We found that the lipolytic enzyme, ATGL is highly expressed in human HCC tissues and predicts poor prognosis. We also found that high levels of DAG and FFA are present in HCC tissues. Furthermore, the lncRNA-NEAT1 was found to modulate ATGL expression and disrupt lipolysis in HCC cells via ATGL. Notably, ATGL and its products, DAG and FFA, were shown to be responsible for NEAT1-mediated HCC cell growth. NEAT1 regulated ATGL expression by binding miR-124-3p. Additionally, NEAT1 knockdown attenuated HCC cell growth through miR-124-3p/ATGL/DAG+FFA/PPARα signaling. Our results reveal that NEAT1-modulates abnormal lipolysis via ATGL to drive HCC proliferation.

Systems biology analysis of hepatitis C virus infection reveals the role of copy number increases in regions of chromosome 1q in hepatocellular carcinoma metabolism.

PubMed

Elsemman, Ibrahim E; Mardinoglu, Adil; Shoaie, Saeed; Soliman, Taysir H; Nielsen, Jens

2016-04-26

Hepatitis C virus (HCV) infection is a worldwide healthcare problem; however, traditional treatment methods have failed to cure all patients, and HCV has developed resistance to new drugs. Systems biology-based analyses could play an important role in the holistic analysis of the impact of HCV on hepatocellular metabolism. Here, we integrated HCV assembly reactions with a genome-scale hepatocyte metabolic model to identify metabolic targets for HCV assembly and metabolic alterations that occur between different HCV progression states (cirrhosis, dysplastic nodule, and early and advanced hepatocellular carcinoma (HCC)) and healthy liver tissue. We found that diacylglycerolipids were essential for HCV assembly. In addition, the metabolism of keratan sulfate and chondroitin sulfate was significantly changed in the cirrhosis stage, whereas the metabolism of acyl-carnitine was significantly changed in the dysplastic nodule and early HCC stages. Our results explained the role of the upregulated expression of BCAT1, PLOD3 and six other methyltransferase genes involved in carnitine biosynthesis and S-adenosylmethionine metabolism in the early and advanced HCC stages. Moreover, GNPAT and BCAP31 expression was upregulated in the early and advanced HCC stages and could lead to increased acyl-CoA consumption. By integrating our results with copy number variation analyses, we observed that GNPAT, PPOX and five of the methyltransferase genes (ASH1L, METTL13, SMYD2, TARBP1 and SMYD3), which are all located on chromosome 1q, had increased copy numbers in the cancer samples relative to the normal samples. Finally, we confirmed our predictions with the results of metabolomics studies and proposed that inhibiting the identified targets has the potential to provide an effective treatment strategy for HCV-associated liver disorders.

Genetic alterations of hepatocellular carcinoma by random amplified polymorphic DNA analysis and cloning sequencing of tumor differential DNA fragment

PubMed Central

Xian, Zhi-Hong; Cong, Wen-Ming; Zhang, Shu-Hui; Wu, Meng-Chao

2005-01-01

AIM: To study the genetic alterations and their association with clinicopathological characteristics of hepatocellular carcinoma (HCC), and to find the tumor related DNA fragments. METHODS: DNA isolated from tumors and corresponding noncancerous liver tissues of 56 HCC patients was amplified by random amplified polymorphic DNA (RAPD) with 10 random 10-mer arbitrary primers. The RAPD bands showing obvious differences in tumor tissue DNA corresponding to that of normal tissue were separated, purified, cloned and sequenced. DNA sequences were analyzed and compared with GenBank data. RESULTS: A total of 56 cases of HCC were demonstrated to have genetic alterations, which were detected by at least one primer. The detestability of genetic alterations ranged from 20% to 70% in each case, and 17.9% to 50% in each primer. Serum HBV infection, tumor size, histological grade, tumor capsule, as well as tumor intrahepatic metastasis, might be correlated with genetic alterations on certain primers. A band with a higher intensity of 480 bp or so amplified fragments in tumor DNA relative to normal DNA could be seen in 27 of 56 tumor samples using primer 4. Sequence analysis of these fragments showed 91% homology with Homo sapiens double homeobox protein DUX10 gene. CONCLUSION: Genetic alterations are a frequent event in HCC, and tumor related DNA fragments have been found in this study, which may be associated with hepatocarcin-ogenesis. RAPD is an effective method for the identification and analysis of genetic alterations in HCC, and may provide new information for further evaluating the molecular mechanism of hepatocarcinogenesis. PMID:15996039

Hair cortisol concentration in preschoolers with attention-deficit/hyperactivity symptoms-Roles of gender and family adversity.

PubMed

Pauli-Pott, Ursula; Schloß, Susan; Ruhl, Isabelle; Skoluda, Nadine; Nater, Urs M; Becker, Katja

2017-12-01

Previous studies on the association between hypothalamic-pituitary-adrenal axis (HPAA) activity and ADHD yielded inconsistent findings, particularly in younger children. This might be due to the heterogeneity of the disorder, making moderator effects of variables probable, which circumscribe more homogenous subgroups. There have been indications of moderator effects on this association by gender of child and exposure to family adversity. Moreover, difficulties in capturing long-term basal HPAA activity in younger children might have contributed to the inconsistencies. We therefore analyzed moderator effects of gender and family adversity while using the hair cortisol concentration (HCC) to assess integrated long-term HPAA. The community-based sample consisted of 122 4-5-year-old preschoolers (71 screened positive for elevated ADHD symptoms). ADHD symptoms were measured by a clinical parent interview and parent and teacher questionnaires. HCC in the most proximal 3-cm scalp hair segment was analyzed using luminescence immunoassay. An extended family adversity index was used. Hierarchical linear regression analyses yielded an interaction effect (p<.05) between ADHD symptom groups and gender on HCC, indicating a low HCC in boys with elevated ADHD symptoms. Further exploratory analyses revealed that this interaction effect was most pronounced under the condition of family adversity. The results held after controlling for oppositional, anxiety, and depressive symptoms. Low HCC might indicate a specific pathogenic mechanism in boys with elevated ADHD symptoms. This mechanism might further involve an exposure to family adversity. However, the results need to be cross-validated before definitive conclusions can be drawn. Copyright © 2017 Elsevier Ltd. All rights reserved.

Proteomic Profiling of β-hCG-Induced Spheres in BRCA1 Defective Triple Negative Breast Cancer Cells.

PubMed

Sengodan, Satheesh Kumar; Rajan, Arathi; Hemalatha, Sreelatha Krishnakumar; Nadhan, Revathy; Jaleel, Abdul; Srinivas, Priya

2018-01-05

Previously, we identified that β-hCG is expressed by BRCA1 mutated but not wild type breast cancers in vitro/in vivo and exhibited a novel event in β-hCG overexpressing BRCA1 mutated HCC1937 cells where the cells were able to form spheres (HCC1937 β spheres) in adherent cell culture plates even in the absence of any growth factors. These spheres express stem cell and EMT markers. In the present study, we carried out the total proteomic profiling of these HCC1937 β spheres obtained from BRCA1 defective β-hCG expressing stable breast cancer cells to analyze the cell signaling pathways that are active in these cells. Functional annotation revealed proteins (164 cellular and 97 secretory) predominantly involved in oxygen binding, nucleosome assembly, cytoskeleton organization, protein folding, etc. Many of the proteins identified from HCC1937 β spheres in this study are also up regulated in breast cancers, which are directly linked with poor prognosis in human cancer samples as analyzed using TCGA data set. Survival analysis shows that β-hCG expressing cancer patients are linked with poor survival rate. Interestingly, hemoglobins were identified at both cellular and secretory level in HCC1937 β spheres and experiments after treating with ROS inducers revealed that β-hCG induces hemoglobin and protects the cancer cells during oxidative stress. Our proteomic data strongly propose β-hCG as an oncogenic molecule associated with BRCA1 mutation, and hence, targeting β-hCG could be a strategy to treat BRCA1 defective breast cancers.

miR2Pathway: A novel analytical method to discover MicroRNA-mediated dysregulated pathways involved in hepatocellular carcinoma.

PubMed

Li, Chaoxing; Dinu, Valentin

2018-05-01

MicroRNAs (miRNAs) are small, non-coding RNAs involved in the regulation of gene expression at a post-transcriptional level. Recent studies have shown miRNAs as key regulators of a variety of biological processes, such as proliferation, differentiation, apoptosis, metabolism, etc. Aberrantly expressed miRNAs influence individual gene expression level, but rewired miRNA-mRNA connections can influence the activity of biological pathways. Here, we define rewired miRNA-mRNA connections as the differential (rewiring) effects on the activity of biological pathways between hepatocellular carcinoma (HCC) and normal phenotypes. Our work presented here uses a PageRank-based approach to measure the degree of miRNA-mediated dysregulation of biological pathways between HCC and normal samples based on rewired miRNA-mRNA connections. In our study, we regard the degree of miRNA-mediated dysregulation of biological pathways as disease risk of biological pathways. Therefore, we propose a new method, miR2Pathway, to measure and rank the degree of miRNA-mediated dysregulation of biological pathways by measuring the total differential influence of miRNAs on the activity of pathways between HCC and normal states. miR2Pathway proposed here systematically shows the first evidence for a mechanism of biological pathways being dysregulated by rewired miRNA-mRNA connections, and provides new insight into exploring mechanisms behind HCC. Thus, miR2Pathway is a novel method to identify and rank miRNA-dysregulated pathways in HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

Cortactin is a sensitive biomarker relative to the poor prognosis of human hepatocellular carcinoma

PubMed Central

2013-01-01

Background Cortactin is an important regulator involved in invasion and migration of hepatocellular carcinoma (HCC). The aim of this study was to elucidate the forecasting role of cortactin in resectable HCCs. Methods We compared the invasiveness and motility among liver epithelial cell line and HCC cell lines by using Transwell assay and wound healing assay. We further investigated the CTTN mRNA expression by real-time PCR. Next, 91 HCC and 20 normal liver tissue samples were detected by IHC and real-time PCR. Finally, we analyzed the clinicopathologic features and survival time of the HCC cases. Results We identified that HepG2, LM3, and SK-Hep-1 had more invasiveness and motility (P <0.05). Compared with liver epithelial cell line, CTTN expression was higher in LM3, HepG2, and MHCC97-L (P <0.01) and lower in SK-Hep-1 (P <0.05). IHC examination showed cortactin expression was closely relative to TNM stage (AJCC/UICC), cancer embolus, and metastasis (P <0.01). Cortactin overexpression indicated a longer survival time of 52 ± 8.62 months and low expression of a shorter survival time of 20 ± 4.95 months (P <0.01). Cortactin examination has more predictive power in patients with Child-Pugh grade A and BCLC stage 0-B. Conclusions Overexpression of cortactin is closely associated with poor human HCCs prognosis that caused by cancer embolus and metastasis. Cortactin and CTTN should be used for differentiating varieties of survival for patients after HCC resection. PMID:23518204

Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes.

PubMed

Rietschel, Liz; Streit, Fabian; Zhu, Gu; McAloney, Kerrie; Frank, Josef; Couvy-Duchesne, Baptiste; Witt, Stephanie H; Binz, Tina M; McGrath, John; Hickie, Ian B; Hansell, Narelle K; Wright, Margaret J; Gillespie, Nathan A; Forstner, Andreas J; Schulze, Thomas G; Wüst, Stefan; Nöthen, Markus M; Baumgartner, Markus R; Walker, Brian R; Crawford, Andrew A; Colodro-Conde, Lucía; Medland, Sarah E; Martin, Nicholas G; Rietschel, Marcella

2017-11-10

Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.

Different Sex-Based Responses of Gut Microbiota During the Development of Hepatocellular Carcinoma in Liver-Specific Tsc1-Knockout Mice.

PubMed

Huang, Rong; Li, Ting; Ni, Jiajia; Bai, Xiaochun; Gao, Yi; Li, Yang; Zhang, Peng; Gong, Yan

2018-01-01

Gut microbial dysbiosis is correlated with the development of hepatocellular carcinoma (HCC). Therefore, analyzing the changing patterns in gut microbiota during HCC development, especially before HCC occurrence, is essential for the diagnosis and prevention of HCC based on gut microbial composition. However, these changing patterns in HCC are poorly understood, especially considering the sex differences in HCC incidence and mortality. Here, with an aim to determine the relationship between gut microbiota and HCC development in both sexes, and to screen potential microbial biomarkers for HCC diagnosis, we studied the changing patterns in the gut microbiota from mice of both sexes with liver-specific knockout of Tsc1 ( LTsc1KO ) that spontaneously developed HCC by 9-10 months of age and compared them to the patterns observed in their wide-type Tsc1 fl/fl cohorts using high-throughput sequencing. Using the LTsc1KO model, we were able to successfully exclude the continuing influence of diet on the gut microbiota. Based on gut microbial composition, the female LTsc1KO mice exhibited gut microbial disorder earlier than male LTsc1KO mice during the development of HCC. Our findings also indicated that the decrease in the relative abundance of anaerobic bacteria and the increase in the relative abundance of facultative anaerobic bacteria can be used as risk indexes of female HCC, but would be invalid for male HCC. Most of the changes in the gut bacteria were different between female and male LTsc1KO mice. In particular, the increased abundances of Allobaculum , Erysipelotrichaceae, Neisseriaceae, Sutterella , Burkholderiales, and Prevotella species have potential for use as risk indicators of female HCC, and the increased abundances of Paraprevotella, Paraprevotellaceae, and Prevotella can probably be applied as risk indicators of male HCC. These relationships between the gut microbiota and HCC discovered in the present study may serve as a platform for the identification of potential targets for the diagnosis and prevention of HCC in the future.

Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis.

PubMed

Sia, Daniela; Villanueva, Augusto; Friedman, Scott L; Llovet, Josep M

2017-03-01

Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore a major public health challenge. We review hypotheses of the cell of origin of liver tumorigenesis and clarify the classes of liver cancer based on molecular features and how they affect patient prognosis. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and other rare tumors, notably fibrolamellar carcinoma and hepatoblastoma. The molecular and clinical features of HCC versus iCCA are distinct, but these conditions have overlapping risk factors and pathways of oncogenesis. A better understanding of the cell types originating liver cancer can aid in exploring molecular mechanisms of carcinogenesis and therapeutic options. Molecular studies have identified adult hepatocytes as the cell of origin. These cells have been proposed to transform directly into HCC cells (via a sequence of genetic alterations), to dedifferentiate into hepatocyte precursor cells (which then become HCC cells that express progenitor cell markers), or to transdifferentiate into biliary-like cells (which give rise to iCCA). Alternatively, progenitor cells also give rise to HCCs and iCCAs with markers of progenitor cells. Advances in genome profiling and next-generation sequencing have led to the classification of HCCs based on molecular features and assigned them to categories such as proliferation-progenitor, proliferation-transforming growth factor β, and Wnt-catenin β1. iCCAs have been assigned to categories of proliferation and inflammation. Overall, proliferation subclasses are associated with a more aggressive phenotype and poor outcome of patients, although more specific signatures have refined our prognostic abilities. Analyses of genetic alterations have identified those that might be targeted therapeutically, such as fusions in the FGFR2 gene and mutations in genes encoding isocitrate dehydrogenases (in approximately 60% of iCCAs) or amplifications at 11q13 and 6p21 (in approximately 15% of HCCs). Further studies of these alterations are needed before they can be used as biomarkers in clinical decision making. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

A population health approach to reducing observational intensity bias in health risk adjustment: cross sectional analysis of insurance claims.

PubMed

Wennberg, David E; Sharp, Sandra M; Bevan, Gwyn; Skinner, Jonathan S; Gottlieb, Daniel J; Wennberg, John E

2014-04-10

To compare the performance of two new approaches to risk adjustment that are free of the influence of observational intensity with methods that depend on diagnoses listed in administrative databases. Administrative data from the US Medicare program for services provided in 2007 among 306 US hospital referral regions. Cross sectional analysis. 20% sample of fee for service Medicare beneficiaries residing in one of 306 hospital referral regions in the United States in 2007 (n = 5,153,877). The effect of health risk adjustment on age, sex, and race adjusted mortality and spending rates among hospital referral regions using four indices: the standard Centers for Medicare and Medicaid Services--Hierarchical Condition Categories (HCC) index used by the US Medicare program (calculated from diagnoses listed in Medicare's administrative database); a visit corrected HCC index (to reduce the effects of observational intensity on frequency of diagnoses); a poverty index (based on US census); and a population health index (calculated using data on incidence of hip fractures and strokes, and responses from a population based annual survey of health from the Centers for Disease Control and Prevention). Estimated variation in age, sex, and race adjusted mortality rates across hospital referral regions was reduced using the indices based on population health, poverty, and visit corrected HCC, but increased using the standard HCC index. Most of the residual variation in age, sex, and race adjusted mortality was explained (in terms of weighted R2) by the population health index: R2=0.65. The other indices explained less: R2=0.20 for the visit corrected HCC index; 0.19 for the poverty index, and 0.02 for the standard HCC index. The residual variation in age, sex, race, and price adjusted spending per capita across the 306 hospital referral regions explained by the indices (in terms of weighted R2) were 0.50 for the standard HCC index, 0.21 for the population health index, 0.12 for the poverty index, and 0.07 for the visit corrected HCC index, implying that only a modest amount of the variation in spending can be explained by factors most closely related to mortality. Further, once the HCC index is visit corrected it accounts for almost none of the residual variation in age, sex, and race adjusted spending. Health risk adjustment using either the poverty index or the population health index performed substantially better in terms of explaining actual mortality than the indices that relied on diagnoses from administrative databases; the population health index explained the majority of residual variation in age, sex, and race adjusted mortality. Owing to the influence of observational intensity on diagnoses from administrative databases, the standard HCC index over-adjusts for regional differences in spending. Research to improve health risk adjustment methods should focus on developing measures of risk that do not depend on observation influenced diagnoses recorded in administrative databases.

Predicting hepatocellular carcinoma through cross-talk genes identified by risk pathways

PubMed Central

Shao, Zhuo; Huo, Diwei; Zhang, Denan; Xie, Hongbo; Yang, Jingbo; Liu, Qiuqi; Chen, Xiujie

2018-01-01

Hepatocellular carcinoma (HCC) is the most frequent type of liver cancer with poor survival rate and high mortality. Despite efforts on the mechanism of HCC, new molecular markers are needed for exact diagnosis, evaluation and treatment. Here, we combined transcriptome of HCC with networks and pathways to identify reliable molecular markers. Through integrating 249 differentially expressed genes with syncretic protein interaction networks, we constructed a HCC-specific network, from which we further extracted 480 pivotal genes. Based on the cross-talk between the enriched pathways of the pivotal genes, we finally identified a HCC signature of 45 genes, which could accurately distinguish HCC patients with normal individuals and reveal the prognosis of HCC patients. Among these 45 genes, 15 showed dysregulated expression patterns and a part have been reported to be associated with HCC and/or other cancers. These findings suggested that our identified 45 gene signature could be potential and valuable molecular markers for diagnosis and evaluation of HCC. PMID:29765536

Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C.

PubMed

Bruix, Jordi; Poynard, Thierry; Colombo, Massimo; Schiff, Eugene; Burak, Kelly; Heathcote, Elizabeth J L; Berg, Thomas; Poo, Jorge-Luis; Mello, Carlos Brandao; Guenther, Rainer; Niederau, Claus; Terg, Ruben; Bedossa, Pierre; Boparai, Navdeep; Griffel, Louis H; Burroughs, Margaret; Brass, Clifford A; Albrecht, Janice K

2011-06-01

Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC)3 program. Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n=311) or no treatment (controls, n=315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event. There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.880-2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.130-2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls (P=.016). There were no new safety observations. Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma and oligometastatic liver disease.

PubMed

Gerum, Sabine; Heinz, Christian; Belka, Claus; Walter, Franziska; Paprottka, Philipp; De Toni, Enrico N; Roeder, Falk

2018-05-29

To report our experience with SBRT in primary and secondary liver tumors. We retrospectively analysed 55 patients (70 lesions) with a median follow-up of 10 months (range 1-57) treated from 2011 to 2016. All patients had not been eligible for other local treatment options. Median age was 64 years and 64% were male. 27 patients (36 lesions) suffered from hepatocellular carcinoma (HCC, Child A:78%, Child B:18%, Child C:4%), 28 patients (34 lesions) had oligometastatic liver disease (MD). Treatment planning was based on 4D-CT usually after placement of fiducials. Dose and fractionation varied depending on localization and size, most commonly 3 × 12.5 Gy (prescribed to the surrounding 65%-isodose) in 56% and 5x8Gy (80% isodose) in 20% of the treated lesions. Local recurrence was observed in 7 patients (13%) and 8 lesions (11%), resulting in estimated 1- and 2-year local control rates (LC) of 91 and 74%. Estimated 1- and 2-year rates of Freedom from hepatic failure (FFHF) were 42 and 28%. Number of lesions was predictive for LC and FFHF in the entire cohort. Estimated 1- and 2-year overall survival (OS) was 76 and 57%. OS was significantly affected by number of treated lesions and performance status. In the HCC subgroup, pretreatment liver function and gender were also predictive for OS. Maximum acute non-hepatic toxicity was grade 1 in 16% and grade 2 in 10% of the patients. Three HCC patients (11%) developed marked deterioration of liver function (grade 3/4). SBRT resulted in high local control and acceptable survival rates in patients with HCC or MD not amendable to other locally-ablative treatment options with limited toxicity. Care should be taken in HCC patients with Child B cirrhosis.

A mouse radiation-induced liver disease model for stereotactic body radiation therapy validated in patients with hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Zhi-Feng, E-mail: wuzhifeng2@126.com, E-mail:

Purpose: Lower radiation tolerance of the whole liver hinders dose escalations of stereotactic body radiation therapy (SBRT) in hepatocellular carcinoma (HCC) treatment. This study was conducted to define the exact doses that result in radiation-induced liver disease (RILD) as well as to determine dose constraints for the critical organs at risk (OARs) in mice; these parameters are still undefined in HCC SBRT. Methods: This study consisted of two phases. In the primary phase, mice treated with helical tomotherapy-based SBRT were stratified according to escalating radiation doses to the livers. The pathological differences, signs [such as mouse performance status (MPS)], andmore » serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/albumin levels were observed. Radiation-induced disease severities of the OARs were scored using systematic evaluation standards. In the validation phase in humans, 13 patients with HCC who had undergone radiotherapy before hepatectomy were enrolled to validate RILD pathological changes in a mouse study. Results: The evaluation criteria of the mouse liver radiotherapy-related signs were as follows: MPS ≥ 2.0 ± 0.52, AST/ALT ≥ 589.2 ± 118.5/137.4 ± 15.3 U/L, serum albumin ≤ 16.8 ± 2.29 g/L. The preliminary dose constraints of the OARs were also obtained, such as those for the liver (average dose ≤ 26.36 ± 1.71 Gy) and gastrointestinal tract (maximum dose ≤ 22.63 Gy). Mouse RILD models were able to be developed when the livers were irradiated with average doses of ≥31.76 ± 1.94 Gy (single fraction). RILD pathological changes in mice have also been validated in HCC patients. Conclusions: Mouse RILD models could be developed with SBRT based on the dose constraints for the OARs and evaluation criteria of mouse liver radiotherapy-related signs, and the authors’ results favor the study of further approaches to treat HCC with SBRT.« less

MicroRNA Profile Predicts Recurrence after Resection in Patients with Hepatocellular Carcinoma within the Milan Criteria

PubMed Central

Sato, Fumiaki; Hatano, Etsuro; Kitamura, Koji; Myomoto, Akira; Fujiwara, Takeshi; Takizawa, Satoko; Tsuchiya, Soken; Tsujimoto, Gozoh; Uemoto, Shinji; Shimizu, Kazuharu

2011-01-01

Objective Hepatocellular carcinoma (HCC) is difficult to manage due to the high frequency of post-surgical recurrence. Early detection of the HCC recurrence after liver resection is important in making further therapeutic options, such as salvage liver transplantation. In this study, we utilized microRNA expression profiling to assess the risk of HCC recurrence after liver resection. Methods We examined microRNA expression profiling in paired tumor and non-tumor liver tissues from 73 HCC patients who satisfied the Milan Criteria. We constructed prediction models of recurrence-free survival using the Cox proportional hazard model and principal component analysis. The prediction efficiency was assessed by the leave-one-out cross-validation method, and the time-averaged area under the ROC curve (ta-AUROC). Results The univariate Cox analysis identified 13 and 56 recurrence-related microRNAs in the tumor and non-tumor tissues, such as miR-96. The number of recurrence-related microRNAs was significantly larger in the non-tumor-derived microRNAs (N-miRs) than in the tumor-derived microRNAs (T-miRs, P<0.0001). The best ta-AUROC using the whole dataset, T-miRs, N-miRs, and clinicopathological dataset were 0.8281, 0.7530, 0.7152, and 0.6835, respectively. The recurrence-free survival curve of the low-risk group stratified by the best model was significantly better than that of the high-risk group (Log-rank: P = 0.00029). The T-miRs tend to predict early recurrence better than late recurrence, whereas N-miRs tend to predict late recurrence better (P<0.0001). This finding supports the concept of early recurrence by the dissemination of primary tumor cells and multicentric late recurrence by the ‘field effect’. Conclusion microRNA profiling can predict HCC recurrence in Milan criteria cases. PMID:21298008

Composite fatty acid ether amides suppress growth of liver cancer cells in vitro and in an in vivo allograft mouse model.

PubMed

Cao, Mengde; Prima, Victor; Nelson, David; Svetlov, Stanislav

2013-06-01

The heterogeneity of liver cancer, in particular hepatocellular carcinoma (HCC), portrays the requirement of multiple targets for both its treatment and prevention. Multifaceted agents, minimally or non-toxic for normal hepatocytes, are required to address the molecular diversity of HCC, including the resistance of putative liver cancer stem cells to chemotherapy. We designed and synthesized two fatty acid ethers of isopropylamino propanol, C16:0-AIP-1 and C18:1-AIP-2 (jointly named AIPs), and evaluated their anti-proliferative effects on the human HCC cell line Huh7 and the murine hepatoma cell line BNL 1MEA.7R.1, both in vitro and in an in vivo allograft mouse model. We found that AIP-1 and AIP-2 inhibited proliferation and caused cell death in both Huh7 and BNL 1MEA.7R.1 cells. Importantly, AIP-1 and AIP-2 were found to block the activation of putative liver cancer stem cells as manifested by suppression of clonal 'carcinosphere' development in growth factor-free and anchorage-free medium. The AIPs exhibited a relatively low toxicity against normal human or rat hepatocytes in primary cultures. In addition, we found that the AIPs utilized multifaceted pathways that mediate both autophagy and apoptosis in HCC, including the inhibition of AKTs and CAMK-1. In immune-competent mice, the AIPs significantly reduced BNL 1MEA.7R.1 cell-driven tumor allograft development, with a higher efficiency than sorafenib. A combination of AIP-1 + AIP-2 was most effective in reducing the tumor allograft incidence. AIPs represent a novel class of simple fatty acid derivatives that are effective against liver tumors via diverse pathways. They show a low toxicity towards normal hepatocytes. The addition of AIPs may represent a new avenue towards the management of chronic liver injury and, ultimately, the prevention and treatment of HCC.

Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer.

PubMed

Yamamoto, Mizuki; Sakane, Kota; Tominaga, Kana; Gotoh, Noriko; Niwa, Takayoshi; Kikuchi, Yasuko; Tada, Keiichiro; Goshima, Naoki; Semba, Kentaro; Inoue, Jun-Ichiro

2017-06-01

Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition MET, are crucial in several stages of cancer metastasis. Epithelial-mesenchymal transition allows cancer cells to move to proximal blood vessels for intravasation. However, because EMT and MET processes are dynamic, mesenchymal cancer cells are likely to undergo MET transiently and subsequently re-undergo EMT to restart the metastatic process. Therefore, spatiotemporally coordinated mutual regulation between EMT and MET could occur during metastasis. To elucidate such regulation, we chose HCC38, a human triple-negative breast cancer cell line, because HCC38 is composed of epithelial and mesenchymal populations at a fixed ratio even though mesenchymal cells proliferate significantly more slowly than epithelial cells. We purified epithelial and mesenchymal cells from Venus-labeled and unlabeled HCC38 cells and mixed them at various ratios to follow EMT and MET. Using this system, we found that the efficiency of EMT is approximately an order of magnitude higher than that of MET and that the two populations significantly enhance the transition of cells from the other population to their own. In addition, knockdown of Zinc finger E-box-binding homeobox 1 (ZEB1) or Zinc finger protein SNAI2 (SLUG) significantly suppressed EMT but promoted partial MET, indicating that ZEB1 and SLUG are crucial to EMT and MET. We also show that primary breast cancer cells underwent EMT that correlated with changes in expression profiles of genes determining EMT status and breast cancer subtype. These changes were very similar to those observed in EMT in HCC38 cells. Consequently, we propose HCC38 as a suitable model to analyze EMT-MET dynamics that could affect the development of triple-negative breast cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

The role of genetic factors in patients with hepatocellular carcinoma and iron overload - a prospective series of 234 patients.

PubMed

Funakoshi, Natalie; Chaze, Iphigénie; Alary, Anne-Sophie; Tachon, Gaëlle; Cunat, Séverine; Giansily-Blaizot, Muriel; Bismuth, Michael; Larrey, Dominique; Pageaux, Georges-Philippe; Schved, Jean-François; Donnadieu-Rigole, Hélène; Blanc, Pierre; Aguilar-Martinez, Patricia

2016-05-01

Iron overload (IO) in HFE-related hereditary haemochromatosis is associated with increased risk of liver cancer. This study aimed to investigate the role of other genes involved in hereditary IO among patients with hepatocellular carcinoma (HCC). Patients with HCC diagnosed in our institution were included in this prospective study. Those with ferritin levels ≥300 μg/L (males) or ≥200 μg/L (females) and/or transferrin saturation ≥50% (males) or ≥45% (females) had liver iron concentration (LIC) evaluated by MRI. HFE C282Y and H63D mutations were screened. Genetic analyses of genes involved in hereditary IO (HFE, HJV/HFE2, HAMP, TFR2, SLC40A1, GNPAT) were performed in patients with increased LIC. A total of 234 patients were included; 215 (92%) had common acquired risk factors of HCC (mainly alcoholism or chronic viral hepatitis). 119 patients had abnormal iron parameters. Twelve (5.1%) were C282Y homozygotes, three were compound C282Y/H63D heterozygotes. LIC was measured by MRI in 100 patients. Thirteen patients with a LIC>70 μmol/g were enrolled in further genetic analyses: two unrelated patients bore the HAMP:c.-153C>T mutation at the heterozygous state, which is associated with increased risk of IO and severe haemochromatosis. Specific haplotypes of SLC40A1 were also studied. Additional genetic risk factors of IO were found in 18 patients (7.7%) among a large series of 234 HCC patients. Screening for IO and the associated at-risk genotypes in patients who have developed HCC, is useful for both determining etiologic diagnosis and enabling family screening and possibly primary prevention in relatives. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Long noncoding RNA MINCR regulates cellular proliferation, migration, and invasion in hepatocellular carcinoma.

PubMed

Cao, Jinyu; Zhang, Deyuan; Zeng, Liangtao; Liu, Fanrong

2018-06-01

Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are aberrantly expressed in many cancer types, including hepatocellular carcinoma (HCC). lncRNA MYC-induced long non-coding RNA (MINCR) were revealed to be markedly up-regulated in gallbladder cancer and Burkitt lymphoma cells. However, the biological role and function of MINCR in HCC progression are still unknown. The expression of MINCR in HCC tissues and cell lines was determined using quantitative real-time polymerase chain reaction assays. The effects of MINCR in HCC cell proliferation, migration, and invasion were determined using cell-counting kit 8 (CCK8) assay, wound healing assay, and Transwell assays in vitro. MINCR expression was up-regulated in HCC tissues and cell lines as compared with that in the negative control. The decreased expression of MINCR in vitro markedly inhibited HCC cell proliferation, migration, and invasion. Our results showed that MINCR is important in HCC development and may act as a therapeutic target that regulates HCC cellular proliferation, migration, and invasion, which are involved in HCC tumorigenesis. To the best of our know ledge, MINCR in HCC has not been studied. Our findings showed that this study is the first to reveal that MINCR may act as a therapeutic target in HCC. The in-depth exploration of the molecular mechanism is required to illuminate the molecular mechanisms of MINCR in HCC development. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV OLT study.

PubMed

Han, Steven-Huy; Reddy, K Rajender; Keeffe, Emmet B; Soldevila-Pico, Consuelo; Gish, Robert; Chung, Raymond T; Degertekin, Bulent; Lok, Anna

2011-01-01

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is an indication for orthotopic liver transplantation (OLT) in patients with tumor stage within the United Network for Organ Sharing criteria. The number of patients listed for HBV-related HCC is increasing, while the number of patients listed for HBV-related cirrhosis is declining presumptively because of the availability of more effective oral nucleos(t)ide analogues. This study presents the final, long-term outcome of patients transplanted for HBV-related HCC in the National Institutes of Health (NIH) HBV OLT Study Group. Ninety-eight patients (52.4%) in the NIH HBV OLT cohort underwent OLT for HBV-related HCC. With a mean follow-up of 36.5 months post-OLT, 12 (12.2%) patients developed recurrence of HCC. Multivariate analysis did not find a statistically significant role of gender, tumor stage at OLT, pre-OLT HCC treatment, recurrence of HBV, or duration of HCC diagnosis pre-OLT in predicting HCC recurrence. Serum alpha-fetoprotein (AFP) level >200 ng/mL at transplant was found to be statistically significant in predicting HCC recurrence (p=0.003). HCC recurrence was significantly associated with decreased post-OLT survival. HCC is the most common indication for OLT in patients with chronic hepatitis B in the era of more effective oral antivirals. Serum AFP at the time of OLT is significantly associated with HCC recurrence. © 2010 John Wiley & Sons A/S.

Diabetes is associated with chronic liver disease and liver cancer in the adult population of Puerto Rico.

PubMed

Ortiz, Ana P; Romero, Carlos; Disdier, Orville; Santana, Erik; Torres, Margaret; Torres, Esther A; Pérez, Cynthia M

2011-09-01

Diabetes mellitus (DM) has been proposed as a risk factor for both chronic liver disease (CLD) and for hepatocellular carcinoma (HCC); however, studies among Hispanics are limited. Puerto Rico (PR) has a high prevalence of DM (13%), supporting the need for a better understanding of the public health implications associated with DM in this population. We assessed the association of DM with CLD and with HCC in a population of Puerto Rican adults with health insurance. The study sample consisted of 1,040,025 individuals, aged > or = 18 years, all covered by the government-run healthcare program in PR, in 2002. The ICD-9 codes for DM, CLD, and HCC were obtained in order to determine the prevalence of these conditions. Logistic regression models were used to determine the association of DM with CLD and with HCC, after adjusting for covariates. The prevalence of DM was higher in patients with CLD (17%) and those with HCC (18%) than it was in patients without either of these conditions (8% and 7%, respectively). Among women, those with DM were significantly more likely to have CLD than were those without DM (POR: 35-49 yrs: 3.26, 95% CI = 2.12, 5.00; POR: 50-64 yrs: 2.10, 95% CI = 1.63, 2.71; POR: > or = 65 yrs: 2.33, 95% CI = 1.67, 3.25). Among men, those with DM were more likely to have CLD than were those without DM; this association was significant among males aged 50-64 (POR: 1.30, 95% CI = 1.03-1.63) and those aged > or = 65 yrs (POR: 1.94, 95% CI = 1.35-2.80). Consistent with other studies, we observed a strong association of DM with CLD and HCC. In order to reduce the burden of these conditions in PR, research and public health efforts should be concentrated on gaining a better understanding of these associations.

Expression of the Long Intergenic Non-Protein Coding RNA 665 (LINC00665) Gene and the Cell Cycle in Hepatocellular Carcinoma Using The Cancer Genome Atlas, the Gene Expression Omnibus, and Quantitative Real-Time Polymerase Chain Reaction.

PubMed

Wen, Dong-Yue; Lin, Peng; Pang, Yu-Yan; Chen, Gang; He, Yun; Dang, Yi-Wu; Yang, Hong

2018-05-05

BACKGROUND Long non-coding RNAs (lncRNAs) have a role in physiological and pathological processes, including cancer. The aim of this study was to investigate the expression of the long intergenic non-protein coding RNA 665 (LINC00665) gene and the cell cycle in hepatocellular carcinoma (HCC) using database analysis including The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and quantitative real-time polymerase chain reaction (qPCR). MATERIAL AND METHODS Expression levels of LINC00665 were compared between human tissue samples of HCC and adjacent normal liver, clinicopathological correlations were made using TCGA and the GEO, and qPCR was performed to validate the findings. Other public databases were searched for other genes associated with LINC00665 expression, including The Atlas of Noncoding RNAs in Cancer (TANRIC), the Multi Experiment Matrix (MEM), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) networks. RESULTS Overexpression of LINC00665 in patients with HCC was significantly associated with gender, tumor grade, stage, and tumor cell type. Overexpression of LINC00665 in patients with HCC was significantly associated with overall survival (OS) (HR=1.47795%; CI: 1.046-2.086). Bioinformatics analysis identified 469 related genes and further analysis supported a hypothesis that LINC00665 regulates pathways in the cell cycle to facilitate the development and progression of HCC through ten identified core genes: CDK1, BUB1B, BUB1, PLK1, CCNB2, CCNB1, CDC20, ESPL1, MAD2L1, and CCNA2. CONCLUSIONS Overexpression of the lncRNA, LINC00665 may be involved in the regulation of cell cycle pathways in HCC through ten identified hub genes.

High burden of hepatocellular carcinoma and viral hepatitis in Southern and Central Vietnam: Experience of a large tertiary referral center, 2010 to 2016

PubMed Central

Nguyen-Dinh, Song-Huy; Do, Albert; Pham, Trang Ngoc Doan; Dao, Doan Y; Nguy, Trinh Nhu; Chen, Moon S

2018-01-01

AIM To examine the largest tertiary referral center in southern and central Vietnam from 2010 to 2016, evaluating epidemiological trends of hepatocellular carcinoma (HCC) and viral hepatitis B-C in this resource-limited setting. METHODS We extracted data of patients receiving care from Cho Ray Hospital (Ho Chi Minh City), the largest oncology referral center in southern and central Vietnam, from 2010 to 2016. We collected information on patient age, gender, geographic distribution, and disease characteristics including disease stage, tumor biomarker levels [serum alpha-fetoprotein (AFP), AFP-L3 isoform percentage, and prothrombin induced by induced by vitamin K absence-II], and serological testing for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. RESULTS Data from 24091 HCC patients were extracted, with sample demographics comprising mostly male (81.8%) and older age (however with 8.5% younger than 40 years old). This patient sample included a geographic catchment population of 56 million people (60% of the country’s total population of 92.7 million), derived from 38 provinces and municipalities in Vietnam. Chronic HBV infection was found in 62.3% of cases, and chronic HCV infection in 26.0%. HBV and HCV co-infection was seen in 2.7%. Cirrhosis was found in an estimated 30% to 40% of cases. Nine percent of patients were not found to have chronic viral hepatitis. Twenty three point two percent of the patients had a normal AFP level. A total of 2199 patients were tested with AFP-L3 and PIVKA II over two years, with 57.7% having elevated AFP-L3%, and 88.5% with elevated PIVKA II levels. Over this 7-year period, the incidence of HCC increased, with a large proportion of cases (overall 40.8%) presenting initially an advanced stage, not amendable to surgical or locoregional therapy. CONCLUSION HCC contributes significant health care burden in southern and central Vietnam, with increasing case volume over this seven-year period. Viral hepatitis likely explains this high HCC prevalence. PMID:29399285

High burden of hepatocellular carcinoma and viral hepatitis in Southern and Central Vietnam: Experience of a large tertiary referral center, 2010 to 2016.

PubMed

Nguyen-Dinh, Song-Huy; Do, Albert; Pham, Trang Ngoc Doan; Dao, Doan Y; Nguy, Trinh Nhu; Chen, Moon S

2018-01-27

To examine the largest tertiary referral center in southern and central Vietnam from 2010 to 2016, evaluating epidemiological trends of hepatocellular carcinoma (HCC) and viral hepatitis B-C in this resource-limited setting. We extracted data of patients receiving care from Cho Ray Hospital (Ho Chi Minh City), the largest oncology referral center in southern and central Vietnam, from 2010 to 2016. We collected information on patient age, gender, geographic distribution, and disease characteristics including disease stage, tumor biomarker levels [serum alpha-fetoprotein (AFP), AFP-L3 isoform percentage, and prothrombin induced by induced by vitamin K absence-II], and serological testing for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Data from 24091 HCC patients were extracted, with sample demographics comprising mostly male (81.8%) and older age (however with 8.5% younger than 40 years old). This patient sample included a geographic catchment population of 56 million people (60% of the country's total population of 92.7 million), derived from 38 provinces and municipalities in Vietnam. Chronic HBV infection was found in 62.3% of cases, and chronic HCV infection in 26.0%. HBV and HCV co-infection was seen in 2.7%. Cirrhosis was found in an estimated 30% to 40% of cases. Nine percent of patients were not found to have chronic viral hepatitis. Twenty three point two percent of the patients had a normal AFP level. A total of 2199 patients were tested with AFP-L3 and PIVKA II over two years, with 57.7% having elevated AFP-L3%, and 88.5% with elevated PIVKA II levels. Over this 7-year period, the incidence of HCC increased, with a large proportion of cases (overall 40.8%) presenting initially an advanced stage, not amendable to surgical or locoregional therapy. HCC contributes significant health care burden in southern and central Vietnam, with increasing case volume over this seven-year period. Viral hepatitis likely explains this high HCC prevalence.

Links between Human LINE-1 Retrotransposons and Hepatitis Virus-Related Hepatocellular Carcinoma.

PubMed

Honda, Tomoyuki

2016-01-01

Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers, the third most frequent cause of cancer mortality. The most prevalent risk factors for HCC are infections by hepatitis B or hepatitis C virus. Findings suggest that hepatitis virus-related HCC might be a cancer in which LINE-1 retrotransposon, often termed L1, activity plays a potential role. Firstly, hepatitis viruses can suppress host defense factors that also control L1 mobilization. Secondly, many recent studies also have indicated that hypomethylation of L1 affects the prognosis of HCC patients. Thirdly, endogenous L1 retrotransposition was demonstrated to activate oncogenic pathways in HCC. Fourthly, several L1 chimeric transcripts with host or viral genes are found in hepatitis virus-related HCC. Such lines of evidence suggest a linkage between L1 retrotransposons and hepatitis virus-related HCC. Here, I briefly summarize current understandings of the association between hepatitis virus-related HCC and L1. Then, I discuss potential mechanisms of how hepatitis viruses drive the development of HCC via L1 retrotransposons. An increased understanding of the contribution of L1 to hepatitis virus-related HCC may provide unique insights related to the development of novel therapeutics for this disease.

AURKA promotes cancer metastasis by regulating epithelial-mesenchymal transition and cancer stem cell properties in hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Chenlin; Song, Guangyuan; Xiang, Jue

AURKA (aurora kinase A) has been confirmed as an oncogene in cancer development; however, its role and underlying mechanisms in the metastasis of hepatocellular carcinoma (HCC) remain unknown. In this study, We found that AURKA was up-regulated in HCC tissues and correlated with pathological stage and distant metastasis. Further found that AURKA was involved in the cancer metastases after radiation in HCC. While overexpression of AURKA induced epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) behaviors though PI3K/AKT pathway, silencing AURKA suppressed radiation-enhanced cell invasiveness of HCC. Taken together, our results suggested that AURKA contributed in metastasis of irradiated residulmore » HCC though facilitating EMT and CSC properties, suggesting the potential clinical application of AURKA inhibitors in radiotherapy for patients with HCC. - Highlights: • First reported overexpression of AURKA in HCC and correlation with poor OS. • AURKA was involved in the cancer metastases after radiation in HCC. • Further found AURKA promoted EMT and CSC behaviors though PI3K/AKT pathway. • Silencing AURKA suppressed radiation-enhanced cell invasiveness of HCC. • AURKA may be potential therapeutic target of HCC.« less

Management of hepatocellular carcinoma with portal vein tumor thrombosis: Review and update at 2016

PubMed Central

Chan, Stephen L; Chong, Charing C N; Chan, Anthony W H; Poon, Darren M C; Chok, Kenneth S H

2016-01-01

Portal vein tumor thrombosis (PVTT) is a common phenomenon in hepatocellular carcinoma (HCC). Compared to HCC without PVTT, HCC with PVTT is characterized by an aggressive disease course, worse hepatic function, a higher chance of complications related to portal hypertension and poorer tolerance to treatment. Conventionally, HCC with PVTT is grouped together with metastatic HCC during the planning of its management, and most patients are offered palliative treatment with sorafenib or other systemic agents. As a result, most data on the management of HCC with PVTT comes from subgroup analyses or retrospective series. In the past few years, there have been several updates on management of HCC with PVTT. First, it is evident that HCC with PVTT consists of heterogeneous subgroups with different prognoses. Different classifications have been proposed to stage the degree of portal vein invasion/thrombosis, suggesting that different treatment modalities may be individualized to patients with different risks. Second, more studies indicate that more aggressive treatment, including surgical resection or locoregional treatment, may benefit select HCC patients with PVTT. In this review, we aim to discuss the recent conceptual changes and summarize the data on the management of HCC with PVTT. PMID:27621575

Links between human LINE-1 retrotransposons and hepatitis virus-related hepatocellular carcinoma

NASA Astrophysics Data System (ADS)

Honda, Tomoyuki

2016-05-01

Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers, the third most frequent cause of cancer mortality. The most prevalent risk factors for HCC are infections by hepatitis B or hepatitis C virus. Findings suggest that hepatitis virus-related HCC might be a cancer in which LINE-1 retrotransposons, often termed L1, activity plays a potential role. Firstly, hepatitis viruses can suppress host defense factors that also control L1 mobilization. Secondly, many recent studies also have indicated that hypomethylation of L1 affects the prognosis of HCC patients. Thirdly, endogenous L1 retrotransposition was demonstrated to activate oncogenic pathways in HCC. Fourthly, several L1 chimeric transcripts with host or viral genes are found in hepatitis virus-related HCC. Such lines of evidence suggest a linkage between L1 retrotransposons and hepatitis virus-related HCC. Here, I briefly summarize current understandings of the association between hepatitis virus-related HCC and L1. Then, I discuss potential mechanisms of how hepatitis viruses drive the development of HCC via L1 retrotransposons. An increased understanding of the contribution of L1 to hepatitis virus-related HCC may provide unique insights related to the development of novel therapeutics for this disease.

Prescription frequency and patterns of Chinese herbal medicine for liver cancer patients in Taiwan: a cross-sectional analysis of the National Health Insurance Research Database.

PubMed

Ting, Chin-Tsung; Kuo, Chian-Jue; Hu, Hsiao-Yun; Lee, Ya-Ling; Tsai, Tung-Hu

2017-02-20

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Chinese herbal medicine (CHM) is frequently provided to HCC patients. The aim of this study was to understand the prescription frequency and patterns of CHM for HCC patients by analyzing the claims data from the National Health Insurance (NHI) in Taiwan. We identified 73918 newly diagnosed HCC subjects from the database of Registry for Catastrophic Illness during 2002 to 2009 and to analyze the frequency and pattern of corresponding CHM prescriptions for HCC patients. There were a total of 685,079 single Chinese herbal prescriptions and 553,952 Chinese herbal formula prescriptions used for 17,373 HCC subjects before 2 years of HCC diagnosis. Among the 13,093 HCC subjects who used CHMs after HCC diagnosis, there were 462,786 single Chinese herbal prescriptions and 300,153 Chinese herbal formula prescriptions were counted. By adjusting with person-year and ratio of standardized incidence rate, the top ten prescribed single herbal drugs and Chinese herbal formulas for HCC patients were described in our study. Among them, we concluded that, Oldenlandia diffusa (Chinese herbal name: Bai-Hua-She-She-Cao), Radix et Rhizoma Rhei (Da Huang) and the herbal preparation of Xiao-Chai-Hu-Tang and Gan-Lu-Yin, were the most obviously increased and important CHMs been used for HCC patients. We established an accurate and validated method for the actual frequency and patterns of CHM use in treating HCC in Taiwan. We propose that these breakthrough findings may have important implications for HCC therapy, clinical trials and modernization of CHM.

Serum DHCR24 Auto-antibody as a new Biomarker for Progression of Hepatitis C

PubMed Central

Ezzikouri, Sayeh; Kimura, Kiminori; Sunagozaka, Hajime; Kaneko, Shuichi; Inoue, Kazuaki; Nishimura, Tomohiro; Hishima, Tsunekazu; Kohara, Michinori; Tsukiyama-Kohara, Kyoko

2015-01-01

Background New biomarkers are needed to identify the stage of hepatitis C virus (HCV)-infected diseases in order to reduce the mortality rates. Herein, we investigated whether serum 3β-hydroxysterol Δ24-reductase antibody (DHCR24 Ab) may serve as a prognostic marker for hepatitis C infection progression to hepatocellular carcinoma (HCC). Methods Serum DHCR24 Abs from 395 HCV-positive patients, including 133 chronic hepatitis (CHC), 85 liver cirrhosis (LCC), and 177 HCC (HCC-C) patients; 232 hepatitis B virus (HBV)-positive patients, including 103 chronic hepatitis (CHB), 56 liver cirrhosis (LCB), and 73 HCC (HCC-B) patients; and 24 healthy controls, were measured using enzyme-linked immunosorbent assay. Results The serum DHCR24 Ab levels were significantly higher in patients with CHC than in healthy controls, in LCC than in CHC, and in LCC than in HCC-C (P < 0.0001 for all). The concentration of serum DHCR24 Ab in HCC-B patients showed no significant difference compared to CHB and LCB patients (P = 0.1247). The DHCR24 Ab levels were significantly higher in early HCC-C than CHC or LCC patients and in late HCC-C compared to early HCC-C patients. The sensitivity of the DHCR24 Ab for HCC-C detection (70.6%) was higher than that of alpha-fetoprotein (AFP; 54.8%) and protein induced by vitamin K absence or antagonist-II (PIVKA-II; 42 · 5%). Moreover, DHCR24 was up-regulated in HCV-positive, but not HBV-positive tissues or HBV-negative, HCV-negative HCC specimens. Conclusions DHCR24 auto-antibody represents a potential noninvasive biomarker for HCV-related liver disease and may facilitate the diagnosis of PIVKA-II and AFP-negative HCC. PMID:26288822

Microvascular Invasion Does Not Predict Long-Term Survival in Hepatocellular Carcinoma up to 2 cm: Reappraisal of the Staging System for Solitary Tumors

PubMed Central

Shindoh, Junichi; Andreou, Andreas; Aloia, Thomas A.; Zimmitti, Giuseppe; Lauwers, Gregory Y.; Laurent, Alexis; Nagorney, David M.; Belghiti, Jacques; Cherqui, Daniel; Poon, Ronnie Tung-Ping; Kokudo, Norihiro; Vauthey, Jean-Nicolas

2013-01-01

Background Excellent long-term outcomes have been reported recently for patients with small (≤2 cm) hepatocellular carcinoma (HCC). However, the significance of microvascular invasion (MVI) in small HCC remains unclear. The purpose of this study was to determine the impact of MVI in small HCC up to 2 cm. Methods In 1,109 patients with solitary HCC from six major international hepatobiliary centers, the impact of MVI on long-term survival in patients with small HCC (≤2 cm) and patients with tumors larger than 2 cm was analyzed. Results In patients with small HCC, long-term survival was not affected by MVI (p = 0.8), whereas in patients with larger HCC, significantly worse survival was observed in patients with MVI (p < 0.0001). In multivariate analysis, MVI (hazard ratio [HR] 1.59; 95 % confidence interval (CI) 1.27–1.99; p < 0.001), elevated alpha-fetoprotein (HR 1.41; 95 % CI 1.11–1.8; p = 0.005), and higher histologic grade (HR 1.29; 95 % CI 1.01–1.64; p = 0.04) were significant predictors of worse survival in patients with HCC larger than 2 cm but were not correlated with long-term survival in small HCC. When the cohort was divided into three groups—HCC ≤2, >2 cm without MVI, and HCC >2 cm with MVI—significant between-group survival difference was observed (p < 0.0001). Conclusions Small HCC is associated with an excellent prognosis that is not affected by the presence of MVI. The discriminatory power of the 7th edition of the AJCC classification for solitary HCC could be further improved by subdividing tumors according to size (≤2 vs. >2 cm). PMID:23179993

Risk Assessment of Hepatocellular Carcinoma in Patients with Hepatitis C in China and the USA.

PubMed

Parikh, Neehar D; Fu, Sherry; Rao, Huiying; Yang, Ming; Li, Yumeng; Powell, Corey; Wu, Elizabeth; Lin, Andy; Xing, Baocai; Wei, Lai; Lok, Anna S F

2017-11-01

Hepatitis C (HCV) infection is an increasingly common cause of hepatocellular carcinoma (HCC) in China. We aimed to determine differences in demographic and behavioral profiles associated with HCC in HCV+ patients in China and the USA. Consecutive HCV+ patients were recruited from centers in China and the USA. Clinical data and lifestyle profiles were obtained through standardized questionnaires. Multivariable analysis was conducted to determine factors associated with HCC diagnosis within groups. We included 41 HCC patients from China and 71 from the USA, and 931 non-HCC patients in China and 859 in China. Chinese patients with HCC were significantly younger, less likely to be male and to be obese than US patients with HCC (all p < 0.001). Chinese patients with HCC had a significantly lower rate of cirrhosis diagnosis (36.6 vs. 78.9%, p < 0.001); however, they also had a higher rate of hepatitis B core antibody positivity (63.4 vs. 36.8%, p = 0.007). In a multivariable analysis of the entire Chinese cohort, age > 55, male sex, the presence of diabetes, and time from maximum weight were associated with HCC, while tea consumption was associated with a decreased HCC risk (OR 0.37, 95% CI 0.16-0.88). In the US cohort, age > 55, male sex, and cirrhosis were associated with HCC on multivariable analysis. With the aging Chinese population and increasing rates of diabetes, there will likely be continued increase in the incidence of HCV-related HCC in China. The protective effect of tea consumption on HCC development deserves further validation.

Gadolinium Ethoxybenzyl Diethylenetriamine Pentaacetic Acid (Gd-EOB-DTPA)-Enhanced Magnetic Resonance Imaging and Multidetector-Row Computed Tomography for the Diagnosis of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

PubMed

Ye, Feng; Liu, Jun; Ouyang, Han

2015-08-01

The purpose of this meta-analysis was to compare the diagnostic accuracy of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and multidetector-row computed tomography (MDCT) for hepatocellular carcinoma (HCC).Medline, Cochrane, EMBASE, and Google Scholar databases were searched until July 4, 2014, using combinations of the following terms: gadoxetic acid disodium, Gd-EOB-DTPA, multidetector CT, contrast-enhanced computed tomography, and magnetic resonance imaging. Inclusion criteria were as follows: confirmed diagnosis of primary HCC by histopathological examination of a biopsy specimen; comparative study of MRI using Gd-EOB-DTPA and MDCT for diagnosis of HCC; and studies that provided quantitative outcome data. The pooled sensitivity and specificity of the 2 methods were compared, and diagnostic accuracy was assessed with alternative-free response receiver-operating characteristic analysis.Nine studies were included in the meta-analysis, and a total of 1439 lesions were examined. The pooled sensitivity and specificity for 1.5T MRI were 0.95 and 0.96, respectively, for 3.0T MRI were 0.91 and 0.96, respectively, and for MDCT were 0.74 and 0.93, respectively. The pooled diagnostic odds ratio for 1.5T and 3.0T MRI was 242.96, respectively, and that of MDCT was 33.47. To summarize, Gd-EOB-DTPA-enhanced MRI (1.5T and 3.0T) has better diagnostic accuracy for HCC than MDCT.

Quantitative estimated exposure to vinyl chloride and risk of angiosarcoma of the liver and hepatocellular cancer in the US industry-wide vinyl chloride cohort: mortality update through 2013

PubMed Central

Mundt, Kenneth A; Dell, Linda D; Crawford, Lori; Gallagher, Alexa E

2017-01-01

Objective To evaluate mortality risks of angiosarcoma of the liver (ASL), primary hepatocellular carcinoma (HCC) and other cancers among 9951 men employed between 1942 and 1972 at 35 US vinyl chloride (VC) or polyvinyl chloride plants followed for mortality through 31 December 2013. Methods SMR and time-dependent Cox proportional hazards analyses were used to evaluate mortality risks by cumulative VC exposure. Results Liver cancer mortality was elevated (SMR=2.87, 95% CI 2.40 to 3.40), and ASL and HCC were strongly associated with cumulative VC exposure ≥865 parts per million-years (ppm-years) (ASL: HR=36.3, 95% CI 13.1 to 100.5; and HCC: HR=5.3, 95% CI 1.6 to 17.7 for ≥2271 ppm-years). Excess deaths due to connective and soft tissue cancers (SMR=2.43, 95% CI 1.48 to 3.75), mesothelioma (SMR=2.29, 95% CI 1.18 to 4.00) and explosions (SMR=3.43, 95% CI 1.25 to 7.47) were seen. Mortalities due to melanoma, brain cancer, lung cancer and non-Hodgkin’s lymphoma were not increased or associated with VC exposure. Conclusion The association between VC and ASL first reported in this cohort 44 years ago persisted and was strongest among workers most highly exposed. VC exposure also was associated with HCC mortality, although it remains possible that misdiagnosis of early ASLs influenced findings. PMID:28490663

Encapsulated human hepatocellular carcinoma cells by alginate gel beads as an in vitro metastasis model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Xiao-xi; Liu, Chang; University of Chinese Academy of Sciences, 19A Yuquanlu, Beijing 100049

2013-08-15

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and often forms metastases, which are the most important prognostic factors. For further elucidation of the mechanism underlying the progression and metastasis of HCC, a culture system mimicking the in vivo tumor microenvironment is needed. In this study, we investigated the metastatic ability of HCC cells cultured within alginate gel (ALG) beads. In the culture system, HCC cells formed spheroids by proliferation and maintained in nuclear abnormalities. The gene and protein expression of metastasis-related molecules was increased in ALG beads, compared with the traditional adhesion culture. Furthermore, several gene expressionmore » levels in ALG bead culture system were even closer to liver cancer tissues. More importantly, in vitro invasion assay showed that the invasion cells derived from ALG beads was 7.8-fold higher than adhesion cells. Our results indicated that the in vitro three-dimensional (3D) model based on ALG beads increased metastatic ability compared with adhesion culture, even partly mimicked the in vivo tumor tissues. Moreover, due to the controllable preparation conditions, steady characteristics and production at large-scale, the 3D ALG bead model would become an important tool used in the high-throughput screening of anti-metastasis drugs and the metastatic mechanism research. -- Highlights: •We established a 3D metastasis model mimicking the metastatic ability in vivo. •The invasion ability of cells derived from our model was increased significantly. •The model is easy to reproduce, convenient to handle, and amenable for large-scale.« less

Multicenter Study of Staging and Therapeutic Predictors of Hepatocellular Carcinoma Recurrence following Transplantation.

PubMed

Welling, Theodore H; Eddinger, Kevin; Carrier, Kristen; Zhu, Danting; Kleaveland, Tyler; Moore, Derek E; Schaubel, Douglas E; Abt, Peter L

2018-05-05

Orthotopic liver transplantation (OLT) and resection are effective treatments for hepatocellular carcinoma (HCC). However, optimizing OLT and limiting HCC recurrence remains a vexing problem. New HCC MELD and allocation algorithms provide greater observation of HCC patients, many while receiving local-regional treatments. Potential benefits of local-regional treatment for limiting HCC recurrence post-OLT remain incompletely understood. Therefore we aimed to define HCC specific prognostic factors affecting recurrence in a contemporary, multi-center cohort of HCC patients undergoing OLT and specifically whether local-regional therapies limited recurrence. We identified 441 patients undergoing OLT for HCC at three major transplant centers from 2008-2013. Cox regression was used to analyze covariate-adjusted recurrence and mortality rates post-OLT. "Bridging" or "down-staging" therapy was used in 238 patients (54%) with transarterial chemoembolization (TACE) being used in 170 (71%) of treated patients. The survival rate post-OLT was 88% and 78% at 1 and 3 years, respectively, with HCC recurrence (28% of deaths) significantly increasing mortality rate (HR=19.87, p<0.0001). Tumor size, not tumor number, either at presentation or on explant independently predicted HCC recurrence (HR 1.36 and 1.73, respectively, p<0.05) with a threshold effect noted at 4.0 cm size. Local-regional therapy (TACE) reduced HCC recurrence by 64% when adjusting for presenting tumor size (HR 0.36, p<0.05). Explant tumor size and microvascular invasion predicted mortality (HR 1.19 and 1.51, respectively, p<0.05) and pathologic response to therapy (TACE or RFA) significantly decreased explant tumor size (0.56-1.62 cm diameter reduction, p<0.05). HCC tumor size at presentation or explant is the most important predictor for HCC recurrence post-OLT. Local-regional therapy to achieve a pathologic response (decreasing tumor size) can limit HCC recurrences post-OLT. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Long noncoding RNA FTX inhibits hepatocellular carcinoma proliferation and metastasis by binding MCM2 and miR-374a.

PubMed

Liu, F; Yuan, J-H; Huang, J-F; Yang, F; Wang, T-T; Ma, J-Z; Zhang, L; Zhou, C-C; Wang, F; Yu, J; Zhou, W-P; Sun, S-H

2016-10-13

It has long been known that males are more susceptible than females to hepatocellular carcinoma (HCC), but the reason remains elusive. In this study, we investigated the expression and function of the long noncoding RNA FTX (lnc-FTX), an X-inactive-specific transcript (XIST) regulator transcribed from the X chromosome inactivation center, in both HCC and HCC gender disparity. lnc-FTX is expressed at higher levels in female livers than in male livers and is significantly downregulated in HCC tissues compared with normal liver tissues. Patients with higher lnc-FTX expression exhibited longer survival, suggesting that lnc-FTX is a useful prognostic factor for HCC patients. lnc-FTX inhibits HCC cell growth and metastasis both in vitro and in vivo. Mechanistically, lnc-FTX represses Wnt/β-catenin signaling activity by competitively sponging miR-374a and inhibits HCC cell epithelial-mesenchymal transition and invasion. In addition, lnc-FTX binds to the DNA replication licensing factor MCM2, thereby impeding DNA replication and inhibiting proliferation in HCC cells. In conclusion, these findings suggest that lnc-FTX may act as a tumor suppressor in HCC through physically binding miR-374a and MCM2. It may also be one of the reasons for HCC gender disparity and may potentially contribute to HCC treatment.

Circular RNA 0068669 as a new biomarker for hepatocellular carcinoma metastasis.

PubMed

Yao, Ting; Chen, Qingqing; Shao, Zhouwei; Song, Zhihua; Fu, Liyun; Xiao, Bingxiu

2018-05-21

Circular RNAs (circRNAs) play important roles in disease occurrence. However, the roles of circRNAs in the diagnosis of hepatocellular carcinoma (HCC) are largely unknown. The aim of this study is to investigate the clinical diagnostic values of hsa_circ_0068669 (Alias: hsa_circ_103561), one of the representative HCC-associated circRNAs. Hsa_circ_0068669 expression levels in HCC tissues, HCC cell lines, and chronic hepatitis tissues were detected by real-time quantitative reverse transcription-polymerase chain reaction. Its expression levels between HCC tissues and adjacent non-tumorous tissues were analyzed using paired t test. Independent t test and one-way analysis of variance (ANOVA) were performed to analyze the relationships between hsa_circ_0068669 expression levels and clinicopathological factors of patients with HCC. A receiver operating characteristic (ROC) curve was established to estimate the value of hsa_circ_0068669 as a biomarker in HCC. Hsa_circ_0068669 expression was significantly downregulated in HCC tissues and HCC cell lines compared with paired non-tumorous tissues and normal hepatic cell line, respectively. Moreover, hsa_circ_0068669 expression in HCC tissues was decreased comparing with chronic hepatitis tissues. Furthermore, hsa_circ_0068669 expression was correlated with microvascular invasion and TNM stages. Our findings indicate that hsa_circ_0068669 might be served as a novel potential biomarker for HCC metastasis. © 2018 Wiley Periodicals, Inc.

Mammalian-enabled (MENA) protein enhances oncogenic potential and cancer stem cell-like phenotype in hepatocellular carcinoma cells.

PubMed

Hu, Kunpeng; Huang, Pinzhu; Luo, Hui; Yao, Zhicheng; Wang, Qingliang; Xiong, Zhiyong; Lin, Jizong; Huang, He; Xu, Shilei; Zhang, Peng; Liu, Bo

2017-08-01

Mammalian-enabled (MENA) protein is an actin-regulatory protein that influences cell motility and adhesion. It is known to play a role in tumorigenicity of hepatocellular carcinoma (HCC) but the underlying molecular mechanism remains unknown. This study aimed to investigate the oncogenic potential of MENA and its capacity to regulate cancer stem cell (CSC)-like phenotypes in HCC cells. Real-time-PCR and western blot were used to assess mRNA and protein levels of target genes in human HCC tissue specimens and HCC cell lines, respectively. Stable MENA-overexpressing HCC cells were generated from HCC cell lines. Transwell cell migration and colony formation assays were employed to evaluate tumorigenicity. Ectopic expression of MENA significantly enhanced cell migration and colony-forming ability in HCC cells. Overexpression of MENA upregulated several hepatic progenitor/stem cell markers in HCC cells. A high MENA protein level was associated with high mRNA levels of MENA, CD133, cytokeratin 19 (CK19), and epithelial cell adhesion molecule (EpCAM) in human HCC tissues. Overexpression of MENA enhanced epithelial-to-mesenchymal transition (EMT) markers, extracellular signal-regulated kinases (ERK) phosphorylation, and the level of β-catenin in HCC cells. This study demonstrated that overexpression of MENA in HCC cells promoted stem cell markers, EMT markers, and tumorigenicity. These effects may involve, at least partially, the ERK and β-catenin signaling pathways.

Liver precancerous lesions and hepatocellular carcinoma: the histology report.

PubMed

Roncalli, Massimo; Terracciano, Luigi; Di Tommaso, Luca; David, Ezio; Colombo, Massimo

2011-03-01

The current ability to increase the survival of patients with hepatocellular carcinoma (HCC) relies upon the surveillance of cirrhotic patients. Surveillance allows HCC precursors (dysplastic nodules) and malignant tumors to be recognized at an earlier stage making cure possible. Radiology plays a major role in HCC diagnosis because HCC is characterized by neoarterial vascularisation with a typical imaging pattern. Current international guidelines have restricted the use of the liver biopsy to the characterization of hepatocellular nodules which remain diagnostically equivocal after imaging. Thus pathologists are today facing very challenging and often well differentiated lesions, leading to difficulties in distinguishing high grade dysplasia and well differentiated HCC. In this scenario novel concepts obtained through international consensus have been proposed with emphasis on HCC of small size (up to 2 cm) which includes 2 distinct types, the early and progressed HCC. In this paper we will report the main histopathological criteria of a biopsy which allow the differentiation of HCC precursors (dysplastic nodules) from well differentiated HCC with attention to the role and weight of both classical histopathological criteria and novel immunocytochemical markers. The second part of the paper is devoted to the histopathology report of HCC on surgical specimens including explanted livers and on the differential diagnosis between HCC and liver metastasis. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.. All rights reserved.

miR-361-5p inhibits hepatocellular carcinoma cell proliferation and invasion by targeting VEGFA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cui, Wenxian; Li, Yuanguo; Xu, Keqing

MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. Here, we found that miR-361-5p is down-regulated in 135 patients with HCV-related hepatocellular carcinoma (HCC). Moreover, the expressions of miR-361-5p were highly correlated with VEGFA in these HCC patients. Further, CCK-8 proliferation assay indicated that miR-361-5p mimics inhibited the cell proliferation of HepG2 and SNU-398 HCC cells. Transwell assay showed that miR-361-5p mimics inhibited the invasion and migration of HepG2 and SNU-398 HCC cells. Luciferase assays revealed that miR-361-5p directly bound to the 3'untranslated region of VEGFA, and westernmore » blotting showed that miR-361-5p inhibited the expression of VEGFA. Generally, this study indicated that miR-361-5p is down-regulated in HCC and inhibits proliferation and invasion of HCC cell lines via VEGFA. In future, miR-361-5p will be a potential therapeutic agent for HCC. - Highlights: • miR-361-5p is down-regulated in HCV-related HCC. • miR-361-5p mimics inhibit the proliferation and invasion of HCC cells. • miR-361-5p inhibitors promote the proliferation and invasion of HCC cells. • miR-361-5p targets 3′ UTR of VEGFA in HCC cells. • miR-361-5p inhibits VEGFA in HCC cells.« less

Androgen receptor mitigates postoperative disease progression of hepatocellular carcinoma by suppressing CD90+ populations and cell migration and by promoting anoikis in circulating tumor cells

PubMed Central

Lai, Hsueh-Chou; Yeh, Chun-Chieh; Jeng, Long-Bin; Huang, Shang-Fen; Liao, Pei-Ying; Lei, Fu-Ju; Cheng, Wei-Chun; Hsu, Cheng-Lung; Cai, Xiujun; Chang, Chawnshang; Ma, Wen-Lung

2016-01-01

Purpose Although hepatectomy and liver transplantation surgery for hepatocellular carcinoma (HCC) are effective treatment modalities, the risk of recurrence remains high, particularly in patients with a high number of circulating tumor cells (CTCs) expressing cancer stem/progenitor cell markers. Androgen receptor (AR) signaling has been shown to suppress HCC metastasis in rodent models of HCC. In this study, we investigated whether AR is associated with postoperative HCC recurrence. Experimental Design CTCs were obtained from patients with HCC who had undergone hepatectomy to investigate whether they are associated with disease outcome. AR knockout was introduced in two mouse models of spontaneous HCC (carcinogen- and hepatitis B virus-related HCC) to delineate the role that AR plays in HCC recurrence. Biological systems analysis was used to investigate the cellular and molecular mechanisms. Results We found that the expression of AR in CTCs was negatively associated with HCC recurrence/progression after hepatectomy. Our results suggest that AR-mediated suppression of HCC recurrence/progression is governed by a three-pronged mechanism. First, AR suppresses the expression of CD90 in CTCs by upregulating Histone 3H2A. Second, AR suppresses cell migration at the transcriptome level. Third, AR promotes anoikis of CTCs via dysregulation of cytoskeletal adsorption. Conclusions The results indicate that AR expression may be the gatekeeper of postoperative HCC recurrence. Therefore, targeting AR in presurgical down-staging procedures may serve as a secondary prevention measure against HCC recurrence in the future. PMID:27340775

Perfusion machines and hepatocellular carcinoma: a good match between a marginal organ and an advanced disease?

PubMed Central

Rreka, Erion; Pezzati, Daniele; Filipponi, Franco; De Simone, Paolo

2017-01-01

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers, is the second leading cause of cancer-related deaths and the leading cause of death in patients with cirrhosis. Liver transplantation (LT) represents the ideal treatment for selected patients as it removes both the tumor and the underlying cirrhotic liver with 5-year survival rates higher than 70%. Unfortunately, due to tumor characteristics, patient co-morbidities or shortage of organs available for transplant, only 20% of patients can undergo curative treatment. Ex situ machine perfusion (MP) is a technology recently introduced that might potentially improve organ preservation, allow graft assessment and increase the pool of available organs. The purpose of this review is to provide an update on the current role of ex situ liver MP in liver transplantation for HCC patients. PMID:29264425

Circulating microRNAs (cmiRNAs) as novel potential biomarkers for hepatocellular carcinoma

PubMed Central

Qi, Jiahui; Wang, Jin; Katayama, Hiroshi; Sen, Subrata; Liu, Song-mei

2013-01-01

Incidence and mortality associated with hepatocellular carcinoma (HCC) is rising throughout the world. Accurate, noninvasive biomarkers for the early detection of HCC are urgently needed to reduce worldwide morbidity and mortality related to HCC. MicroRNAs (miRNAs), 17- to 25-nucleotide noncoding RNAs that are frequently dysregulated in HCC, have shown great promise as tissue-based markers for HCC diagnosis and prognosis. Moreover, they are stably expressed in serum and urine, and these circulating microRNAs (cmiRNAs) are emerging as novel noninvasive biomarkers for the early detection and prognosis of HCC. This article summarizes the latest findings on the role of circulating miRNAs as potential minimally invasive diagnostic and prognostic biomarkers for HCC. PMID:23259781

Association Between P2RX7 Gene and Hepatocellular Carcinoma Susceptibility: A Case-Control Study in a Chinese Han Population

PubMed Central

Duan, Shaobo; Yu, Jie; Han, Zhiyu; Cheng, Zhigang; Liang, Ping

2016-01-01

Background Hepatocellular carcinoma (HCC) is one of the most common types of liver cancer. It is hypothesized that P2RX7 genetic polymorphisms have strong association with HCC susceptibility. Therefore, a case-control study was designed and performed to verify the association between P2RX7 gene polymorphisms and HCC susceptibility. Material/Methods A total of 646 subjects were recruited in our study, including 323 HCC patients and 323 healthy controls. Five gene polymorphisms, −762C>T (rs2393799), 946G>A (rs28360457), 1513A>C (rs3751143), 1068G>A (rs1718119), and 1096C>G (rs2230911), were selected. Odds ratio (ORs) and 95% confidence interval (CI) were used to quantify the association between P2RX7 gene polymorphisms and the susceptibility to HCC. All tests were performed using SPSS 20 and a 2-sided P value of less than 0.05 was considered to be statistically significant. Results Our results suggest that allelic frequencies of these 5 SNPs all conformed to Hardy-Weinberg equilibrium (HWE). There was no significant difference in genotype and allele distributions of −762C>T and 1096C>G between the case group and the control group. However, an increased risk of HCC was associated with 946G>A (A vs. G: OR=1.48, 95%CI=1.09–2.01, P=0.013; GA+AA vs. GG: OR=1.46, 95%CI=1.03–2.07, P=0.033). A similar increased risk was associated with 1513A>C polymorphism (C vs. A: OR=1.37, 95%CI=1.05–1.79, P=0.021; AC+CC vs. AA: OR=1.40, 95%CI=1.01–1.93, P=0.041). On the other hand, a decreased risk of HCC was associated with gene polymorphism of 1068G>A (A vs. G: OR=0.68, 95%CI=0.51–0.91, P=0.010; GA+AA vs. GG: OR=0.68, 95%CI=0.49–0.96, P=0.027; AA vs. GG: OR=0.42, 95%CI=0.18–0.99, P=0.048). Conclusions Our results suggest that 3 of the 5 polymorphisms of P2RX7 described above (1513A>C, 946G>A, and 1068G>A) are significantly associated with HCC susceptibility in a Chinese Han population. Studies with larger sample sizes are recommended to confirm whether our results will be applicable to different ethnic populations in China. PMID:27272229

Radiofrequency ablation for single hepatocellular carcinoma 3 cm or less as first-line treatment

PubMed Central

Gao, Jun; Wang, Shao-Hong; Ding, Xue-Mei; Sun, Wen-Bing; Li, Xiao-Long; Xin, Zong-Hai; Ning, Chun-Min; Guo, Shi-Gang

2015-01-01

AIM: To evaluate long-term outcomes of radiofrequency (RF) ablation as first-line therapy for single hepatocellular carcinoma (HCC) ≤ 3 cm and to determine survival and prognostic factors. METHODS: We included all 184 patients who underwent RF ablation as a first-line treatment for single HCC ≤ 3 cm between April 2005 and December 2013. According to the criteria of Livraghi, the 184 patients were divided into two groups: those suitable for surgical resection (84 cases) and those unsuitable for surgical resection (100 cases). The primary endpoints were the overall survival (OS) rate and safety; the secondary endpoints were primary technique effectiveness and recurrence rate. RESULTS: There were 19 (10.3%) cases of ablation related minor complications. The complete tumor ablation rate after one RF session was 97.8% (180/184). The rate of local tumor progression, extrahepatic metastases and intrahepatic distant recurrence were 4.9% (9/184), 9.8% (18/184) and 37.5% (69/184), respectively. In the 184 patients, the 1-, 3-, and 5-year OS rates were 99.5%, 81.0%, and 62.5%, respectively. The 1-, 3-, and 5-year OS rates were 100%, 86.9%, and 71.4%, respectively, in those suitable for surgical resection and 99.0%, 76.0%, and 55.0%, respectively, in those unsuitable for surgical resection (P = 0.021). On univariate and multivariate analyses, poorer OS was associated with Child-Pugh B class and portal hypertension (P < 0.05). CONCLUSION: RF ablation is a safe and effective treatment for single HCC ≤ 3 cm. The OS rate of patients suitable for surgical resection was similar to those reported in surgical series. PMID:25954102

Does pyogenic liver abscess increase the risk of delayed-onset primary liver cancer?

PubMed Central

Chu, Chia-Sheng; Lin, Che-Chen; Peng, Cheng-Yuan; Chuang, Po-Heng; Su, Wen-Pang; Lai, Shih-Wei; Chen, Hsuan-Ju; Chung, Chi-Jung; Lai, Hsueh-Chou

2017-01-01

Abstract Delayed-onset primary liver cancer (PLC) including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in patients with pyogenic liver abscess (PLA) is not common. The relationship between PLA and delayed-onset PLC is unclear. We investigated the association in a nationwide cohort study. From Taiwan National Health Insurance claims data, a cohort of 17,531 patients with PLA was generated after excluding patients with a history of cancer (n = 2034) and those diagnosed with PLC (n = 572) and other cancers (n = 627) within 1 year of a diagnosis of PLA. An age-, sex-, index year-, and diabetes mellitus (DM)-matched control cohort of 70,124 persons without PLA was selected from the same dataset. Both cohorts were followed up until the end of 2011. The risk of PLC was estimated for both cohorts. The incidence of PLC was nearly 2-fold greater in the PLA group than in the control cohort (29.3 per 10,000 person-years vs. 16.2 per 10,000 person-years). The incidences of HCC and ICC were 1.5- (22.1 per 10,000 person-years vs. 15.0 per 10,000 person-years) and 11-fold greater (6.73 per 10,000 person-years vs. 0.62 per 10,000 person-years), respectively, in the PLA group than in the control cohort. The PLA cohort also had high risks of PLC (adjusted hazard ratio [aHR] = 1.56; 95% confidence interval [CI] = 1.35–1.81), HCC (aHR = 1.34; 95% CI = 1.15–1.57), and ICC (aHR = 6.94; 95% CI = 4.23–11.57). In conclusion, in this nationwide cohort study, PLA increased the risk of delayed-onset PLC. PMID:28834881

Relation between sex hormones and hepatocellular carcinoma.

PubMed

El Mahdy Korah, T; Abd Elfatah Badr, E; Mohamed Emara, M; Ahmed Samy Kohla, M; Gamal Saad Michael, G

2016-11-01

Males have higher incidence of hepatocellular carcinoma (HCC) than females. Sex hormones may be a risk factor. The aim was to determine the levels of sex hormones in male and female patients with HCC and cirrhosis versus controls and its possible relationship with HCC. This study was conducted on 90 subjects divided into 40 patients with HCC, 30 patients with liver cirrhosis and 20 apparently healthy subjects complete blood picture, liver function tests. Determination of AFP levels and hormonal assay of oestrogen, progesterone, total testosterone, prolactin, FSH and LH were performed on all subjects. Total testosterone levels were significantly decreased in the two patients groups compared with controls. While oestrogen levels were significantly decreased in the HCC group in comparison with other two groups, prolactin levels were significantly decreased in the HCC group compared with the liver cirrhosis group and increased in the liver cirrhosis group when compared to controls. FSH and LH levels were significantly increased in the HCC group when compared to controls. There is no significant correlation between sex hormones assay and both the size of HCC and degree of cirrhosis in both patient groups. It is concluded that there is no strong relation between sex hormones and HCC when the study was carried out on the levels of sex hormones in patients with HCC. © 2016 Blackwell Verlag GmbH.

Recent advances in multidisciplinary management of hepatocellular carcinoma

PubMed Central

Gomaa, Asmaa I; Waked, Imam

2015-01-01

The incidence of hepatocellular carcinoma (HCC) is increasing, and it is currently the second leading cause of cancer-related death worldwide. Potentially curative treatment options for HCC include resection, transplantation, and percutaneous ablation, whereas palliative treatments include trans-arterial chemoembolization (TACE), radioembolization, and systemic treatments. Due to the diversity of available treatment options and patients’ presentations, a multidisciplinary team should decide clinical management of HCC, according to tumor characteristics and stage of liver disease. Potentially curative treatments are suitable for very-early- and early-stage HCC. However, the vast majority of HCC patients are diagnosed in later stages, where the tumor characteristics or progress of liver disease prevent curative interventions. For patients with intermediate-stage HCC, TACE and radioembolization improve survival and are being evaluated in addition to potentially curative therapies or with systemic targeted therapy. There is currently no effective systemic chemotherapy, immunologic, or hormonal therapy for HCC, and sorafenib is the only approved molecular-targeted treatment for advanced HCC. Other targeted agents are under investigation; trials comparing new agents in combination with sorafenib are ongoing. Combinations of systemic targeted therapies with local treatments are being evaluated for further improvements in HCC patient outcomes. This article provides an updated and comprehensive overview of the current standards and trends in the treatment of HCC. PMID:25866604

3-bromopyruvate and buthionine sulfoximine effectively kill anoikis-resistant hepatocellular carcinoma cells

PubMed Central

Lee, Minjong; Jo, Ara; Lee, Seulki; Kim, Jong Bin; Chang, Young; Nam, Joon Yeul; Cho, Hyeki; Cho, Young Youn; Cho, Eun Ju; Lee, Jeong-Hoon; Yu, Su Jong; Yoon, Jung-Hwan

2017-01-01

Background & aims Acquisition of anoikis resistance is a prerequisite for metastasis in hepatocellular carcinoma (HCC). However, little is known about how energy metabolism and antioxidant systems are altered in anoikis-resistant (AR) HCC cells. We evaluated anti-tumor effects of a combination treatment of 3-bromopyruvate (3-BP) and buthionine sulfoximine (BSO) in AR HCC cells. Methods We compared glycolysis, reactive oxygen species (ROS) production, and chemoresistance among Huh-BAT, HepG2 HCC cells, and the corresponding AR cells. Expression of hexokinase II, gamma-glutamylcysteine synthetase (rGCS), and epithelial–mesenchymal transition (EMT) markers in AR cells was assessed. Anti-tumor effects of a combination treatment of 3-BP and BSO were evaluated in AR cells and an HCC xenograft mouse model. Results AR HCC cells showed significantly higher chemoresistance, glycolysis and lower ROS production than attached cells. Expression of hexokinase II, rGCS, and EMT markers was higher in AR HCC cells than attached cells. A combination treatment of 3-BP/BSO effectively suppressed proliferation of AR HCC cells through apoptosis by blocking glycolysis and enhancing ROS levels. In xenograft mouse models, tumor growth derived from AR HCC cells was significantly suppressed in the group treated with 3-BP/BSO compared to the group treated with 3-BP or sorafenib. Conclusions These results demonstrated that a combination treatment of 3-BP/BSO had a synergistic anti-tumor effect in an AR HCC model. This strategy may be an effective adjuvant therapy for patients with sorafenib-resistant HCC. PMID:28362858

3-bromopyruvate and buthionine sulfoximine effectively kill anoikis-resistant hepatocellular carcinoma cells.

PubMed

Lee, Minjong; Jo, Ara; Lee, Seulki; Kim, Jong Bin; Chang, Young; Nam, Joon Yeul; Cho, Hyeki; Cho, Young Youn; Cho, Eun Ju; Lee, Jeong-Hoon; Yu, Su Jong; Yoon, Jung-Hwan; Kim, Yoon Jun

2017-01-01

Acquisition of anoikis resistance is a prerequisite for metastasis in hepatocellular carcinoma (HCC). However, little is known about how energy metabolism and antioxidant systems are altered in anoikis-resistant (AR) HCC cells. We evaluated anti-tumor effects of a combination treatment of 3-bromopyruvate (3-BP) and buthionine sulfoximine (BSO) in AR HCC cells. We compared glycolysis, reactive oxygen species (ROS) production, and chemoresistance among Huh-BAT, HepG2 HCC cells, and the corresponding AR cells. Expression of hexokinase II, gamma-glutamylcysteine synthetase (rGCS), and epithelial-mesenchymal transition (EMT) markers in AR cells was assessed. Anti-tumor effects of a combination treatment of 3-BP and BSO were evaluated in AR cells and an HCC xenograft mouse model. AR HCC cells showed significantly higher chemoresistance, glycolysis and lower ROS production than attached cells. Expression of hexokinase II, rGCS, and EMT markers was higher in AR HCC cells than attached cells. A combination treatment of 3-BP/BSO effectively suppressed proliferation of AR HCC cells through apoptosis by blocking glycolysis and enhancing ROS levels. In xenograft mouse models, tumor growth derived from AR HCC cells was significantly suppressed in the group treated with 3-BP/BSO compared to the group treated with 3-BP or sorafenib. These results demonstrated that a combination treatment of 3-BP/BSO had a synergistic anti-tumor effect in an AR HCC model. This strategy may be an effective adjuvant therapy for patients with sorafenib-resistant HCC.

Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy

PubMed Central

Sun, Cheng; Sun, Hao-yu; Xiao, Wei-hua; Zhang, Cai; Tian, Zhi-gang

2015-01-01

The mechanisms linking hepatitis B virus (HBV) and hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) remain largely unknown. Natural killer (NK) cells account for 25%–50% of the total number of liver lymphocytes, suggesting that NK cells play an important role in liver immunity. The number of NK cells in the blood and tumor tissues of HCC patients is positively correlated with their survival and prognosis. Furthermore, a group of NK cell-associated genes in HCC tissues is positively associated with the prolonged survival. These facts suggest that NK cells and HCC progression are strongly associated. In this review, we describe the abnormal NK cells and their functional impairment in patients with chronic HBV and HCV infection, which contribute to the progression of HCC. Then, we summarize the association of NK cells with HCC based on the abnormalities in the numbers and phenotypes of blood and liver NK cells in HCC patients. In particular, the exhaustion of NK cells that represents lower cytotoxicity and impaired cytokine production may serve as a predictor for the occurrence of HCC. Finally, we present the current achievements in NK cell immunotherapy conducted in mouse models of liver cancer and in clinical trials, highlighting how chemoimmunotherapy, NK cell transfer, gene therapy, cytokine therapy and mAb therapy improve NK cell function in HCC treatment. It is conceivable that NK cell-based anti-HCC therapeutic strategies alone or in combination with other therapies will be great promise for HCC treatment. PMID:26073325

Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression

PubMed Central

Yoo, Byoung Kwon; Emdad, Luni; Su, Zao-zhong; Villanueva, Augusto; Chiang, Derek Y.; Mukhopadhyay, Nitai D.; Mills, Alan Scott; Waxman, Samuel; Fisher, Robert A.; Llovet, Josep M.; Fisher, Paul B.; Sarkar, Devanand

2009-01-01

Hepatocellular carcinoma (HCC) is a highly aggressive vascular cancer characterized by diverse etiology, activation of multiple signal transduction pathways, and various gene mutations. Here, we have determined a specific role for astrocyte elevated gene-1 (AEG1) in HCC pathogenesis. Expression of AEG1 was extremely low in human hepatocytes, but its levels were significantly increased in human HCC. Stable overexpression of AEG1 converted nontumorigenic human HCC cells into highly aggressive vascular tumors, and inhibition of AEG1 abrogated tumorigenesis by aggressive HCC cells in a xenograft model of nude mice. In human HCC, AEG1 overexpression was associated with elevated copy numbers. Microarray analysis revealed that AEG1 modulated the expression of genes associated with invasion, metastasis, chemoresistance, angiogenesis, and senescence. AEG1 also was found to activate Wnt/β-catenin signaling via ERK42/44 activation and upregulated lymphoid-enhancing factor 1/T cell factor 1 (LEF1/TCF1), the ultimate executor of the Wnt pathway, important for HCC progression. Inhibition studies further demonstrated that activation of Wnt signaling played a key role in mediating AEG1 function. AEG1 also activated the NF-κB pathway, which may play a role in the chronic inflammatory changes preceding HCC development. These data indicate that AEG1 plays a central role in regulating diverse aspects of HCC pathogenesis. Targeted inhibition of AEG1 might lead to the shutdown of key elemental characteristics of HCC and could lead to an effective therapeutic strategy for HCC. PMID:19221438

Pokemon and MEF2D co-operationally promote invasion of hepatocellular carcinoma.

PubMed

Hong, Xin; Hong, Xing-Yu; Li, Tao; He, Cheng-Yan

2015-12-01

Hepatocellular carcinoma (HCC) is one of the most deadly human malignancy, and frequent invasion and metastasis is closely associated with its poor prognosis. However, the molecular mechanism underlying HCC invasion is still not completely elucidated. Pokemon is a well-established oncogene for HCC growth, but its contribution to HCC invasion has not been studied yet. In this paper, Pokemon was found to be overexpressed in MHCC-97H HCC cell line, which possesses higher invasiveness. Downregulation of Pokemon abolished the invasion of MHCC-97H HCC cell lines. Pokemon overexpression was able to enhance the invasion of MHCC-97L cells with lower invasiveness. MEF2D, an oncogene promoting the invasion of HCC cells, was further detected to be upregulated and downregulated when Pokemon was overexpressed and silenced, respectively. Online database analysis indicated that one Pokemon recognition site was located within the promoter of MEF2D. Chromatin co-precipitation, luciferase, and qPCR assays all proved that Pokemon can promote the expression of MEF2D in HCC cells. Restoration of MEF2D expression can prevent the impaired invasion of HCC cells with Pokemon silencing, while suppression of MEF2D abolished the effect of Pokemon overexpression on HCC invasion. More interestingly, MEF2D was also found to increase the transcription of Pokemon by binding myocyte enhancer factor 2 (MEF2) sites within its promoter region, implying an auto-regulatory circuit consisting of these two oncogenes that can promote HCC invasion. Our findings can contribute to the understanding of molecular mechanism underlying HCC invasion, and provided evidence that targeting this molecular loop may be a promising strategy for anti-invasion therapy.

Serum oxidative-anti-oxidative stress balance is dysregulated in patients with hepatitis C virus-related hepatocellular carcinoma.

PubMed

Nishimura, Mamoru; Takaki, Akinobu; Tamaki, Naofumi; Maruyama, Takayuki; Onishi, Hideki; Kobayashi, Sayo; Nouso, Kazuhiro; Yasunaka, Tetsuya; Koike, Kazuko; Hagihara, Hiroaki; Kuwaki, Kenji; Nakamura, Shinichiro; Ikeda, Fusao; Iwasaki, Yoshiaki; Tomofuji, Takaaki; Morita, Manabu; Yamamoto, Kazuhide

2013-10-01

Oxidative stress is associated with progression of chronic liver disease (CLD). This association is best established in chronic hepatitis C. However, the anti-oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti-oxidative stress in CLD patients. We recruited a study population of 208 patients, including healthy volunteers (HV; n = 15), patients with hepatitis B virus (HBV)-related CLD without or with hepatocellular carcinoma (HBV-non-HCC, n = 25, and HBV-HCC, n = 50, respectively), and patients with hepatitis C virus (HCV)-related CLD without or with HCC (HCV-non-HCC, n = 49, and HCV-HCC, n = 69, respectively). Serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY-adsorbent test; OXY) were determined, and the balance of these values was used as the oxidative index. Correlations among ROM, OXY, oxidative index and clinical characteristics were investigated. Patients with CLD exhibited elevated ROM and oxidative index compared to HV. Among patients with CLD, HCV positive status correlated with increased ROM. In CLD, HCV-HCC patients exhibited the highest ROM levels. Among HCV-related CLD patients, lower OXY correlated with HCC positive status, but was recovered by eradication of HCC. In HCV-HCC, lower OXY correlated with high PT-INR. HCV positive CLD patients displayed higher oxidative stress and HCV-HCC patients displayed lower anti-oxidative state. Anti-oxidative state depression was associated with liver reservoir-related data in HCV-HCC and could be reversed with HCC eradication. © 2012 The Japan Society of Hepatology.

Evaluation of Abdominal Ultrasonography Mass Screening for Hepatocellular Carcinoma in Taiwan

PubMed Central

Yeh, Yen-Po; Hu, Tsung-Hui; Cho, Po-Yuan; Chen, Hsiu-Hsi; Yen, Amy Ming-Fang; Chen, Sam Li-Sheng; Chiu, Sherry Yueh-Hsia; Fann, Jean Ching-Yuan; Su, Wei-Wen; Fang, Yi-Jen; Chen, Shih-Tien; San, Hsiao-Ching; Chen, Hung-Pin; Liao, Chao-Sheng

2014-01-01

Mass screening with abdominal ultrasonography (AUS) has been suggested as a tool to control adult hepatocellular carcinoma (HCC) in individuals, but its efficacy in reducing HCC mortality has never been demonstrated. This study aimed to assess the effectiveness of reducing HCC mortality by mass AUS screening for HCC based on a program designed and implemented in the Changhua Community-based Integrated Screening (CHCIS) program with an efficient invitation scheme guided by the risk score. We invited 11,114 (27.0%) of 41,219 eligible Taiwanese subjects between 45 and 69 years of age who resided in an HCC high-incidence area to attend a risk score-guided mass AUS screening between 2008 and 2010. The efficacy of reducing HCC mortality was estimated. Of the 8,962 AUS screening attendees (with an 80.6% attendance rate), a total of 16 confirmed HCC cases were identified through community-based ultrasonography screening. Among the 16 screen-detected HCC cases, only two died from HCC, indicating a favorable survival. The cumulative mortality due to HCC (per 100,000) was considerably lower in the invited AUS group (17.26) compared with the uninvited AUS group (42.87) and the historical control group (47.51), yielding age- and gender-adjusted relative mortality rates of 0.69 (95% confidence interval [CI]: 0.56-0.84) and 0.63 (95% CI: 0.52-0.77), respectively. Conclusion: The residents invited to community-based AUS screening for HCC, compared with those who were not invited, showed a reduction in HCC mortality by ∼31% among subjects aged 45-69 years who had not been included in the nationwide vaccination program against hepatitis B virus infection. (Hepatology 2014;59:1840–1849) PMID:24002724

Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C.

PubMed

Kurosaki, Masayuki; Hiramatsu, Naoki; Sakamoto, Minoru; Suzuki, Yoshiyuki; Iwasaki, Manabu; Tamori, Akihiro; Matsuura, Kentaro; Kakinuma, Sei; Sugauchi, Fuminaka; Sakamoto, Naoya; Nakagawa, Mina; Izumi, Namiki

2012-03-01

Assessment of the risk of hepatocellular carcinoma (HCC) development is essential for formulating personalized surveillance or antiviral treatment plan for chronic hepatitis C. We aimed to build a simple model for the identification of patients at high risk of developing HCC. Chronic hepatitis C patients followed for at least 5 years (n=1003) were analyzed by data mining to build a predictive model for HCC development. The model was externally validated using a cohort of 1072 patients (472 with sustained virological response (SVR) and 600 with nonSVR to PEG-interferon plus ribavirin therapy). On the basis of factors such as age, platelet, albumin, and aspartate aminotransferase, the HCC risk prediction model identified subgroups with high-, intermediate-, and low-risk of HCC with a 5-year HCC development rate of 20.9%, 6.3-7.3%, and 0-1.5%, respectively. The reproducibility of the model was confirmed through external validation (r(2)=0.981). The 10-year HCC development rate was also significantly higher in the high-and intermediate-risk group than in the low-risk group (24.5% vs. 4.8%; p<0.0001). In the high-and intermediate-risk group, the incidence of HCC development was significantly reduced in patients with SVR compared to those with nonSVR (5-year rate, 9.5% vs. 4.5%; p=0.040). The HCC risk prediction model uses simple and readily available factors and identifies patients at a high risk of HCC development. The model allows physicians to identify patients requiring HCC surveillance and those who benefit from IFN therapy to prevent HCC. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

BTG2 Is Down-Regulated and Inhibits Cancer Stem Cell-Like Features of Side Population Cells in Hepatocellular Carcinoma.

PubMed

Huang, Chen-Song; Zhai, Jing-Ming; Zhu, Xiao-Xu; Cai, Jian-Peng; Chen, Wei; Li, Jian-Hui; Yin, Xiao-Yu

2017-12-01

Our previous study found that B cell translocation gene 2 (BTG2) was hyper-methylated and down-regulated in side population (SP) cells of hepatocellular carcinoma (HCC) cell line. However, its clinical significances and biological impacts on HCC SP cells remained unclear. To investigate the prognostic value of BTG2 gene in HCC and its influences on cancer stem cells (CSCs)-like traits of HCC cell line SP cells. BTG2 expression in human HCC and adjacent non-cancerous tissues was detected by immunohistochemical staining and quantitative real-time PCR, and also obtained from GEO and TCGA data. Its prognostic values were assessed. Its biological influences on HCC cell line SP cells were evaluated using cell viability, cell cycle, plate clone-forming assay, and chemoresistance in vitro and tumorigenicity in vivo. BTG2 expression was significantly suppressed in human HCC compared to adjacent non-cancerous tissues. BTG2 expression was correlated with TNM stage, tumor size and vascular invasion. Lower expression of BTG2 was associated with poorer overall survival and disease-free survival. In vitro, overexpression of BTG2 substantially suppressed cell proliferation and accumulation of HCC cell line SP cells in G0/G1 phase. Colony formation ability was markedly suppressed by BTG2 overexpression. Moreover, sensitivity of HCC cell line SP cells to 5-fluorouracil was substantially increased by overexpression of BTG2. Furthermore, tumorigenicity of HCC cell line SP cells transfected with BTG2 plasmids was significantly reduced in vivo. BTG2 gene could regulate the CSC-like traits of HCC cell line SP cells, and it represented as a molecular prognostic marker for HCC.

Diabetes and Cirrhosis Are Risk Factors for Hepatocellular Carcinoma After Successful Treatment of Chronic Hepatitis C.

PubMed

Hedenstierna, Magnus; Nangarhari, Ali; Weiland, Ola; Aleman, Soo

2016-09-15

Successful treatment of hepatitis C virus (HCV) infection reduces the risk for hepatocellular carcinoma (HCC), but a risk remains. Current guidelines recommend continued HCC surveillance after sustained virologic response (SVR) has been achieved. This study aimed to investigate risk factors and incidence rates for HCC after SVR in HCV patients with pretreatment advanced liver disease (Metavir stage F3/F4). All patients with advanced liver disease successfully treated for HCV at Karolinska University Hospital during 1992-2013 (n = 399) were followed up for a median of 7.8 years. Data from national registries were used to minimize loss to follow-up. Incidence rates and hazard ratios (HRs) for development of HCC were calculated by Cox regression analysis. Seventeen patients developed HCC during 3366 person-years (PY) of follow-up. The HCC incidence rate was 0.95 (95% confidence interval [CI], .57-1.6) and 0.15 (95% CI, .05-.49) per 100 PY for patients with pretreatment F4 and F3, respectively. Patients with pretreatment cirrhosis and diabetes had a HR to develop HCC of 6.3, and an incidence rate of 7.9 per 100 PY (95% CI, 3.3-19) during the first 2 years of follow-up. The risk for HCC decreased significantly 2 years after SVR had been achieved. Diabetes mellitus and cirrhosis are strong risk factors for HCC development after SVR has been achieved. The risk to develop HCC diminishes significantly 2 years after SVR. Patients without cirrhosis have a low risk to develop HCC after SVR, and the benefit of HCC surveillance for this group is questionable. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

The Impact of Race on Survival After Hepatocellular Carcinoma in a Diverse American Population.

PubMed

Jones, Patricia D; Diaz, Carlos; Wang, Danlu; Gonzalez-Diaz, Joselin; Martin, Paul; Kobetz, Erin

2018-02-01

Hepatocellular carcinoma (HCC) incidence is increasing at differential rates depending on race. We aimed to identify associations between race and survival after HCC diagnosis in a diverse American population. Using the cancer registry from Sylvester Comprehensive Cancer Center, University of Miami and Jackson Memorial Hospitals, we performed retrospective analysis of 999 patients diagnosed with HCC between 9/24/2004 and 12/19/2014. We identified clinical characteristics by reviewing available electronic medical records. The association between race and survival was analyzed using Cox proportional hazards regression. Median survival in days was 425 in Blacks, 904.5 in non-Hispanic Whites, 652 in Hispanics, 570 in Asians, and 928 in others, p < 0.01. Blacks and Asians presented at more advanced stages with larger tumors. Although Whites had increased severity of liver disease at diagnosis compared to other races, they had 36% reduced rate of death compared to Blacks, [hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.51-0.8, p < 0.01]. After adjusting for significant covariates, Whites had 22% (HR 0.78, 95% CI 0.61-0.99, p 0.04) reduced risk of death, compared to Blacks. Transplant significantly reduced rate of death; however, only 13.3% of Blacks had liver transplant, compared to 40.1% of Whites, p < 0.01. In this diverse sample of patients, survival among Blacks is the shortest after HCC diagnosis. Survival differences reflect a more advanced tumor stage at presentation rather than severity of underlying liver disease precluding treatment. Improving survival in minority populations, in whom HCC incidence is rapidly increasing, requires identification and modification of factors contributing to late-stage presentation.

USP39 promotes the growth of human hepatocellular carcinoma in vitro and in vivo.

PubMed

Yuan, Xianwen; Sun, Xitai; Shi, Xiaolei; Jiang, Chunping; Yu, Decai; Zhang, Weiwei; Guan, Wenxian; Zhou, Jianxin; Wu, Yafu; Qiu, Yudong; Ding, Yitao

2015-08-01

Ubiquitin specific protease 39 (USP39) plays an important role in mRNA splicing. In the present study, we investigated the role of USP39 in regulating the growth of hepatocellular carcinoma (HCC). We detected USP39 expression in more than 100 HCC clinical samples. The USP39 expression was significantly higher in the tumor tissues compared to the adjacent normal tissues, and was strongly associated with the pathological grade of HCC. USP39 knockdown inhibited cell proliferation and colony formation in vitro in the HepG2 cells, while upregulation of USP39 promoted tumor cell growth. FCM assay showed that USP39 knockdown led to G2/M arrest and induced apoptosis in the HepG2 cells. USP39 knockdown by shRNA inhibited xenograft tumor growth in nude mice. Moreover, USP39 knockdown led to the upregulation of p-Cdc2 and downregulation of p-Cdc25c and p-myt1, while the expression of total Cdc2, Cdc25c and myt1 was not changed in the USP39-knockdown cells. We also found that p-Cdc2 was decreased in the USP39-overexpressing cells and was upregulated in the xenografted tumors derived from the HepG2/KD cells from nude mice. Meanwhile, the expression levels of FoxM1 and its target genes PLK1 and cyclin B1 were decreased in the USP39-knockdown cells. These results suggest that USP39 may contribute to FoxM1 splicing in HCC tumor cells. Our data indicate that USP39 knockdown inhibited the growth of HCC both in vitro and in vivo through G2/M arrest, which was partly achieved via the inhibition of FoxM1 splicing.

Synergistic role of Sprouty2 inactivation and c-Met up-regulation in mouse and human hepatocarcinogenesis.

PubMed

Lee, Susie A; Ladu, Sara; Evert, Matthias; Dombrowski, Frank; De Murtas, Valentina; Chen, Xin; Calvisi, Diego F

2010-08-01

Sprouty2 (Spry2), a negative feedback regulator of the Ras/mitogen-activated protein kinase (MAPK) pathway, is frequently down-regulated in human hepatocellular carcinoma (HCC). We tested the hypothesis that loss of Spry2 cooperates with unconstrained activation of the c-Met protooncogene to induce hepatocarcinogenesis via in vitro and in vivo approaches. We found coordinated down-regulation of Spry2 protein expression and activation of c-Met as well as its downstream effectors extracellular signal-regulated kinase (ERK) and v-akt murine thymoma viral oncogene homolog (AKT) in a subset of human HCC samples with poor outcome. Mechanistic studies revealed that Spry2 function is disrupted in human HCC via multiple mechanisms at both transcriptional and post-transcriptional level, including promoter hypermethylation, loss of heterozygosity, and proteosomal degradation by neural precursor cell expressed, developmentally down-regulated 4 (NEDD4). In HCC cell lines, Spry2 overexpression inhibits c-Met-induced cell proliferation as well as ERK and AKT activation, whereas loss of Spry2 potentiates c-Met signaling. Most importantly, we show that blocking Spry2 activity via a dominant negative form of Spry2 cooperates with c-Met to promote hepatocarcinogenesis in the mouse liver by sustaining proliferation and angiogenesis. The tumors exhibited high levels of activated ERK and AKT, recapitulating the subgroup of human HCC with a clinically aggressive phenotype. The occurrence of frequent genetic, epigenetic, and biochemical events leading to Spry2 inactivation provides solid evidence that Spry2 functions as a tumor suppressor gene in liver cancer. Coordinated deregulation of Spry2 and c-Met signaling may be a pivotal oncogenic mechanism responsible for unrestrained activation of ERK and AKT pathways in human hepatocarcinogenesis.

Epidermal growth factor receptor pathway polymorphisms and the prognosis of hepatocellular carcinoma

PubMed Central

Wang, Wenjia; Ma, Xiao-Pin; Shi, Zhuqing; Zhang, Pengyin; Ding, Dong-Lin; Huang, Hui-Xing; Saiyin, Hexi Ge; Chen, Tao-Yang; Lu, Pei-Xin; Wang, Neng-Jin; Yu, Hongjie; Sun, Jielin; Zheng, S Lilly; Yu, Long; Xu, Jianfeng; Jiang, De-Ke

2015-01-01

The EGFR signaling pathway is important in the control of vital processes in the carcinogenesis of hepatocellular carcinoma (HCC), including cell survival, cell cycle progression, tumor invasion and angiogenesis. In the current study, we aim to assess if genetic variants in the genes of the EGFR signaling pathway are associated with the prognosis of HCC. We genotyped 36 single nucleotide polymorphisms (SNP) in four core genes (EGF, EGFR, VEGF, and VEGFR2) by using DNA from blood samples of 363 HCC patients with surgical resection. The associations between genotypes and overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confident intervals (CIs) were estimated for the multivariate survival analyses by Cox proportional hazards regression models, adjusting for age, gender, family history, HBsAg and AFP. We found that five SNPs in the VEGFR2 gene were significantly associated with clinical outcomes of HCC patients. Among them, four SNPs (rs7692791, rs2305948, rs13109660, rs6838752) were associated with OS (p=0.035, 0.038, 0.029 and 0.028, respectively), and two SNPs (rs7692791 and rs2034965) were associated with DFS (p=0.039 and 0.017, respectively). Particularly, rs7692791 TT genotype was associated with both reduced OS (p=0.037) and DFS (p=0.043). However, only one SNP rs2034965 with the AA genotype was shown to be an independent effect on DFS (p=0.009) in the multivariate analysis. None of the other 31 polymorphisms or 9 haplotypes attained from the four genes was significantly associated with OS or DFS. Our results illustrated the potential use of VEGFR2 polymorphisms as prognostic markers for HCC patients. PMID:25628948

Cell expression patterns of CD147 in N-diethylnitrosamine/phenobarbital-induced mouse hepatocellular carcinoma.

PubMed

Lu, Meng; Wu, Jiao; He, Feng; Wang, Xi-Long; Li, Can; Chen, Zhi-Nan; Bian, Huijie

2015-02-01

Overexpression of CD147/basigin in hepatic cells promotes the progression of hepatocellular carcinoma (HCC). Whether CD147 also expressed in liver non-parenchymal cells and associated with HCC development was unknown. The aim of the study was to explore time-dependent cell expression patterns of CD147 in a widely accepted N-diethylnitrosamine/phenobarbital (DEN/PB)-induced HCC mouse model. Liver samples collected at month 1-12 of post-DEN/PB administration were assessed the localization of CD147 in hepatocytes, endothelial cells, hepatic stellate cells, and macrophages. Immunohistochemistry analysis showed that CD147 was upregulated in liver tumors during month 1-8 of DEN/PB induction. Expression of CD147 was positively correlated with cytokeratin 18, a hepatocyte marker (r = 0.7857, P = 0.0279), CD31 (r = 0.9048, P = 0.0046), an endothelial cell marker, and CD68, a macrophage marker (r = 0.7619, P = 0.0368). A significant correlation was also observed between CD147 and alpha-smooth muscle actin (r = 0.8857, P = 0.0333) at DEN/PB initiation and early stage of tumor formation. Immunofluorescence and fluorescence in situ hybridization showed that CD147 co-expressed with cytokeratin 18, CD31, alpha-smooth muscle actin, and CD68. Moreover, there existed positive correlations between CD147 and microvessel density (r = 0.7857, P = 0.0279), CD147 and Ki-67 (r = 0.9341, P = 0.0022) in the development of DEN/PB-induced HCC. In conclusion, our results demonstrated that CD147 was upregulated in the liver parenchymal and mesenchymal cells and involved in angiogenesis and tumor cell proliferation in the development of DEN/PB-induced HCC.

A multiple mediator analysis approach to quantify the effects of the ADH1B and ALDH2 genes on hepatocellular carcinoma risk.

PubMed

Shih, Stephannie; Huang, Yen-Tsung; Yang, Hwai-I

2018-06-01

Previous work suggested a genetic component affecting the risk of hepatocellular carcinoma (HCC) and mediation analyses have elucidated potential indirect pathways of these genetic effects. Specifically, the effects of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase (ALDH2) genes on HCC risk vary based on alcohol consumption habits. However, alcohol consumption may not be the only mediator in the identified pathway: factors related to alcohol consumption may contribute to the same indirect pathway. Thus, we developed a multimediator model to quantify the genetic effects on HCC risk through sequential dichotomous mediators under the counterfactual framework. Our method provided a closed form formula for the mediation effects through different indirect paths, which requires no assumption for the rarity of outcome. In simulation studies of a finite sample, we presented the utility of the method with the variance of the effects estimated using the delta method and bootstrapping. We applied our method to data from participants in Taiwan (580 cases and 3,207 controls) and quantified the mediation effects of single nucleotide polymorphisms (SNPs) in the ADH1B and ALDH2 genes on HCC through alcohol consumption (yes/no) and high alanine transaminase (ALT) levels (greater than or equal to 45 U/L or below 45 U/L). Assuming a dominant risk model, we identified that the SNPs' effects through alcohol consumption is more significant than through ALT levels on HCC risk. This new method provides insight to the magnitude of various casual mechanisms as a closed form solution and can be readily applied in other genomic studies. © 2018 WILEY PERIODICALS, INC.

Study of Aided Diagnosis of Hepatic Carcinoma Based on Artificial Neural Network Combined with Tumor Marker Group

NASA Astrophysics Data System (ADS)

Tan, Shanjuan; Feng, Feifei; Wu, Yongjun; Wu, Yiming

To develop a computer-aided diagnostic scheme by using an artificial neural network (ANN) combined with tumor markers for diagnosis of hepatic carcinoma (HCC) as a clinical assistant method. 140 serum samples (50 malignant, 40 benign and 50 normal) were analyzed for α-fetoprotein (AFP), carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), sialic acid (SA) and calcium (Ca). The five tumor marker values were then used as ANN inputs data. The result of ANN was compared with that of discriminant analysis by receiver operating characteristic (ROC) curve (AUC) analysis. The diagnostic accuracy of ANN and discriminant analysis among all samples of the test group was 95.5% and 79.3%, respectively. Analysis of multiple tumor markers based on ANN may be a better choice than the traditional statistical methods for differentiating HCC from benign or normal.

Diagnostic Evaluation of Des-Gamma-Carboxy Prothrombin versus α-Fetoprotein for Hepatitis B Virus-Related Hepatocellular Carcinoma in China: A Large-Scale, Multicentre Study

PubMed Central

Zheng, Lei; Yin, Yuepeng; Zou, Zhenzhen; Zhou, Feiguo; Zhou, Weiping; Shen, Feng; Gao, Chunfang

2016-01-01

An efficient serum marker for hepatocellular carcinoma (HCC) is currently lacking and requires intensive exploration. We aimed to evaluate the performance of des-gamma-carboxy prothrombin (DCP) for identifying hepatitis B virus-related HCC in a large, multicentre study in China. A total of 1034 subjects in three cohorts (A, B, and C) including HCC and various non-HCC controls were enrolled from 4 academic medical centers in China from January 2011 to February 2014. Blind parallel detections were conducted for DCP and AFP. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic efficacies. In cohort A, which comprised 521 subjects, including patients with HCC, liver metastasis, liver cirrhosis (LC), and liver hemangiomas as well as healthy controls (HCs), the accuracy of DCP for distinguishing HCC from various controls was 6.2–9.7% higher than that of AFP. In cohort B, which comprised 447 subjects, including patients with HCC, LC, and chronic hepatitis B as well as HC, the accuracy of DCP was further elevated (12.3–20.67% higher than that of AFP). The superiority of DCP to AFP was more profound in the surveillance of early HCC [AUC 0.837 (95% CI: 0.771–0.903) vs. 0.650 (0.555–0.745)] and AFP-negative HCC [AUC: 0.856 (0.798–0.914)] and in discriminating HCC from LC (accuracy: 92.9% vs.64.71%). Higher DCP levels were associated with worse clinical behaviors and shorter disease-free survival. DCP not only is complementary to AFP in identifying AFP-negative HCC and in excluding AFP-positive non-HCC (liver cirrhosis), but also demonstrates improved performance in HCC surveillance, early diagnosis, treatment response and recurrence monitoring in the HBV-related population. PMID:27070780