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Sample records for esophageal squamous carcinoma

  1. Neoadjuvant treatment for esophageal squamous cell carcinoma

    PubMed Central

    Baba, Yoshifumi; Watanabe, Masayuki; Yoshida, Naoya; Baba, Hideo

    2014-01-01

    Squamous cell carcinoma and adenocarcinoma are types of esophageal cancer, one of the most aggressive malignant diseases. Since both histological types present entirely different diseases with different epidemiology, pathogenesis and tumor biology, separate therapeutic strategies should be developed against each type. While surgical resection remains the dominant therapeutic intervention for patients with operable esophageal squamous cell carcinoma (ESCC), alternative strategies are actively sought to reduce the frequency of post-operative local or distant disease recurrence. Such strategies are particularly sought in the preoperative setting. Currently, the optimal management of resectable ESCC differs widely between Western and Asian countries (such as Japan). While Western countries focus on neoadjuvant or definitive chemoradiotherapy, neoadjuvant chemotherapy followed by surgery is the standard treatment in Japan. Importantly, each country and region has established its own therapeutic strategy from the results of local randomized control trials. This review discusses the current knowledge, available data and information regarding neoadjuvant treatment for operable ESCC. PMID:24834142

  2. Chemoprevention of esophageal squamous cell carcinoma

    SciTech Connect

    Stoner, Gary D. Wang Lishu; Chen Tong

    2007-11-01

    Esophageal squamous cell carcinoma (SCC) is responsible for approximately one-sixth of all cancer-related mortality worldwide. This malignancy has a multifactorial etiology involving several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. Chemoprevention offers a viable alternative that could well be effective against the disease. Clinical investigations have shown that primary chemoprevention of this disease is feasible if potent inhibitory agents are identified. The Fischer 344 (F-344) rat model of esophageal SCC has been used extensively to investigate the biology of the disease, and to identify chemopreventive agents that could be useful in human trials. Multiple compounds that inhibit tumor initiation by esophageal carcinogens have been identified using this model. These include several isothiocyanates, diallyl sulfide and polyphenolic compounds. These compounds influence the metabolic activation of esophageal carcinogens resulting in reduced genetic (DNA) damage. Recently, a few agents have been shown to inhibit the progression of preneoplastic lesions in the rat esophagus into tumors. These agents include inhibitors of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and c-Jun [a component of activator protein-1 (AP-1)]. Using a food-based approach to cancer prevention, we have shown that freeze-dried berry preparations inhibit both the initiation and promotion/progression stages of esophageal SCC in F-344 rats. These observations have led to a clinical trial in China to evaluate the ability of freeze-dried strawberries to influence the progression of esophageal dysplasia to SCC.

  3. Endoscopic screening for esophageal squamous cell carcinoma.

    PubMed

    Roshandel, Gholamreza; Nourouzi, Alireza; Pourshams, Akram; Semnani, Shahryar; Merat, Shahin; Khoshnia, Masoud

    2013-06-01

    Esophageal cancer (EC) is the eighth common cancer and the sixth most common cause of death from cancer worldwide. Esophageal squamous cell carcinoma (ESCC) remains the most common type of EC in the developing world and an important health problem in high-risk areas. Most of ESCC cases present in late stages, resulting in delayed diagnosis and poor prognosis. Prevention is the most effective strategy to control ESCC. Primary and secondary preventive methods may be considered for ESCC. In primary prevention, we try to avoid known risk factors. The aim of the secondary preventive method (ESCC screening programs) is to detect and eliminate premalignant precursor lesion of ESCC, preventing its progression into advanced stages. Similar to all population-based screening programs, any screening for early detection of ESCC must be cost-effective; otherwise, screening may not be indicated in that population. Endoscopy with iodine staining has been accepted as a population-level ESCC screening program in some high-risk areas including parts of China. This method may be too expensive and invasive in other high-risk communities. Nonendoscopic methods may be more applicable in these populations for population-based screenings. The limitations (questionable validity and costs) of new endoscopic imaging modalities, including narrow-band imaging (NBI), made them inappropriate to be used in population-level ESCC screening programs. Low-cost, less-invasive endoscopic imaging methods with acceptable diagnostic performance may make screening of ESCC in high-risk areas cost-effective. PMID:23725069

  4. Oral Rigosertib for Squamous Cell Carcinoma

    ClinicalTrials.gov

    2016-05-18

    Head and Neck Squamous Cell Carcinoma; Anal Squamous Cell Carcinoma; Lung Squamous Cell Carcinoma; Cervical Squamous Cell Carcinoma; Esophageal Squamous Cell Carcinoma; Skin Squamous Cell Carcinoma; Penile Squamous Cell Carcinoma

  5. Personalized targeted therapy for esophageal squamous cell carcinoma.

    PubMed

    Kang, Xiaozheng; Chen, Keneng; Li, Yicheng; Li, Jianying; D'Amico, Thomas A; Chen, Xiaoxin

    2015-07-01

    Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic data, and identify the driver-gene mutations, pathways, and networks. The emergence of a legion of novel targeted agents has generated much hope and hype regarding more potent treatment regimens, but the accuracy of drug selection is still arguable. Other problems, such as cancer heterogeneity, drug resistance, exceptional responders, and side effects, have to be surmounted. Evolving topics in personalized oncology, such as interpretation of genomics data, issues in targeted therapy, research approaches for targeted therapy, and future perspectives, will be discussed in this editorial. PMID:26167067

  6. Personalized targeted therapy for esophageal squamous cell carcinoma

    PubMed Central

    Kang, Xiaozheng; Chen, Keneng; Li, Yicheng; Li, Jianying; D'Amico, Thomas A; Chen, Xiaoxin

    2015-01-01

    Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic data, and identify the driver-gene mutations, pathways, and networks. The emergence of a legion of novel targeted agents has generated much hope and hype regarding more potent treatment regimens, but the accuracy of drug selection is still arguable. Other problems, such as cancer heterogeneity, drug resistance, exceptional responders, and side effects, have to be surmounted. Evolving topics in personalized oncology, such as interpretation of genomics data, issues in targeted therapy, research approaches for targeted therapy, and future perspectives, will be discussed in this editorial. PMID:26167067

  7. [Chemoprevention of esophageal squamous cell carcinoma--clinical trials].

    PubMed

    Szumiło, Justyna

    2008-09-01

    Esophageal squamous cell carcinoma is one of the most lethal malignances of digestive tract. Epidemiological data confirmed influence of the diet especially Mediterranean one that decreases the risk of cancer. High consumption of fresh vegetables and fruits, mainly citrus and tea drinking, also has a beneficial effect on decreasing incidence of the cancer. High intake of various antioxidants and natural fibers found in the plant diet as well as prolonged administration of cyclooxygenase-inhibitors, especially aspirin, plays also a protective role. Results of sparse, prospective, randomized trials on chemoprevention of esophageal squamous cell carcinoma are not so unequivocal. Supplementation of six traditional Chinese herbs, retinamide and riboflavin provided the most promising effects, but intake of multiple vitamins and minerals, including calcium and decaffeinated green tea, was ineffective. However, the studies were performed on small populations inhabiting select Chinese provinces known for their high esophageal cancer incidence. Due to a number of limitations, the collected data cannot be compared directly to other populations who are exposed to different environmental factors and with different genetic predispositions. PMID:19112850

  8. Polycyclic aromatic hydrocarbons and esophageal squamous cell carcinoma.

    PubMed

    Roshandel, Gholamreza; Semnani, Shahryar; Malekzadeh, Reza; Dawsey, Sanford M

    2012-11-01

    Esophageal cancer (EC) is the 8th most common cancer and the 6th most frequent cause of cancer mortality worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common type of EC. Exposure to polycyclic aromatic hydrocarbons (PAHs) has been suggested as a risk factor for developing ESCC. In this paper we will review different aspects of the relationship between PAH exposure and ESCC. PAHs are a group of compounds that are formed by incomplete combustion of organic matter. Studies in humans have shown an association between PAH exposure and development of ESCC in many populations. The results of a recent case-control study in a high risk population in northeastern Iran showed a dramatic dose-response relationship between PAH content in non-tumor esophageal tissue (the target tissue for esophageal carcinogenesis) and ESCC case status, consistent with a causal role for PAH exposure in the pathogenesis of ESCC.  Identifying the main sources of exposure to PAHs may be the first and most important step in designing appropriate PAH-reduction interventions for controlling ESCC, especially in high risk areas. Coal smoke and drinking mate have been suggested as important modifiable sources of PAH exposure in China and Brazil, respectively. But the primary source of exposure to PAHs in other high risk areas for ESCC, such as northeastern Iran, has not yet been identified. Thus, environmental studies to determining important sources of PAH exposure should be considered as a high priority in future research projects in these areas. PMID:23102250

  9. Esophageal squamous cell carcinoma - precursor lesions and early diagnosis

    PubMed Central

    Lopes, Antonio Barros; Fagundes, Renato Borges

    2012-01-01

    Squamous cell carcinoma of the esophagus (SCCE) carries a poor prognosis due to late diagnosis. Early detection is highly desirable, since surgical and endoscopic resection offers the only possible cure for esophageal cancer. Population screening should be undertaken in high risk areas, and in low or moderate risk areas for people with risk factors (alcoholics, smokers, mate drinkers, history of head and neck cancer, achalasia and lye stricture of the esophagus). Esophageal balloon cytology is an easy and inexpensive sampling technique, but the current methods are insufficient for primary screening due to sampling errors. Conventional endoscopy with biopsy remains the standard procedure for the identification of pre-malignant and early malignant changes in esophageal mucosa and endoscopic detection. It may be enhanced by several techniques such as dye and optic chromoendoscopy, magnifying endoscopy, and optical-based spectroscopic and imaging modalities. Since more than 80% of SCCE deaths occur in developing countries, where expensive techniques such as narrow band imaging (NBI) and autofluorescence imaging are unavailable, the most cost-effective tool for targeting biopsies may be Lugol dye chromoendoscopy, since it is easy, accurate, inexpensive and available worldwide. In ideal conditions, or in developed countries, is it reasonable to think that optimal detection will require a combination of techniques, such as the combination of Lugol’s chromoendoscopy and NBI to identify esophageal areas that require further characterization by a high resolution technique. The efficacy and cost-effectiveness will determine whether these modalities will become part of standard endoscopy practice. PMID:22267978

  10. Photodynamic therapy in early esophageal squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Spinelli, Pasquale; Dal Fante, Marco; Mancini, Andrea; Massetti, Renato; Meroni, Emmanuele

    1995-03-01

    From 1/1985 to 7/1993, 18 patients underwent endoscopic photodynamic therapy (PDT) for early stage esophageal squamous cell carcinoma -- as two patients had two synchronous esophageal cancers, 20 lesions were treated. Tumors were staged as Tis in 7 cases and T1 in 13. The average light energy delivered was 50 J/cm2 and 70 J/cm2 for the treatment of Tis and T1, respectively. To obtain a more uniform distribution of laser light in 12 cases the irradiation was performed through the wall of a transparent tube previously placed over the endoscope and advanced into the stomach. The overall results show a complete response in 14/20 (70%) tumors. Three patients developed a local recurrence, 6, 12, and 14 months after therapy. After a follow-up of 5 to 75 months, there was no evidence of disease in 10/18 patients (56%). The actuarial survival rate was 95%, 79%, and 26% at 1, 3, and 5 years, respectively. Complications were skin reaction in one patient and esophageal stenosis at the treatment site, that gradually responded to endoscopic bougienage, in 2 patients. Endoscopic PDT proved to be safe and effective in the treatment of superficial carcinoma of the esophagus.

  11. Prognostic significance of phosphorylated RON in esophageal squamous cell carcinoma.

    PubMed

    Hui, Marco K C; Lai, Kenneth K Y; Chan, Kwok Wah; Luk, John M; Lee, Nikki P; Chung, Yvonne; Cheung, Leo C; Srivastava, Gopesh; Tsao, Sai Wah; Tang, Johnny C; Law, Simon

    2012-09-01

    Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer. RON is a transmembrane receptor overexpressed in various cancers; however, the clinical significance of its phosphorylated form (pRON) is not fully deciphered. This report is the first to investigate the expression and clinical significance of pRON in human ESCC. Quantitative polymerase chain reaction revealed an up-regulation of RON mRNA in 70% (7/10) of ESCC tissues when compared to the adjacent nontumor tissues. An overexpression of pRON protein was found in most of the ESCC cell lines studied (4/5) when compared to two non-neoplastic esophageal epithelial cells using immunoblot. In 64 ESCC tissues, pRON was localized at the cell membrane, cytoplasm and nucleus in 15 (23.4%), 63 (98.4%) and 61 (95.3%) cases using immunohistochemistry. Patients having high expression of cytoplasmic pRON significantly associated with shorter median survival when compared to those with low expression (25.41 months vs. 14.43 months), suggesting cytoplasmic pRON as a potential marker for poor prognosis in ESCC patients. PMID:22086736

  12. Human papillomavirus tumor infection in esophageal squamous cell carcinoma

    PubMed Central

    Ludmir, Ethan B.; Stephens, Sarah J.; Palta, Manisha; Willett, Christopher G.

    2015-01-01

    The association between human papillomavirus (HPV) and esophageal squamous cell carcinoma (ESCC) has been recognized for over three decades. Recently, multiple meta-analyses have drawn upon existing literature to assess the strength of the HPV-ESCC linkage. Here, we review these analyses and attempt to provide a clinically-relevant overview of HPV infection in ESCC. HPV-ESCC detection rates are highly variable across studies. Geographic location likely accounts for a majority of the variation in HPV prevalence, with high-incidence regions including Asia reporting significantly higher HPV-ESCC infection rates compared with low-incidence regions such as Europe, North America, and Oceania. Based on our examination of existing data, the current literature does not support the notion that HPV is a prominent carcinogen in ESCC. We conclude that there is no basis to change the current clinical approach to ESCC patients with respect to tumor HPV status. PMID:26029456

  13. Evaluation of preoperative staging for esophageal squamous cell carcinoma

    PubMed Central

    Luo, Lin-Na; He, Long-Jun; Gao, Xiao-Yan; Huang, Xin-Xin; Shan, Hong-Bo; Luo, Guang-Yu; Li, Yin; Lin, Shi-Yong; Wang, Guo-Bao; Zhang, Rong; Xu, Guo-Liang; Li, Jian-Jun

    2016-01-01

    Esophageal squamous cell carcinoma (ESCC) is known for its rapid progression and poor outcomes. China has the highest incidence and mortality in the world. Diagnoses made at early stages and accurate staging are associated with better outcomes, all of which can play a significant role in the selection of treatment protocols. ESCC is staged according to the widely accepted TNM system. Common imaging modalities used in staging ESCC before treatment include endoscopy, computed tomography (CT), positron emission tomography (PET) and magnetic resonance imaging (MRI). Endoscopic ultrasound is useful for staging tumor depth and nodal status. Narrow band imaging is valuable for early stage disease assessment. CT and PET provide additional valuable information regarding node and metastasis staging. The ability of MRI to delineate ESCC is continuously being improved and adds information regarding locoregional status to routine examinations. PMID:27547011

  14. A case of simultaneous esophageal squamous cell carcinoma and Barrett's adenocarcinoma.

    PubMed

    Yamazaki, Tomoo; Iwaya, Yugo; Iwaya, Mai; Watanabe, Takayuki; Seki, Ayako; Ochi, Yasuhide; Hara, Etsuo; Sekiguchi, Tomohiro; Hosaka, Noriko; Arakura, Norikazu; Tanaka, Eiji; Hasebe, Osamu

    2016-08-01

    A 77-year-old male with a long history of alcohol consumption and smoking was admitted for hoarseness and dysphagia. Computed tomography revealed thickening of the middle intrathoracic esophageal wall and multiple mediastinal lymph node swellings. Esophagogastroduodenoscopic examination disclosed an advanced-stage squamous cell carcinoma lesion in the middle intrathoracic esophagus with synchronous early stage Barrett's adenocarcinoma. The patient underwent endoscopic submucosal dissection for the adenocarcinoma followed by chemoradiation therapy for the squamous cell carcinoma. In spite of their common risk factors, the simultaneous manifestation of esophageal squamous cell carcinoma and Barrett's adenocarcinoma is extremely rare and requires further study. PMID:27220657

  15. Genomic and molecular characterization of esophageal squamous cell carcinoma

    PubMed Central

    Lin, De-Chen; Hao, Jia-Jie; Nagata, Yasunobu; Xu, Liang; Shang, Li; Meng, Xuan; Sato, Yusuke; Okuno, Yusuke; Varela, Ana Maria; Ding, Ling-Wen; Garg, Manoj; Liu, Li-Zhen; Yang, Henry; Yin, Dong; Shi, Zhi-Zhou; Jiang, Yan-Yi; Gu, Wen-Yue; Gong, Ting; Zhang, Yu; Xu, Xin; Kalid, Ori; Shacham, Sharon; Ogawa, Seishi; Wang, Ming-Rong; Koeffler, H. Phillip

    2014-01-01

    Esophageal squamous cell carcinoma (ESCC) is a world-wide prevalent cancer, which is particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified novel significantly mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to previously discovered ones (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Moreover, our approaches uncovered many novel druggable candidates, and XPO1 was further explored as a therapeutic target because of its mutation and protein overexpression. Together, our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets. PMID:24686850

  16. Genomic and molecular characterization of esophageal squamous cell carcinoma.

    PubMed

    Lin, De-Chen; Hao, Jia-Jie; Nagata, Yasunobu; Xu, Liang; Shang, Li; Meng, Xuan; Sato, Yusuke; Okuno, Yusuke; Varela, Ana Maria; Ding, Ling-Wen; Garg, Manoj; Liu, Li-Zhen; Yang, Henry; Yin, Dong; Shi, Zhi-Zhou; Jiang, Yan-Yi; Gu, Wen-Yue; Gong, Ting; Zhang, Yu; Xu, Xin; Kalid, Ori; Shacham, Sharon; Ogawa, Seishi; Wang, Ming-Rong; Koeffler, H Phillip

    2014-05-01

    Esophageal squamous cell carcinoma (ESCC) is prevalent worldwide and particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified previously uncharacterized mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to those already known (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Our approaches also uncovered many druggable candidates, and XPO1 was further explored as a therapeutic target because it showed both gene mutation and protein overexpression. Our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets. PMID:24686850

  17. Family history of esophageal cancer increases the risk of esophageal squamous cell carcinoma.

    PubMed

    Chen, Tiantian; Cheng, Hongwei; Chen, Xingdong; Yuan, Ziyu; Yang, Xiaorong; Zhuang, Maoqiang; Lu, Ming; Jin, Li; Ye, Weimin

    2015-01-01

    A population-based case-control was performed to explore familial aggregation of esophageal squamous cell carcinoma (ESCC). Family history of cancer was assessed by a structured questionnaire, and from which 2 cohorts of relatives of cases and controls were reconstructed. Unconditional logistic regression and Cox proportional hazards regression were applied for case-control design and reconstructed cohort design, respectively. We observed a close to doubled risk of ESCC associated with a positive family history of esophageal cancer among first degree relatives (odds ratio [OR] = 1.85, 95% confidence interval [CI]: 1.42-2.41), after adjusting age, sex, family size and other confounders. The excess risks of ESCC increased with the increasing of first-degree relatives affected by esophageal cancer (p < 0.001). In particular, those individuals whose both parents with esophageal cancer had an 8-fold excess risk of ESCC (95% CI: 1.74-36.32). The reconstructed cohort analysis showed that the cumulative risk of esophageal cancer to age 75 was 12.2% in the first-degree relatives of cases and 7.0% in those of controls (hazard ratio = 1.91, 95% CI: 1.54-2.37). Our results suggest family history of esophageal cancer significantly increases the risk for ESCC. Future studies are needed to understand how the shared genetic susceptibility and/or environmental exposures contribute to the observed excess risk. PMID:26526791

  18. Variations of gastric corpus microbiota are associated with early esophageal squamous cell carcinoma and squamous dysplasia

    PubMed Central

    Nasrollahzadeh, Dariush; Malekzadeh, Reza; Ploner, Alexander; Shakeri, Ramin; Sotoudeh, Masoud; Fahimi, Saman; Nasseri-Moghaddam, Siavosh; Kamangar, Farin; Abnet, Christian C.; Winckler, Björn; Islami, Farhad; Boffetta, Paolo; Brennan, Paul; Dawsey, Sanford M.; Ye, Weimin

    2015-01-01

    Observational studies revealed a relationship between changes in gastric mucosa and risk of esophageal squamous cell carcinoma (ESCC) which suggested a possible role for gastric microbiota in ESCC carcinogenesis. In this study we aimed to compare pattern of gastric corpus microbiota in ESCC with normal esophagus. Cases were included subjects with early ESCC (stage I–II) and esophageal squamous dysplasia (ESD) as the cancer precursor. Control groups included age and sex-matched subjects with mid-esophagus esophagitis (diseased-control), and histologically normal esophagus (healthy-control). DNA was extracted from snap-frozen gastric corpus tissues and 16S rRNA was sequenced on GS-FLX Titanium. After noise removal, an average of 3004 reads per sample was obtained from 93 subjects. We applied principal coordinate analysis to ordinate distances from beta diversity data. Pattern of gastric microbiota using Unifrac (p = 0.004) and weighted Unifrac distances (p = 0.018) statistically varied between cases and healthy controls. Sequences were aligned to SILVA database and Clostridiales and Erysipelotrichales orders were more abundant among cases after controling for multiple testing (p = 0.011). No such difference was observed between mid-esophagitis and healthy controls. This study is the first to show that composition of gastric corpus mucosal microbiota differs in early ESCC and ESD from healthy esophagus. PMID:25743945

  19. Expression of Cofilin-1 and Transgelin in Esophageal Squamous Cell Carcinoma

    PubMed Central

    Zhang, Yan; Liao, Ruyi; Li, Hui; Liu, Ling; Chen, Xiao; Chen, Hongming

    2015-01-01

    Background Esophageal squamous cell carcinoma (ESCC) has attracted much research attention around the world, and the number of ESCC cases has increased gradually in recent years. Identifying the specific biomarkers of ESCC is an effective approach for the early diagnosis of tumors. Material/Methods Immunohistochemical streptavidin-peroxidase method was used to determine the expressions of Cofilin-1 and transgelin in 68 patients with esophageal squamous cell carcinoma (ESCC) and 48 individuals with normal esophageal tissues. In addition to the relationships between the expression of Cofilin-1 and transgelin, the clinicopathologic features of ESCC were also discussed. The correlation between Cofilin-1 and transgelin protein expression in ESCC was analyzed. Results (1) The positive expression rates of Cofilin-1 and transgelin were 60.3% (41/68) and 54.4% (37/68) in esophageal carcinoma tissue, respectively. The positive expression rates of Cofilin-1 and transgelin in normal esophageal tissue were 27.1% (13/48) and 29.1% (14/48), respectively. The differences were statistically significant (P<0.05). (2) The positive expression rate of Cofilin-1 did not differ significantly (P>0.05) with sex, age, ethnicity, tumor size, or infiltration depth; but did have a statistically significant (P<0.05) difference with various degrees of tumor differentiation, lymph node metastasis, and clinical stages. (3) The positive expression rate of transgelin did not differ significantly (P>0.05) with sex, age, ethnicity, tumor size, infiltration depth, and clinical stage, but did significantly (P<0.05) differ with degree of tumor differentiation and lymph node metastasis. Conclusions Cofilin-1 and transgelin may play roles in the carcinogenesis and development of esophageal squamous cell carcinoma. Cofilin-1 may be useful as an important biomarker for indicating the degree of malignancy of esophageal squamous cell carcinoma, and the detection of transgelin is valuable in early diagnosis of

  20. Esophageal squamous cell carcinoma in six harbor seals (Phoca vitulina spp.).

    PubMed

    Flower, Jennifer E; Gamble, Kathryn C; Stone, Michael; Lyons, Jeremiah A; Maganti, Rajanikanth J; Tuomi, Pamela A; Olds, June E; Sims, Michele A; Gauger, Phillip; Tuttle, Allison D

    2014-09-01

    Six cases of esophageal squamous cell carcinoma were identified in six captive adult Pacific (Phoca vitulina richardsii; n = 2) and Atlantic (Phoca vitulina concolor; n = 4) harbor seals. These seals presented with intermittent dysphagia, regurgitation, inappetence, and abnormal posturing. Common clinical pathology findings in these seals included azotemia, hyperproteinemia, hyperglobulinemia, and leukocytosis. Gastrointestinal endoscopy commonly revealed an ulcerated mass near the gastroesophageal junction. Each seal was euthanized (n = 3) due to poor prognosis, subsequently died while undergoing an anesthetic procedure (n = 2), or found dead (n = 1). The diagnosis of squamous cell carcinoma was confirmed via biopsy of esophageal mucosa during endoscopy or histopathologic examination of affected tissues after necropsy. On the basis of clinical and postmortem findings, esophageal squamous cell carcinoma should be considered as a differential diagnosis in aged harbor seals exhibiting clinical signs of regurgitation, decreased appetite or anorexia, vomiting, and/or abnormal posturing. PMID:25314830

  1. Significance of Nuclear Accumulation of Foxo3a in Esophageal Squamous Cell Carcinoma

    SciTech Connect

    Chen, M.-F. Fang, F.-M.; Lu, C.-H.; Lu, M.-S.; Chen, W.-C.; Lee, K.-D.; Lin, P.-Y.

    2008-07-15

    Purpose: To investigate the value of Foxo3a in predicting the response to neoadjuvant treatment of, and prognosis for, esophageal squamous cell carcinoma. Methods and Materials: Immunohistochemical staining was performed in a retrospective series of 60 biopsied esophageal squamous cell carcinomas, and the correlation between nuclear accumulation of Foxo3a and clinicopathologic features was analyzed, including patient survival. In addition, in vitro biologic changes, radiosensitivity, and in vivo tumorigenicity of esophageal carcinoma cells after experimental manipulation of Foxo3a expression levels were determined. Results: Clinical findings point to a significant correlation between the nuclear accumulation of Foxo3a and the survival rate of esophageal cancer patients. In addition, Foxo3a is a significant predictor for the response to neoadjuvant therapy. In cell culture, irradiation and oxidative stress seemed to result in nuclear accumulation of Foxo3a. Down-regulation of Foxo3a significantly decreased radiosensitivity but had no obvious effect on tumor growth, as measured by a clonogenic assay in vitro and growth delay in vivo. Conclusions: Nuclear accumulation of Foxo3a in tumor cells was correlated with increased radiosensitivity and with improved patient survival. Thus, it is suggested that Foxo3a may be a potential marker for esophageal cancer.

  2. Protease-activated receptor (PAR)1, PAR2 and PAR4 expressions in esophageal squamous cell carcinoma

    PubMed Central

    LI, Si-Man; JIANG, Ping; XIANG, Yang; WANG, Wei-Wei; ZHU, Yue-Chun; FENG, Wei-Yang; LI, Shu-De; YU, Guo-Yu

    2014-01-01

    Here, we used reverse transcription-PCR (RT-PCR) and western blot to detect protease-activated receptor (PAR) 1, PAR 2 and PAR 4 expression in cancer tissues and cell lines of esophageal squamous cell carcinoma, and investigated the co-relationship between PAR expression and clinic-pathological data for esophageal cancer. The methylation of PAR4 gene promoter involved in esophageal carcinoma was also analyzed. By comparing the mRNA expressions of normal esophageal tissue and human esophageal epithelial cells (HEEpiC), we found that among the 28 cases of esophageal squamous cell carcinoma, PAR1 (60%) and PAR2 (71%) were elevated in 17 and 20 cases, respectively, and PAR4 (68%) expression was lowered in 19 cases. Whereas, in human esophageal squamous cells (TE-1 and TE-10), PAR1 and PAR2 expression was increased but PAR4 was decreased. Combined with clinical data, the expression of PAR1 in poorly differentiated (P=0.016) and middle and lower parts of the esophagus (P=0.016) was higher; expression of PAR4 in poorly differentiated carcinoma was lower (P=0.049). Regarding TE-1 and TE-10 protein expression, we found that in randomized esophageal carcinoma, PAR1 (P=0.027) and PAR2 (P=0.039) expressions were increased, but lowered for PAR4 (P=0.0001). In HEEpiC, TE-1, TE-10, esophageal and normal esophagus tissue samples (case No. 7), the frequency of methylation at the 19 CpG loci of PAR4 was 35.4%, 95.2%, 83.8%, 62.6% and 48.2%, respectively. Our results indicate that the expression of PAR1 and PAR2 in esophageal squamous cell carcinoma is increased but PAR4 is decreased. Hypermethylation of the promoter of the PAR4 gene may contribute to reduced expression of PAR4 in esophageal squamous cell carcinoma. PMID:25297082

  3. Cost-Effectiveness of Cetuximab for Advanced Esophageal Squamous Cell Carcinoma

    PubMed Central

    Bruno, Marco J.; Polinder, Suzanne; Lorenzen, Sylvie; Lordick, Florian; Peppelenbosch, Maikel P.; Spaander, Manon C. W.

    2016-01-01

    Background Costly biologicals in palliative oncology are emerging at a rapid pace. For example, in patients with advanced esophageal squamous cell carcinoma addition of cetuximab to a palliative chemotherapy regimen appears to improve survival. However, it simultaneously results in higher costs. We aimed to determine the incremental cost-effectiveness ratio of adding cetuximab to first-line chemotherapeutic treatment of patients with advanced esophageal squamous cell carcinoma, based on data from a randomized controlled phase II trial. Methods A cost effectiveness analysis model was applied based on individual patient data. It included only direct medical costs from the health-care perspective. Quality-adjusted life-years and incremental cost-effectiveness ratios were calculated. Sensitivity analysis was performed by a Monte Carlo analysis. Results Adding cetuximab to a cisplatin-5-fluorouracil first-line regimen for advanced esophageal squamous cell carcinoma resulted in an the incremental cost-effectiveness ratio of €252,203 per quality-adjusted life-year. Sensitivity analysis shows that there is a chance of less than 0.001 that the incremental cost-effectiveness ratio will be less than a maximum willingness to pay threshold of €40,000 per quality-adjusted life-year, which is representative for the threshold used in The Netherlands and other developed countries. Conclusions Addition of cetuximab to a cisplatin-5-fluorouracil first-line regimen for advanced esophageal squamous cell carcinoma is not cost-effective when appraised according to currently accepted criteria. Cost-effectiveness analyses using outcome data from early clinical trials (i.c. a phase II trial) enable pharmaceutical companies and policy makers to gain early insight into whether a new drug meets the current eligibility standards for reimbursement and thereby potential admittance for use in regular clinical practice. PMID:27100871

  4. Identification of a novel SEREX antigen family, ECSA, in esophageal squamous cell carcinoma

    PubMed Central

    2011-01-01

    Background Diagnosis of esophageal squamous cell carcinoma (SCC) may improve with early diagnosis. Currently it is difficult to diagnose SCC in the early stage because there is a limited number of tumor markers available. Results Fifty-two esophageal SCC SEREX antigens were identified by SEREX (serological identification of antigens by recombinant cDNA expression cloning) using a cDNA phage library and sera of patients with esophageal SCC. Sequence analysis revealed that three of these antigens were similar in amino acid sequences, and they were designated as ECSA (esophageal carcinoma SEREX antigen)-1, -2 and -3. The ECSA family was also similar to an EST clone, hepatocellular carcinoma-associated antigen 25a (HCA25a). Serum antibody levels to ECSA-1, -2 and -3 were significantly higher in patients with esophageal SCC than in healthy donors. Based on the conserved amino acid sequences, three peptides were synthesized and used for enzyme-linked immunosorbent assays (ELISA). The serum antibody levels against one of these peptides were significantly higher in patients with esophageal SCC. This peptide sequence was also conserved in FAM119A, GOSR1 and BBS5, suggesting that these are also ECSA family members. Reverse transcription followed by quantitative PCR analysis showed that the mRNA expression levels of ECSA-1, -2 and -3 and FAM119A but not of HCA25a, GOSR1 and BBS5 were frequently elevated in esophageal SCC tissues. Conclusions We have identified a new gene family designated ECSA. Serum antibodies against the conserved domain of the ECSA family may be a promising tumor marker for esophageal SCC. PMID:21696638

  5. The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma.

    PubMed

    Ma, Kai; Cao, Baoping; Guo, Mingzhou

    2016-01-01

    Esophageal cancer is one of the most common malignancies in the world. Squamous cell carcinoma accounts for approximately 90 % of esophageal cancer cases. Genetic and epigenetic changes have been found to accumulate during the development of various cancers, including esophageal squamous carcinoma (ESCC). Tobacco smoking and alcohol consumption are two major risk factors for ESCC, and both tobacco and alcohol were found to induce methylation changes in ESCC. Growing evidence demonstrates that aberrant epigenetic changes play important roles in the multiple-step processes of carcinogenesis and tumor progression. DNA methylation may occur in the key components of cancer-related signaling pathways. Aberrant DNA methylation affects genes involved in cell cycle, DNA damage repair, Wnt, TGF-β, and NF-κB signaling pathways, including P16, MGMT, SFRP2, DACH1, and ZNF382. Certain genes methylated in precursor lesions of the esophagus demonstrate that DNA methylation may serve as esophageal cancer early detection marker, such as methylation of HIN1, TFPI-2, DACH1, and SOX17. CHFR methylation is a late stage event in ESCC and is a sensitive marker for taxanes in human ESCC. FHIT methylation is associated with poor prognosis in ESCC. Aberrant DNA methylation changes may serve as diagnostic, prognostic, and chemo-sensitive markers. Characterization of the DNA methylome in ESCC will help to better understand its mechanisms and develop improved therapies. PMID:27110300

  6. SU-E-P-18: Intensity-Modulated Radiation Therapy for Cervical Esophageal Squamous Cell Carcinoma

    SciTech Connect

    Bai, W; Qiao, X; Zhou, Z; Song, Y; Zhang, R; Zhen, C

    2015-06-15

    Purpose: To retrospectively analyze the outcomes and prognostic factors of cervical esophageal squamous cell carcinoma (SCC) treated with intensity modulated radiation therapy (IMRT). Methods: Thirty-seven patients with cervical esophageal SCC treated with IMRT were analyzed retrospectively. They received 54–66 Gy in 27–32 fractions. Nineteen patients received concurrent (n=12) or sequential (n=7) platinum-based two drugs chemoradiotherapy. Overall survival (OS), local control rates (LCR) and prognostic factors were evaluated. Acute toxicities and patterns of first failures were observed. Results: The median follow-up was 46 months for alive patients. The l-, 3-, 4- and 5-year OS of the all patients were 83.8%, 59.1%, 47.5% and 32.6% respectively. The median survival time was 46 months. The l-, 3-,4- and 5-year LCR were 82.9%, 63.0%, 54.5% and 54.5%, respectively. Univariate and Multivariate analysis all showed that size of GTV was an independent prognostic factor (p=0.033, p=0.039). There were no patients with Grade 3 acute radiation esophagitis and Grade 2–4 acute pneumonitis. The local failure accounted for 70.0% of all treatment-related failures. Conclusion: IMRT is safe and effective in the treatment of cervical esophageal squamous cell carcinoma. Size of GTV is an independent prognostic factor. Local failure still remains the main reason of treatment failures. The authors declare no conflicts of interest in preparing this article.

  7. Influence of Metastatic Status and Number of Removed Lymph Nodes on Survival of Patients With Squamous Esophageal Carcinoma.

    PubMed

    Yuan, Feng; Qingfeng, Zheng; Jia, Wang; Chao, Lv; Shi, Yan; Yuzhao, Wang; Chao, An; Yue, Yang

    2015-12-01

    The aim of this study was to determine the impact of lymph node (LN) metastasis conditions on the prognosis of patients with esophageal squamous carcinoma and the minimum number of LNs that should be removed to maximize overall postoperative survival among patients with this specific pathologic subtype. In this study, 312 patients with thoracic squamous esophageal carcinoma who received in-patient thoracic surgery by the same surgeon in our hospital from August 1, 2003 to December 31, 2009 were recruited. Subsequently, Kaplan-Meier methods were used to determine associations between LN metastasis conditions and mortality and between the numbers of LNs removed during esophagectomy and mortality. Cox regression models were used to adjust for potential confounding covariates. According to Kaplan-Meier analyses, the number of metastatic LNs was a good predictor for the prognosis of patients with esophageal squamous carcinoma and the dissection of ≥ 29 LNs during thoracic surgery significantly improved patient survival (P = 0.011).Lymph node metastasis rates may be a significant predictor for the prognosis of patients with esophageal squamous carcinoma. The number of LNs removed during esophagectomy is an independent predictor for the survival of patients with esophageal squamous carcinoma with maximal postoperative survival after the removal of ≥ 29 LNs. PMID:26632887

  8. Influence of Metastatic Status and Number of Removed Lymph Nodes on Survival of Patients With Squamous Esophageal Carcinoma

    PubMed Central

    Yuan, Feng; Qingfeng, Zheng; Jia, Wang; Chao, Lv; Shi, Yan; Yuzhao, Wang; Chao, An; Yue, Yang

    2015-01-01

    Abstract The aim of this study was to determine the impact of lymph node (LN) metastasis conditions on the prognosis of patients with esophageal squamous carcinoma and the minimum number of LNs that should be removed to maximize overall postoperative survival among patients with this specific pathologic subtype. In this study, 312 patients with thoracic squamous esophageal carcinoma who received in-patient thoracic surgery by the same surgeon in our hospital from August 1, 2003 to December 31, 2009 were recruited. Subsequently, Kaplan-Meier methods were used to determine associations between LN metastasis conditions and mortality and between the numbers of LNs removed during esophagectomy and mortality. Cox regression models were used to adjust for potential confounding covariates. According to Kaplan-Meier analyses, the number of metastatic LNs was a good predictor for the prognosis of patients with esophageal squamous carcinoma and the dissection of ≥29 LNs during thoracic surgery significantly improved patient survival (P = 0.011). Lymph node metastasis rates may be a significant predictor for the prognosis of patients with esophageal squamous carcinoma. The number of LNs removed during esophagectomy is an independent predictor for the survival of patients with esophageal squamous carcinoma with maximal postoperative survival after the removal of ≥29 LNs. PMID:26632887

  9. Genetic polymorphism at codon 546 of the human RAD17 contributes to the risk for esophageal squamous cell carcinoma

    PubMed Central

    Yasuda, Yukiko; Sakai, Akiko; Ito, Sachio; Mita, Yuichiro; Sonoyama, Takayuki; Tanabe, Shunsuke; Shirakawa, Yasuhiro; Naomoto, Yoshio; Katayama, Hiroshi; Shimizu, Kenji

    2016-01-01

    Human RAD17, a human homolog of the Schizosaccharomyces pombe cell cycle checkpoint gene RAD17, plays a significant role in activating checkpoint signals in response to DNA damage. We evaluated the association of hRAD17 Leu546Arg (rs1045051), a missense single nucleotide polymorphism, with the risk of esophageal squamous cell carcinoma in relation to smoking and alcohol consumption history in 154 esophageal squamous cell carcinoma male patients and 695 cancer-free male controls by a case-control study conducted in Japan. The results showed that the hRAD17 Arg/Arg genotype compared to the Leu/Leu and Leu/Arg genotypes was significantly associated with the risk of the esophageal squamous cell carcinoma with an adjusted odds ratios of 2.22 (95% CI: 1.19-4.16 P=0.013). In stratified studies, the risk of esophageal squamous cell carcinoma was markedly higher in light drinkers (less than 23 g ethanol/day) with the Arg/Arg genotype than in heavy drinkers (excess of 23 g ethanol/day) with the Arg/Arg genotype (OR=2.83, 95% CI: 1.05-7.61, P=0.04). We concluded that the genetic variant of hRAD17 Leu546Arg polymorphism exerts a significant effect on esophageal squamous cell carcinoma risk among Japanese men. PMID:27186329

  10. Reduced nuclear and ectopic cytoplasmic expression of lysyl oxidase-like 2 is associated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma.

    PubMed

    Li, Tian-Yu; Xu, Li-Yan; Wu, Zhi-Yong; Liao, Lian-Di; Shen, Jin-Hui; Xu, Xiu-E; Du, Ze-Peng; Zhao, Qing; Li, En-Min

    2012-07-01

    Lysyl oxidase family members have various roles in cancer progression. The aim of this study was to investigate their expression and clinical significance in esophageal squamous cell carcinoma. We examined messenger RNA expression of lysyl oxidase family members including lysyl oxidase and lysyl oxidase-like proteins (lysyl oxidase L) in 10 esophageal squamous cell carcinoma cell lines and 83 pairs of tumor samples by quantitative real-time polymerase chain reaction. All except lysyl oxidase L3 were expressed at high levels in esophageal squamous cell carcinoma, but only lysyl oxidase L2 was associated with lymph node metastasis (P = .034). We examined lysyl oxidase L2 protein further by immunohistochemistry staining in 178 surgically resected esophageal squamous cell carcinoma tissue samples. The protein manifested decreased nuclear expression and increased cytoplasmic expression. Moreover, these 2 events both had significant correlation with the presence of lymph node metastasis (P = .001 and P < .001). Overall survival rates of the patients with esophageal squamous cell carcinoma with decreased nuclear expression or increased cytoplasmic expression of lysyl oxidase L2 were significantly lower than those of the patients with esophageal squamous cell carcinoma with the reverse expression pattern (P = .040 or P = .022). Multivariate analyses revealed that nuclear expression of lysyl oxidase L2 was an independent prognostic factor for esophageal squamous cell carcinoma. These results suggest that lysyl oxidase L2 exerts a critical effect on esophageal squamous cell carcinoma progression and can be a predictive marker of lymph node metastasis and outcome. PMID:22204712

  11. Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing.

    PubMed

    Sasaki, Yasushi; Tamura, Miyuki; Koyama, Ryota; Nakagaki, Takafumi; Adachi, Yasushi; Tokino, Takashi

    2016-02-21

    Two major types of cancer occur in the esophagus: squamous cell carcinoma, which is associated with chronic smoking and alcohol consumption, and adenocarcinoma, which typically arises in gastric reflux-associated Barrett's esophagus. Although there is increasing incidence of esophageal adenocarcinoma in Western counties, esophageal squamous cell carcinoma (ESCC) accounts for most esophageal malignancies in East Asia, including China and Japan. Technological advances allowing for massively parallel, high-throughput next-generation sequencing (NGS) of DNA have enabled comprehensive characterization of somatic mutations in large numbers of tumor samples. Recently, several studies were published in which whole exome or whole genome sequencing was performed in ESCC tumors and compared with matched normal DNA. Mutations were validated in several genes, including in TP53, CDKN2A, FAT1, NOTCH1, PIK3CA, KMT2D and NFE2L2, which had been previously implicated in ESCC. Several new recurrent alterations have also been identified in ESCC. Combining the clinicopathological characteristics of patients with information obtained from NGS studies may lead to the development of effective diagnostic and therapeutic approaches for ESCC. As this research becomes more prominent, it is important that gastroenterologist become familiar with the various NGS technologies and the results generated using these methods. In the present study, we describe recent research approaches using NGS in ESCC. PMID:26900290

  12. [A Case of Long-Term Survival of Advanced Esophageal Basaloid Squamous Carcinoma Invading the Trachea].

    PubMed

    Tokura, Michiyo; Yoshimura, Tetsunori; Murata, Tomohiro; Matsuyama, Takatoshi; Hoshino, Mayumi; Goto, Hiroshi; Kakimoto, Masaki; Koshiishi, Haruya

    2015-11-01

    A woman in her 50s complained of dysphagia and was diagnosed with locally advanced esophageal cancer in the middle and upper thoracic esophagus, invading the tracheal bronchus. The biopsy indicated esophageal basaloid squamous carcinoma. The pretreatment diagnosis was cT4N2M0, cStage Ⅳa. She was treated with systemic chemotherapy consisting of FAP (5-fluorouracil [5-FU], doxorubicin [DXR] and cisplatin[CDDP]), which resulted in significant tumor shrinkage. One year later, the tumor regrew, and nedaplatin (CDGP) plus docetaxel (DOC) was administered as second-line chemotherapy. The patient complained of dysphagia during the course of chemotherapy, and received radiation therapy for the residual tumor, which again significantly shrunk. Four years after the first round of chemotherapy, the patient can take oral nutrition, and is continuing to undergo chemotherapy. This is a case of long-term survival of locally advanced esophageal cancer of basaloid squamous carcinoma. Effective chemotherapy and radiation can improve the treatment outcome. PMID:26805208

  13. Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing

    PubMed Central

    Sasaki, Yasushi; Tamura, Miyuki; Koyama, Ryota; Nakagaki, Takafumi; Adachi, Yasushi; Tokino, Takashi

    2016-01-01

    Two major types of cancer occur in the esophagus: squamous cell carcinoma, which is associated with chronic smoking and alcohol consumption, and adenocarcinoma, which typically arises in gastric reflux-associated Barrett’s esophagus. Although there is increasing incidence of esophageal adenocarcinoma in Western counties, esophageal squamous cell carcinoma (ESCC) accounts for most esophageal malignancies in East Asia, including China and Japan. Technological advances allowing for massively parallel, high-throughput next-generation sequencing (NGS) of DNA have enabled comprehensive characterization of somatic mutations in large numbers of tumor samples. Recently, several studies were published in which whole exome or whole genome sequencing was performed in ESCC tumors and compared with matched normal DNA. Mutations were validated in several genes, including in TP53, CDKN2A, FAT1, NOTCH1, PIK3CA, KMT2D and NFE2L2, which had been previously implicated in ESCC. Several new recurrent alterations have also been identified in ESCC. Combining the clinicopathological characteristics of patients with information obtained from NGS studies may lead to the development of effective diagnostic and therapeutic approaches for ESCC. As this research becomes more prominent, it is important that gastroenterologist become familiar with the various NGS technologies and the results generated using these methods. In the present study, we describe recent research approaches using NGS in ESCC. PMID:26900290

  14. Molecular Mechanisms of Ethanol-associated Oro-esophageal Squamous Cell Carcinoma

    PubMed Central

    Liu, Yao; Chen, Hao; Sun, Zheng; Chen, Xiaoxin

    2016-01-01

    Alcohol drinking is a major etiological factor of oro-esophageal squamous cell carcinoma (OESCC). Both local and systemic effects of ethanol may promote carcinogenesis, especially among chronic alcoholics. However, molecular mechanisms of ethanol-associated OESCC are still not well understood. In this review, we summarize current understandings and propose three mechanisms of ethanol-associated OESCC: (1) Disturbance of systemic metabolism of nutrients: during ethanol metabolism in the liver, systemic metabolism of retinoids, zinc, iron and methyl groups is altered. These nutrients are known to be associated with the development of OESCC. (2) Disturbance of redox metabolism in squamous epithelial cells: when ethanol is metabolized in oro-esophageal squamous epithelial cells, reactive oxygen species are generated and produce oxidative damage. Meanwhile, ethanol may also disturb fatty-acid metabolism in these cells. (3) Disturbance of signaling pathways in squamous epithelial cells: due to its physico-chemical properties, ethanol changes cell membrane fluidity and shape, and may thus impact multiple signaling pathways. Advanced molecular techniques in genomics, epigenomics, metabolomics and microbiomics will help us elucidate how ethanol promotes OESCC. PMID:25766659

  15. Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma.

    PubMed

    Liu, Yao; Chen, Hao; Sun, Zheng; Chen, Xiaoxin

    2015-06-01

    Alcohol drinking is a major etiological factor of oro-esophageal squamous cell carcinoma (OESCC). Both local and systemic effects of ethanol may promote carcinogenesis, especially among chronic alcoholics. However, molecular mechanisms of ethanol-associated OESCC are still not well understood. In this review, we summarize current understandings and propose three mechanisms of ethanol-associated OESCC: (1) Disturbance of systemic metabolism of nutrients: during ethanol metabolism in the liver, systemic metabolism of retinoids, zinc, iron and methyl groups is altered. These nutrients are known to be associated with the development of OESCC. (2) Disturbance of redox metabolism in squamous epithelial cells: when ethanol is metabolized in oro-esophageal squamous epithelial cells, reactive oxygen species are generated and produce oxidative damage. Meanwhile, ethanol may also disturb fatty-acid metabolism in these cells. (3) Disturbance of signaling pathways in squamous epithelial cells: due to its physico-chemical properties, ethanol changes cell membrane fluidity and shape, and may thus impact multiple signaling pathways. Advanced molecular techniques in genomics, epigenomics, metabolomics and microbiomics will help us elucidate how ethanol promotes OESCC. PMID:25766659

  16. Squamous esophageal carcinoma and mucinous adenocarcinoma of the colon - an unusual association.

    PubMed

    Mirea, Cecil Sorin; Vasile, Manuela Ioana; Vîlcea, Ionică Daniel; Vasile, Ion; Moraru, Emil; Ciorbagiu, Mihai Călin; Sfeclan, Maria Cristina; Marin, Cătălina; Obleagă, Vasile Cosmin; Gheonea, Ioana Andreea; Vîlcea, Alina Maria

    2016-01-01

    The existence of a simultaneous cancer of the esophagus and colon is a rare situation that recognizes an increased incidence in recent years in the world, probably as a result of the improved measures of diagnosis and treatment, as well as the development of screening programs. The aim of this work is to present a case of synchronous esophageal squamous carcinoma with mucinous adenocarcinoma of the hepatic angle of the colon. The patient was hospitalized to our Surgical Clinic with the thoracic squamous esophageal carcinoma diagnosis. On admission, symptoms were dominated by overall dysphagia, patient showing a weight loss of 10 kg for the last 30 days. Preoperative imaging tests did not revealed regional or distant metastatic disease. Preoperative colonoscopy was incomplete (only until the splenic angle of the left colon) due to the insufficient mechanical preparation. On laparotomy, a carcinoma of the hepatic angle of the colon, partially stenosing was discovered. An upper pole esogastrectomy with intrathoracic esogastrostomy and a right colectomy with ileotransversostomy were practiced, at the same operative session. Postoperative evolution was poor and the patient died on the ninth day from the surgery during an alcohol withdrawal crisis. PMID:27151719

  17. None-endoscopic Screening for Esophageal Squamous Cell Carcinoma- A Review

    PubMed Central

    Roshandel, Gholamreza; Semnani, Shahryar; Malekzadeh, Reza

    2012-01-01

    Esophageal cancer (EC) is the eighth most common cancer and sixth most frequent cause of cancer mortality worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common type of EC. ESCC develops by progression from premalignant lesions, which are called esophageal squamous dysplasia (ESD). Prevention is the most effective strategy for controlling this disease. Generally, two methods may be defined for ESCC prevention. The aim of the first preventive method is to prevent the initiation of ESD by avoiding the known risk factors, or primary prevention. Secondary prevention focuses on detection of the disease in its early curable stage, thus preventing its progression into advanced stages. Endoscopy with iodine staining and biopsy is the diagnostic choice for ESD. However it is invasive and expensive, and not accepted by asymptomatic ESD cases. Therefore, it is necessary to find a non-endoscopic screening method. Despite the large number of studies conducted worldwide, no approved method has been developed for ESCC screening. Regarding the multi-factorial nature of ESCC, it is proposed that the use of a combination of various criteria, such as cytological examination, risk factors, genetic alteration, and molecular markers may result in the development of a comprehensive and effective ESCC screening program. PMID:24829644

  18. None-endoscopic Screening for Esophageal Squamous Cell Carcinoma- A Review.

    PubMed

    Roshandel, Gholamreza; Semnani, Shahryar; Malekzadeh, Reza

    2012-04-01

    Esophageal cancer (EC) is the eighth most common cancer and sixth most frequent cause of cancer mortality worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common type of EC. ESCC develops by progression from premalignant lesions, which are called esophageal squamous dysplasia (ESD). Prevention is the most effective strategy for controlling this disease. Generally, two methods may be defined for ESCC prevention. The aim of the first preventive method is to prevent the initiation of ESD by avoiding the known risk factors, or primary prevention. Secondary prevention focuses on detection of the disease in its early curable stage, thus preventing its progression into advanced stages. Endoscopy with iodine staining and biopsy is the diagnostic choice for ESD. However it is invasive and expensive, and not accepted by asymptomatic ESD cases. Therefore, it is necessary to find a non-endoscopic screening method. Despite the large number of studies conducted worldwide, no approved method has been developed for ESCC screening. Regarding the multi-factorial nature of ESCC, it is proposed that the use of a combination of various criteria, such as cytological examination, risk factors, genetic alteration, and molecular markers may result in the development of a comprehensive and effective ESCC screening program. PMID:24829644

  19. Postoperative radiation in esophageal squamous cell carcinoma and target volume delineation

    PubMed Central

    Zhu, Yingming; Li, Minghuan; Kong, Li; Yu, Jinming

    2016-01-01

    Esophageal cancer is the sixth leading cause of cancer death worldwide, and patients who are treated with surgery alone, without neoadjuvant therapies, experience frequent relapses. Whether postoperative therapies could reduce the recurrence or improve overall survival is still controversial for these patients. The purpose of our review is to figure out the value of postoperative adjuvant therapy and address the disputes about target volume delineation according to published data. Based on the evidence of increased morbidity and disadvantages on patient survival caused by postoperative chemotherapy or radiotherapy (RT) alone provided by studies in the early 1990s, the use of postoperative adjuvant therapies in cases of esophageal squamous cell carcinoma has diminished substantially and has been replaced gradually by neoadjuvant chemoradiation. With advances in surgery and RT, accumulating evidence has recently rekindled interest in the delivery of postoperative RT or chemoradiotherapy in patients with stage T3/T4 or N1 (lymph node positive) carcinomas after radical surgery. However, due to complications with the standard radiation field, a nonconforming modified field has been adopted in most studies. Therefore, we analyze different field applications and provide suggestions on the optimization of the radiation field based on the major sites of relapse and the surgical non-clearance area. For upper and middle thoracic esophageal carcinomas, the bilateral supraclavicular and superior mediastinal areas remain common sites of recurrence and should be encompassed within the clinical target volume. In contrast, a consensus has yet to be reached regarding lower thoracic esophageal carcinomas; the “standard” clinical target volume is still recommended. Further studies of larger sample sizes should focus on different recurrence patterns, categorized by tumor locations, refined classifications, and differing molecular biology, to provide more information on the

  20. The Discovery and Validation of Biomarkers for the Diagnosis of Esophageal Squamous Dysplasia and Squamous Cell Carcinoma.

    PubMed

    Couch, George; Redman, James E; Wernisch, Lorenz; Newton, Richard; Malhotra, Shalini; Dawsey, Sanford M; Lao-Sirieix, Pierre; Fitzgerald, Rebecca C

    2016-07-01

    The 5-year survival rate of esophageal cancer is less than 10% in developing countries, where more than 90% of these cancers are esophageal squamous cell carcinomas (ESCC). Endoscopic screening is undertaken in high incidence areas. Biomarker analysis could reduce the subjectivity associated with histologic assessment of dysplasia and thus improve diagnostic accuracy. The aims of this study were therefore to identify biomarkers for esophageal squamous dysplasia and carcinoma. A publicly available dataset was used to identify genes with differential expression in ESCC compared with normal esophagus. Each gene was ranked by a support vector machine separation score. Expression profiles were examined, before validation by qPCR and IHC. We found that 800 genes were overexpressed in ESCC compared with normal esophagus (P < 10(-5)). Of the top 50 genes, 33 were expressed in ESCC epithelium and not in normal esophagus epithelium or stroma using the Protein Atlas website. These were taken to qPCR validation, and 20 genes were significantly overexpressed in ESCC compared with normal esophagus (P < 0.05). TNFAIP3 and CHN1 showed differential expression with IHC. TNFAIP3 expression increased gradually through normal esophagus, mild, moderate and severe dysplasia, and SCC (P < 0.0001). CHN1 staining was rarely present in the top third of normal esophagus epithelium and extended progressively towards the surface in mild, moderate, and severe dysplasia, and SCC (P < 0.0001). Two novel promising biomarkers for ESCC were identified, TNFAIP3 and CHN1. CHN1 and TNFAIP3 may improve diagnostic accuracy of screening methods for ESCC. Cancer Prev Res; 9(7); 558-66. ©2016 AACR. PMID:27072986

  1. Noncoding RNA Expression Aberration Is Associated with Cancer Progression and Is a Potential Biomarker in Esophageal Squamous Cell Carcinoma

    PubMed Central

    Sugihara, Hidetaka; Ishimoto, Takatsugu; Miyake, Keisuke; Izumi, Daisuke; Baba, Yoshifumi; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo

    2015-01-01

    Esophageal cancer is one of the most common cancers worldwide. Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancer in Eastern Asian countries. Several types of noncoding RNAs (ncRNAs) function as key epigenetic regulators of gene expression and are implicated in various physiological processes. Unambiguous evidence indicates that dysregulation of ncRNAs is deeply implicated in carcinogenesis, cancer progression and metastases of various cancers, including ESCC. The current review summarizes recent findings on the ncRNA-mediated mechanisms underlying the characteristic behaviors of ESCC that will help support the development of biomarkers and the design of novel therapeutic strategies. PMID:26610479

  2. Targeting WISP1 to sensitize esophageal squamous cell carcinoma to irradiation

    PubMed Central

    Peng, Jin; Jiang, Zhenzhen; Song, Tao; Wu, Bo; Yue, Jing; Zhou, Rongjing; Xie, Ruifei; Chen, Tian; Wu, Shixiu

    2015-01-01

    Radiotherapy is a primary treatment modality for esophageal squamous cell carcinoma (ESCC). However, most of patients benefited little from radiotherapy due to refractory radioresistance. We found that WISP1, a downstream target gene of Wnt/β-catenin pathway, was re-expressed in 67.3 % of ESCC patients as an oncofetal gene. Expression of WISP1 predicted prognosis of ESCC patients treated with radiotherapy. Overall survival in WISP1-positive patients was significantly poorer than in WISP1-negative patients. Serum concentration of WISP1 after radiotherapy reversely correlated with relapse-free survival. Gain and loss of function studies confirmed that WISP1 mediated radioresistance both in esophageal squamous cancer cells and in xenograft tumor models. Further studies revealed that WISP1 contributed to radioresistance primarily by repressing irradiation-induced DNA damage and activating PI3K kinase. LncRNA BOKAS was up-regulated following radiation and promoted WISP1 expression and resultant radioresistance. Furthermore, WISP1 facilitated its own expression in response to radiation, creating a positive feedback loop and increased radioresistance. Our study revealed WISP1 as a potential target to overcome radioresistance in ESCC.  PMID:25749038

  3. Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma

    PubMed Central

    Zhang, Hongfang; Luo, Honglei; Jiang, Zhenzhen; Yue, Jing; Hou, Qiang; Xie, Ruifei; Wu, Shixiu

    2016-01-01

    The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT-associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy. PMID:27125498

  4. Downregulation of S100 Calcium Binding Protein A9 in Esophageal Squamous Cell Carcinoma

    PubMed Central

    Pawar, Harsh; Srikanth, Srinivas M.; Kashyap, Manoj Kumar; Sathe, Gajanan; Chavan, Sandip; Singal, Mukul; Manju, H. C.; Kumar, Kariyanakatte Veeraiah Veerendra; Vijayakumar, M.; Sirdeshmukh, Ravi; Pandey, Akhilesh; Prasad, T. S. Keshava; Gowda, Harsha; Kumar, Rekha V.

    2015-01-01

    The development of esophageal squamous cell carcinoma (ESCC) is poorly understood and the major regulatory molecules involved in the process of tumorigenesis have not yet been identified. We had previously employed a quantitative proteomic approach to identify differentially expressed proteins in ESCC tumors. A total of 238 differentially expressed proteins were identified in that study including S100 calcium binding protein A9 (S100A9) as one of the major downregulated proteins. In the present study, we carried out immunohistochemical validation of S100A9 in a large cohort of ESCC patients to determine the expression and subcellular localization of S100A9 in tumors and adjacent normal esophageal epithelia. Downregulation of S100A9 was observed in 67% (n = 192) of 288 different ESCC tumors, with the most dramatic downregulation observed in the poorly differentiated tumors (99/111). Expression of S100A9 was restricted to the prickle and functional layers of normal esophageal mucosa and localized predominantly in the cytoplasm and nucleus whereas virtually no expression was observed in the tumor and stromal cells. This suggests the important role that S100A9 plays in maintaining the differentiated state of epithelium and suggests that its downregulation may be associated with increased susceptibility to tumor formation. PMID:26788548

  5. XRCC3 is a promising target to improve the radiotherapy effect of esophageal squamous cell carcinoma.

    PubMed

    Cheng, Jingjing; Liu, Weiran; Zeng, Xianliang; Zhang, Bin; Guo, Yihang; Qiu, Minghan; Jiang, Chao; Wang, Huanhuan; Wu, Zhiqiang; Meng, Maobin; Zhuang, Hongqing; Zhao, Lujun; Hao, Jihui; Cai, Qingqing; Xie, Dan; Pang, Qingsong; Wang, Ping; Yuan, Zhiyong; Qian, Dong

    2015-12-01

    Radiotherapy is widely applied for treatment of esophageal squamous cell carcinoma (ESCC). The Rad51-related protein XRCC3 plays roles in the recombinational repair of DNA double-strand breaks to maintain chromosome stability and repair DNA damage. The present study aimed to investigate the effect of XRCC3 on the radiotherapy response of ESCC and the underlying mechanisms of the roles of XRCC3 in ESCC radiosensitivity. XRCC3 expression in ESCC cells and tissues was higher than that in normal esophageal epithelial cells and corresponding adjacent noncancerous esophageal tissue. High XRCC3 expression was positively correlated with resistance to chemoradiotherapy in ESCC and an independent predictor for short disease-specific survival of ESCC patients. Furthermore, the therapeutic efficacy of radiotherapy in vitro and in vivo was substantially increased by knockdown of XRCC3 in ESCC cells. Ectopic overexpression of XRCC3 in both XRCC3-silenced ESCC cells dramatically enhanced ESCC cells' resistance to radiotherapy. Moreover, radiation resistance conferred by XRCC3 was attributed to enhancement of homologous recombination, maintenance of telomere stability, and a reduction of ESCC cell death by radiation-induced apoptosis and mitotic catastrophe. Our data suggest that XRCC3 protects ESCC cells from ionizing radiation-induced death by promoting DNA damage repair and/or enhancing telomere stability. XRCC3 may be a novel radiosensitivity predictor and promising therapeutic target for ESCC. PMID:26383967

  6. Rapid and sensitive detection of early esophageal squamous cell carcinoma with fluorescence probe targeting dipeptidylpeptidase IV.

    PubMed

    Onoyama, Haruna; Kamiya, Mako; Kuriki, Yugo; Komatsu, Toru; Abe, Hiroyuki; Tsuji, Yosuke; Yagi, Koichi; Yamagata, Yukinori; Aikou, Susumu; Nishida, Masato; Mori, Kazuhiko; Yamashita, Hiroharu; Fujishiro, Mitsuhiro; Nomura, Sachiyo; Shimizu, Nobuyuki; Fukayama, Masashi; Koike, Kazuhiko; Urano, Yasuteru; Seto, Yasuyuki

    2016-01-01

    Early detection of esophageal squamous cell carcinoma (ESCC) is an important prognosticator, but is difficult to achieve by conventional endoscopy. Conventional lugol chromoendoscopy and equipment-based image-enhanced endoscopy, such as narrow-band imaging (NBI), have various practical limitations. Since fluorescence-based visualization is considered a promising approach, we aimed to develop an activatable fluorescence probe to visualize ESCCs. First, based on the fact that various aminopeptidase activities are elevated in cancer, we screened freshly resected specimens from patients with a series of aminopeptidase-activatable fluorescence probes. The results indicated that dipeptidylpeptidase IV (DPP-IV) is specifically activated in ESCCs, and would be a suitable molecular target for detection of esophageal cancer. Therefore, we designed, synthesized and characterized a series of DPP-IV-activatable fluorescence probes. When the selected probe was topically sprayed onto endoscopic submucosal dissection (ESD) or surgical specimens, tumors were visualized within 5 min, and when the probe was sprayed on biopsy samples, the sensitivity, specificity and accuracy reached 96.9%, 85.7% and 90.5%. We believe that DPP-IV-targeted activatable fluorescence probes are practically translatable as convenient tools for clinical application to enable rapid and accurate diagnosis of early esophageal cancer during endoscopic or surgical procedures. PMID:27245876

  7. Rapid and sensitive detection of early esophageal squamous cell carcinoma with fluorescence probe targeting dipeptidylpeptidase IV

    PubMed Central

    Onoyama, Haruna; Kamiya, Mako; Kuriki, Yugo; Komatsu, Toru; Abe, Hiroyuki; Tsuji, Yosuke; Yagi, Koichi; Yamagata, Yukinori; Aikou, Susumu; Nishida, Masato; Mori, Kazuhiko; Yamashita, Hiroharu; Fujishiro, Mitsuhiro; Nomura, Sachiyo; Shimizu, Nobuyuki; Fukayama, Masashi; Koike, Kazuhiko; Urano, Yasuteru; Seto, Yasuyuki

    2016-01-01

    Early detection of esophageal squamous cell carcinoma (ESCC) is an important prognosticator, but is difficult to achieve by conventional endoscopy. Conventional lugol chromoendoscopy and equipment-based image-enhanced endoscopy, such as narrow-band imaging (NBI), have various practical limitations. Since fluorescence-based visualization is considered a promising approach, we aimed to develop an activatable fluorescence probe to visualize ESCCs. First, based on the fact that various aminopeptidase activities are elevated in cancer, we screened freshly resected specimens from patients with a series of aminopeptidase-activatable fluorescence probes. The results indicated that dipeptidylpeptidase IV (DPP-IV) is specifically activated in ESCCs, and would be a suitable molecular target for detection of esophageal cancer. Therefore, we designed, synthesized and characterized a series of DPP-IV-activatable fluorescence probes. When the selected probe was topically sprayed onto endoscopic submucosal dissection (ESD) or surgical specimens, tumors were visualized within 5 min, and when the probe was sprayed on biopsy samples, the sensitivity, specificity and accuracy reached 96.9%, 85.7% and 90.5%. We believe that DPP-IV-targeted activatable fluorescence probes are practically translatable as convenient tools for clinical application to enable rapid and accurate diagnosis of early esophageal cancer during endoscopic or surgical procedures. PMID:27245876

  8. Connexin 43 expression is associated with poor survival in patients with esophageal squamous cell carcinoma

    PubMed Central

    TANAKA, TATSUYA; KIMURA, MASAHIRO; ISHIGURO, HIDEYUKI; MIZOGUCHI, KOUJI; TAKEYAMA, HIROMITSU

    2016-01-01

    Connexin 43 (Cx43) is an important gap junction protein in vertebrates, which has been reported to function as a tumor suppressor in a number of organs. However, the mechanism underlying the effect of Cx43 on tumor progression remains unknown, with only a limited number of studies reporting on the role of Cx43 in esophageal cancer. In the present study, Cx43 expression was analyzed by immunohistochemical staining and the associations between Cx43 expression and clinicopathological characteristics or prognosis were evaluated. Cx43 was expressed at a high frequency in patients with esophageal squamous cell carcinoma (ESCC). Of the 98 ESCC cases investigated, positivity for Cx43 was observed in 62 cases (63.26%). In patients with high Cx43 expression, the survival rates were significantly reduced compared with those in patients with low Cx43 expression. Moreover, the overexpression of Cx43, as measured by immunohistochemistry, was an independent prognostic indicator of ESCC. Thus, our data indicated that Cx43 may be a candidate molecular prognostic marker and molecular target for the development of an effective therapeutic intervention for patients with esophageal cancer. PMID:27284434

  9. Interaction between Esophageal Squamous Cell Carcinoma and Adipose Tissue in Vitro.

    PubMed

    Nakayama, Atsushi; Aoki, Shigehisa; Uchihashi, Kazuyoshi; Nishijima-Matsunobu, Aki; Yamamoto, Mihoko; Kakihara, Nahoko; Iwakiri, Ryuichi; Fujimoto, Kazuma; Toda, Shuji

    2016-05-01

    Esophageal squamous cell carcinoma (ESCC) develops within the squamous epithelial layer and invades the submucosa to the subadventitia that has adipose tissue (AT). AT seems critical to ESCC progression, but the underlying mechanism is unknown. We aimed to address the association between ESCC and AT in vitro. ESCC cells were cultured on rat or human subcutaneous AT-embedded or -non-embedded collagen gel. AT promoted the growth of ESCC cells and inhibited their apoptosis. AT promoted the expression of the squamous differentiation marker involucrin in ESCC cells. AT accelerated the expression of invasion-related factors in poorly differentiated ESCC cells only. AT promoted the expression of phosphorylated-insulin-like growth factor-1 receptor in ESCC cells, whereas it inhibited that of the human epidermal growth factor receptor 2. Insulin-like growth factor-1, but not leptin, adiponectin, or resistin, promoted and inhibited the growth and apoptosis of ESCC cells, respectively. In turn, ESCC cells decreased the production of these adipokines in AT and the number of preadipocytes and mesenchymal stem cell-like cells, which developed from AT. These results suggest that i) AT may influence the progression of ESCC with increased growth or invasion and decreased apoptosis through insulin-like growth factor-1/insulin-like growth factor-1 receptor signaling, ii) AT may affect human epidermal growth factor receptor 2-targeted therapy; and iii) the cancer cells may affect adipokine production in AT. PMID:26952643

  10. Transcriptome network analysis reveals potential candidate genes for esophageal squamous cell carcinoma.

    PubMed

    Ma, Zheng; Guo, Wei; Niu, Hui-Jun; Yang, Fan; Wang, Ru-Wen; Jiang, Yao-Guang; Zhao, Yun-Ping

    2012-01-01

    The esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with a poor prognosis. Understanding molecular changes in ESCC should improve identification of risk factors with different molecular subtypes and provide potential targets for early detection and therapy. Our study aimed to obtain a molecular signature of ESCC through the regulation network based on differentially expressed genes (DEGs). We used the GSE23400 series to identify potential genes related to ESCC. Based on bioinformatics we constructed a regulation network. From the results, we could establish that many transcription factors and pathways closely related with ESCC were linked by our method. STAT1 also arose as a hub node in our transcriptome network, along with some transcription factors like CCNB1, TAP1, RARG and IFITM1 proven to be related with ESCC by previous studies. In conclusion, our regulation network provided information on important genes which might be useful in investigating the complex interacting mechanisms underlying the disease. PMID:22631645

  11. Genetic variants and risk of esophageal squamous cell carcinoma: A GWAS-based pathway analysis

    PubMed Central

    Yang, Xi; Zhu, Hongcheng; Qin, Qin; Yang, Yuehua; Yang, Yan; Cheng, Hongyan; Sun, Xinchen

    2015-01-01

    This study was designed to identify candidate single-nucleotide polymorphisms (SNPs) that may affect the susceptibility to esophageal squamous cell carcinoma (ESCC) and elucidate their potential mechanisms to generate SNP-to-gene-to-pathway hypotheses. A genome-wide association study (GWAS) dataset for ESCC, which included 453,852 SNPs from 1898 ESCC patients and 2100 control subjects of Chinese population, was reviewed. The identify candidate causal SNPs and pathways (ICSNPathway) analysis identified seven candidate SNPs, five genes, and seven pathways, which together revealed seven hypothetical biological mechanisms. The three strongest hypothetical biological mechanisms were as follows: rs4135113 → TDG → BASE EXCISION REPAIR; rs1800450 → MBL2 → MONOSACCHARIDE BINDING; and rs3769823 → CASP8 → d4gdiPathway. The GWAS dataset was evaluated using the ICSNPathway, which showed seven candidate SNPs, five genes, and seven pathways that may contribute to the susceptibility of patients to ESCC. PMID:25431829

  12. Overexpression of Dishevelled-2 contributes to proliferation and migration of human esophageal squamous cell carcinoma.

    PubMed

    Zhou, Guoren; Ye, Jinjun; Sun, Lei; Zhang, Zhi; Feng, Jifeng

    2016-06-01

    Dishevelled-2 (Dvl2) was associated with tumor cell proliferation and migration. We aimed to examine the mechanism of Dvl2 in esophageal squamous cell carcinoma (ESCC). Dvl2 was overexpressed in human ESCC tissues and cell lines ECA109 and TE1 cells. CCK-8 and colony formation assay was performed to evaluate the proliferation in ECA109 cells transfected with Dvl2-shRNA. Wound-healing assay and transwell assay were used to examine the activities of migration and invasion in Dvl2-silenced ESCC cells. Knockdown of Dvl2 significantly reduced ECA109 cell proliferation and migration. Moreover, we demonstrated that the proliferation and migration ability of Dvl2 might through the activation of Wnt pathway by targeting the Cyclin D1 and MMP-9. We came to the conclusion that the proliferation and migration effects of Dvl2 might contribute to malignant development of human ESCC. PMID:27083564

  13. RASSF8 downregulation promotes lymphangiogenesis and metastasis in esophageal squamous cell carcinoma

    PubMed Central

    Huang, Shu-Ting; Xu, Jing; Yuan, Lin-Jing; Huang, Long; Zhou, Yun; Yu, Xing-Juan; Wu, Shao-Yun; Luo, Rong-Zhen; Yun, Jing-Ping; Jia, Wei-Hua; Zheng, Min

    2015-01-01

    Lymphatic vessels are the major routes of human esophageal squamous cell carcinoma (ESCC) metastasis. Tumor cells secrete pro-lymphangiogenic factors to induce new lymphatic vessels, promoting lymph node metastasis. In this study, we show that RAS association domain family 8 (RASSF8) expression in ESCC clinical samples was inversely correlated with lymph node metastasis and patients survival. Tumor cells with low RASSF8 expression had higher apparent migratory ability, and promoted and lymphangiogenesis both in vitro and in vivo. RASSF8 downregulation enhanced VEGF-C expression and caused subcellular redistribution of p65 in ESCC. Our results show that RASSF8 acts as a tumor suppressor in ESCC and is a potential therapeutic target for preventing lymph node metastasis. PMID:26439687

  14. The role of microRNA in esophageal squamous cell carcinoma.

    PubMed

    Harada, Kazuto; Baba, Yoshifumi; Ishimoto, Takatsugu; Shigaki, Hironobu; Kosumi, Keisuke; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo

    2016-06-01

    MicroRNAs (miRNA) are 22-nucleotide non-coding RNAs that post-transcriptionally regulate gene expression by base pairing to partially complementary sequences in the 3'-untranslated region of their target messenger RNA. Altered miRNA expression also changes the expression of oncogenes and tumor suppressors, affecting the proliferation, apoptosis, motility and invasibility of gastrointestinal cancer cells, including the cells of esophageal squamous cell carcinoma (ESCC). It has been suggested that various miRNA expression profiles may provide useful biomarkers and therapeutic targets, but to date few studies have been published on the role of miRNA in ESCC. In this review we summarize the identification and characterization of miRNAs involved in ESCC and discuss their potential as biomarkers and therapeutic targets. PMID:26794004

  15. Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts.

    PubMed

    Kretschmer, Inga; Freudenberger, Till; Twarock, Sören; Yamaguchi, Yu; Grandoch, Maria; Fischer, Jens W

    2016-02-19

    The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less α-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4(+) but not CD8(+) cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response. PMID:26699196

  16. High Intrathoracic Anastomosis with Thoracoscopy Is Safe and Feasible for Treatment of Esophageal Squamous Cell Carcinoma

    PubMed Central

    Jeon, Hyun Woo; Park, Jae Kil; Song, Kyo Young; Sung, Sook Whan

    2016-01-01

    Background Minimally invasive esophagectomy (MIE) has the potential to reduce the morbidity and mortality of esophageal cancer surgery. Esophageal squamous cell carcinoma (ESCC) has a high incidence of earlier lymphatic spread and is usually located more proximal to the incisor than esophageal adenocarcinoma; consequently, the anastomosis should be made more proximal in the thorax or in the neck. We adopted the proximal intrathoracic anastomotic technique using thoracoscopy for mid-to-lower ESCC. Methods From October 2010 to August 2014, fifty-eight consecutive patients underwent MIE for ESCC. After laparoscopic gastric tubing, thoracoscopic esophageal resection and reconstruction were performed using a 28-mm circular stapler following radical mediastinal lymph node dissection. We tried to make an anastomosis at the apex of the chest. Postoperative outcomes, including overall survival and recurrence, were assessed. Results The mean patient age was 64.3±9 years. The mean operative time was 371.8±51.6 minutes, and the duration of the thorax procedure was 254.8±38.3 minutes. The mean number of lymph nodes dissected was 31±11.7. The mean intensive care unit (ICU) stay and hospital stay were 3.5±8.2 hours and 13.6±7.4 days, respectively. The level of anastomosis was 22.3±1.8cm from the incisor. One patient died of uncontrolled sepsis due to necrosis of the gastric graft. Two patients developed small contained leakage. Nine patients exhibited distant metastasis during the follow-up period. Conclusion Thoracoscopic intrathoracic anastomosis at the proximal esophagus is feasible and safe. PMID:27011160

  17. Knockdown of DDX46 inhibits proliferation and induces apoptosis in esophageal squamous cell carcinoma cells.

    PubMed

    Li, Bin; Li, Yu-Min; He, Wen-Ting; Chen, Hao; Zhu, Hong-Wen; Liu, Tao; Zhang, Jian-Hua; Song, Tie-Niu; Zhou, Ya-Li

    2016-07-01

    Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal carcinoma and remains the leading cause of cancer-related death worldwide. DEAD-box RNA helicases play critical roles in cellular metabolism and in many cases have been implicated in cellular proliferation and neoplastic transformation. DDX46 belongs to DEAD-box helicase family, the expression pattern of DDX46 in ESCC tissues and the biologic role in ESCC progression have not been implicated previously. In this study, DDX46 expression in human ESCC and adjacent normal tissues were explored using immunohistochemistry, and ESCC cell lines compared with normal esophageal epithelium cell were quantified using real‑time PCR. Next, lentivirus-mediated RNA interference was applied to silence DDX46 in TE-1 and Eca-109 cells. Cell growth was monitored using high content screening. Cell viability was measured by MTT assay. Cell colony-forming capacity was measured by colony formation assay. Cell cycle progression and apoptosis were determined by flow cytometry. Further, the stress and apoptosis signaling antibody array kit was used to detect the changes of signaling molecules in TE-1 cells after DDX46 knockdown. We found that DDX46 was significantly upregulated in ESCC tissues and cells compared with normal tissues and cells. DDX46 knockdown led to decreased proliferation and increased apoptosis in TE-1 and Eca-109 cells. Moreover, DDX46 silencing resulted in apoptotic induction via decreased phosphorylation of Akt and IκBα, as well as negative regulation of NF-κB signaling. In conclusion, these results demonstrate that DDX46 knockdown inhibited cell growth, and induced apoptosis, suggest that DDX46 is critical for ESCC cells proliferation. In addition, this study provides a foundation for further study into the clinical potential diagnosis and novel therapeutic target for ESCC. PMID:27176873

  18. FGFR1 Amplification Is Often Homogeneous and Strongly Linked to the Squamous Cell Carcinoma Subtype in Esophageal Carcinoma

    PubMed Central

    Burkhardt, Lia; Simon, Ronald; Steurer, Stefan; Burdak-Rothkamm, Susanne; Jacobsen, Frank; Sauter, Guido; Krech, Till

    2015-01-01

    Background and Aims Amplification of the fibroblast growth factor receptor 1 (FGFR1) is believed to predict response to multi-kinase inhibitors targeting FGFR1. Esophageal cancer is an aggressive disease, for which novel targeted therapies are highly warranted. Methods This study was designed to investigate the prevalence and clinical significance of FGFR1 amplification in a tissue microarray containing 346 adenocarcinomas and 254 squamous cell carcinomas of the esophagus, using dual-labeling fluorescence in situ hybridization (FISH) analysis. Results FGFR1 amplification, defined as a ratio of FGFR1:centromere 8 copy numbers ≥ 2.0, was more frequently seen in squamous cell carcinoma (8.9% of 202 interpretable cases) than in adenocarcinoma (1.6% of 308; p<0.0001). There was no association between FGFR1 amplification and tumor phenotype or clinical outcome. To study potential heterogeneity of FGFR1 amplification, all available tumor blocks from 23 FGFR1 amplified tumors were analyzed on conventional large sections. This analysis revealed complete homogeneity of FGFR1 amplification in 20 (86.9%) primary tumors and in all available lymph node metastases. Remarkably, FGFR1 amplification was also seen in dysplasia adjacent to tumor in 6 of 9 patients with FGFR1 amplified primary cancers. Conclusions In conclusion, FGFR1 amplification occurs in a relevant subgroup of carcinomas of the esophagus and may play a particular role for development of squamous cell cancers. The high homogeneity of FGFR1 amplification suggests that patients with FGFR1 amplified esophageal cancers may particularly benefit from anti-FGFR1 therapies and prompt for clinical studies in this tumor type. PMID:26555375

  19. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling

    PubMed Central

    Feng, Y; Ke, C; Tang, Q; Dong, H; Zheng, X; Lin, W; Ke, J; Huang, J; Yeung, S-CJ; Zhang, H

    2014-01-01

    The antidiabetic drug metformin exerts chemopreventive and antineoplastic effects in many types of malignancies. However, the mechanisms responsible for metformin actions appear diverse and may differ in different types of cancer. Understanding the molecular and cellular mechanisms specific for different cancers is important to optimize strategy for metformin treatment in different cancer types. Here, we investigate the in vitro and in vivo effects of metformin on esophageal squamous cell carcinoma (ESCC) cells. Metformin selectively inhibited cell growth in ESCC tumor cells but not immortalized noncancerous esophageal epithelial cells. In addition to apoptosis, metformin triggered autophagy. Pharmacological or genetic inhibition of autophagy sensitized ESCC cells to metformin-induced apoptotic cell death. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream target Bcl-2 was inactivated by metformin treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced metformin-induced autophagy and apoptosis, and concomitantly enhanced the inhibitory effect of metformin on cell viability. Similarly, the Bcl-2 proto-oncogene, an inhibitor of both apoptosis and autophagy, was repressed by metformin. Ectopic expression of Bcl-2 protected cells from metformin-mediated autophagy and apoptosis. In vivo, metformin downregulated Stat3 activity and Bcl-2 expression, induced apoptosis and autophagy, and inhibited tumor growth. Together, inactivation of Stat3-Bcl-2 pathway contributes to metformin-induced growth inhibition of ESCC by facilitating crosstalk between apoptosis and autophagy. PMID:24577086

  20. ICAM1 Is a Potential Cancer Stem Cell Marker of Esophageal Squamous Cell Carcinoma

    PubMed Central

    Tsai, Sheng-Ta; Wang, Po-Jen; Liou, Nia-Jhen; Lin, Pei-Shan; Chen, Chung-Hsuan; Chang, Wei-Chao

    2015-01-01

    Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer diagnosed in Asian countries, with its incidence on the rise. Cancer stem cell (CSC; also known as tumor-initiating cells, TIC) is inherently resistant to cytotoxic chemotherapy and radiation and associates with poor prognosis and therapy failure. Targeting therapy against cancer stem cell has emerged as a potential therapeutic approach to develop effective regimens. However, the suitable CSC marker of ESCC for identification and targeting is still limited. In this study, we screened the novel CSC membrane protein markers using two distinct stemness characteristics of cancer cell lines by a comparative approach. After the validation of RT-PCR, qPCR and western blot analyses, intercellular adhesion molecule 1 (ICAM1) was identified as a potential CSC marker of ESCC. ICAM1 promotes cancer cell migration, invasion as well as increasing mesenchymal marker expression and attenuating epithelial marker expression. In addition, ICAM1 contributes to CSC properties, including sphere formation, drug resistance, and tumorigenesis in mouse xenotransplantation model. Based on the analysis of ICAM1-regulated proteins, we speculated that ICAM1 regulates CSC properties partly through an ICAM1-PTTG1IP-p53-DNMT1 pathway. Moreover, we observed that ICAM1 and CD44 could have a compensation effect on maintaining the stemness characteristics of ESCC, suggesting that the combination of multi-targeting therapies should be under serious consideration to acquire a more potent therapeutic effect on CSC of ESCC. PMID:26571024

  1. High DEPTOR expression correlates with poor prognosis in patients with esophageal squamous cell carcinoma

    PubMed Central

    Liu, Nan-bo; Zhang, Jun-hua; Liu, Yu-fan; Li, Jun; Zhang, Zhen-zhong; Li, Ji-wei; Liu, Wen-yue; Huang, Chen; Shen, Tao; Gu, Cheng-wei; Gao, Dong-yun; Wu, Xia; Wu, Xu

    2015-01-01

    Objective The disheveled, Egl-10, and pleckstrin (DEP) domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) is a binding protein containing mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), and an endogenous mTOR inhibitor. DEPTOR shows abnormal expressions in numerous types of solid tumors. However, how DEP-TOR is expressed in esophageal squamous cell carcinoma (ESCC) remains elusive. Methods The expression of DEPTOR in 220 cases of ESCC and non-cancerous adjacent tissues was detected by immunohistochemistry. DEPTOR levels in ESCC and paired normal tissue were quantified using reverse transcription-polymerase chain reaction and Western blot analysis to verify the immunohistochemical results. The relationship between DEPTOR expression and the clinicopathological features of ESCC was analyzed based on the results of immunohistochemistry. Finally, we analyzed the relationship between DEPTOR expression and the prognosis of patients with ESCC. Results Immunohistochemical staining showed that the expression rate of DEPTOR in ESCC tissues was significantly increased. DEPTOR mRNA and protein expression was significantly higher in ESCC tissues than in normal adjacent esophageal squamous tissues. High DEPTOR expression was significantly correlated with regional lymph node status in the TNM stage of patients with ESCC. Kaplan–Meier survival curves showed that the rate of overall survival was significantly lower in patients with high DEPTOR expression than in those with low DEPTOR expression. Additionally, high DEPTOR expression was an independent prognostic predictor for ESCC patients. Conclusion High DEPTOR expression is an independent prognostic biomarker indicating a worse prognosis for patients with ESCC. PMID:26640385

  2. Endoscopic surveillance of head and neck cancer in patients with esophageal squamous cell carcinoma

    PubMed Central

    Kato, Minoru; Ishihara, Ryu; Hamada, Kenta; Tonai, Yusuke; Yamasaki, Yasushi; Matsuura, Noriko; Kanesaka, Takashi; Yamamoto, Sachiko; Akasaka, Tomofumi; Hanaoka, Noboru; Takeuchi, Yoji; Higashino, Koji; Uedo, Noriya; Iishi, Hiroyasu

    2016-01-01

    Background and study aims: Multiple squamous cell carcinomas (SCCs) frequently arise in the upper aerodigestive tract, referred to as the field cancerization phenomenon. The aim of this study was to elucidate the detailed clinical features of second primary head and neck (H&N) SCCs arising in patients with esophageal SCC. Patients and methods: A total of 818 patients underwent endoscopic resection for superficial esophageal cancer between January 2006 and December 2013. Of these, 439 patients met our inclusion criteria, and we retrospectively investigated the incidence, primary sites, and stages of second primary H&N SCCs in these patients. Results: A total of 53 metachronous H&N SCCs developed in 40 patients after a median follow-up period of 46 months (range 9 – 109). The cumulative incidence rates of metachronous H&N SCCs at 3, 5, and 7 years were 5.3 %, 9.7 %, and 17.2 %, respectively. These lesions were frequently located at pyriform sinus or in the posterior wall of the pharynx (70 %, 37/53 lesions). Most of the lesions were detected at an early stage, though 4 lesions were associated with lymph node metastasis when their primary sites were detected (1 postcricoid area, 2 posterior wall of hypopharynx, and 1 lateral wall of oropharynx). Conclusions: Patients with esophageal SCC should undergo careful inspection of the pyriform sinus and posterior wall of the pharynx for detection of H&N SCCs. Methods to open the hypopharyngeal space, such as the Valsalva maneuver, should be included in the surveillance program. PMID:27556090

  3. Anticancer effects of crocetin in human esophageal squamous cell carcinoma KYSE-150 cells

    PubMed Central

    LI, SHENG; JIANG, SHENG; JIANG, WEI; ZHOU, YUE; SHEN, XIU-YIN; LUO, TAO; KONG, LING-PING; WANG, HUA-QIAO

    2015-01-01

    Crocetin is the main pharmacologically-active component of saffron and has been considered as a promising candidate for cancer chemoprevention. The purpose of the present study was to investigate the anticancer effects of crocetin and the possible mechanisms of these properties in the esophageal squamous cell carcinoma cell line KYSE-150. The KYSE-150 cells were cultured in Dulbecco’s modified Eagle’s medium and incubated with 0, 12.5, 25, 50, 100 or 200 μmol/l crocetin for 48 h. Cell proliferation was measured using an MTT assay. Hoechst 33258 staining and observation under fluorescent microscopy were used to analyze the proapoptotic effects of crocetin. The migration rate was assessed by a wound-healing assay. The cell cycle distribution was analyzed using flow cytometry analysis subsequent to propidium iodide staining. The expression of B-cell lymphoma-2-associated X protein (Bax) and cleaved caspase 3 was determined by western blot analysis. It was found that treatment of KYSE-150 cells with crocetin for 48 h significantly inhibited the proliferation of the cells in a concentration-dependent manner, and the inhibition of proliferation was associated with S phase arrest. Crocetin was also found to induce morphological changes and cell apoptosis in a dose-dependent manner through increased expression of proapoptotic Bax and activated caspase 3. In addition, crocetin suppressed the migration of KYSE-150 cells. The present study provides evidence that crocetin exerts a prominent chemopreventive effect against esophageal cancer through the inhibition of cell proliferation, migration and induction of apoptosis. These findings reveal that crocetin may be considered to be a promising future chemotherapeutic agent for esophageal cancer therapy. PMID:25663893

  4. Prognostic factors for salvage endoscopic resection for esophageal squamous cell carcinoma after chemoradiotherapy or radiotherapy alone

    PubMed Central

    Kondo, Shinya; Tajika, Masahiro; Tanaka, Tsutomu; Kodaira, Takeshi; Mizuno, Nobumasa; Hara, Kazuo; Hijioka, Susumu; Imaoka, Hiroshi; Goto, Hidemi; Yamao, Kenji; Niwa, Yasumasa

    2016-01-01

    Background and study aims: Endoscopic resection is one treatment option for residual or locally recurrent esophageal cancer after definitive chemoradiotherapy or radiotherapy alone. However, little is known about the clinical benefit of salvage endoscopic resection for these lesions. Therefore, the effectiveness and prognostic factors of salvage endoscopic resection were investigated. Patients and methods: A total of 37 patients with esophageal squamous cell carcinoma (SCC) who underwent salvage endoscopic resection after definitive chemoradiotherapy or radiotherapy alone were reviewed. The method of salvage endoscopic resection was endoscopic mucosal resection using a cap (EMR-C), strip biopsy, or endoscopic submucosal dissection. The effectiveness and prognostic factors of salvage endoscopic resection were retrospectively analyzed. Results: A total of 37 patients with 49 lesions underwent salvage endoscopic resection. Baseline clinical stages were I in 23 patients, II in 3 patients, III in 9 patients, and IV in 2 patients. The number of locoregional recurrences and residual lesions were 35 and 14, respectively. The curative en bloc resection rate was 53.1 % (26/49). The total incidence of complications was 18.9 % (7/37); all were successfully managed conservatively. The 3-year and 5-year overall survival rates were 72.9 % and 53.3 %, respectively, with a median follow-up period of 54 months. Baseline clinical T1 – 2 and N0 were significant factors for good prognosis in terms of overall survival on univariate analysis. Conclusions: Salvage endoscopic resection, especially EMR-C, is a safe and feasible procedure to control residual or recurrent superficial esophageal SCC after definitive chemoradiotherapy or radiotherapy alone. The present results showed that baseline clinical T1 – 2 and N0 before chemoradiotherapy or radiotherapy were significant prognostic factors. PMID:27540571

  5. Penile and intramuscular metastases from esophageal squamous cell carcinoma: A rare case report and review of the literature

    PubMed Central

    Ci, Zou; Dexin, Yu; Qi, Wang; Tao, Zhang; Dongdong, Xie; Yi, Wang; Demao, Ding; Lei, Chen; Jie, Min; Zhiqiang, Zhang; Jiaxing, Ma; Daming, Wang

    2014-01-01

    We present a case with penile and intramuscular metastases of esophageal squamous cell carcinoma. A 61-year-old male had undergone a total esophagectomy and later developed metastatic nodules of the penis and intramuscular metastasis of the thigh. We believe this is the first report of this rare case. We describe the clinical manifestation and offer therapeutic regimen; we also summarize the relevant literature. PMID:25485020

  6. Improvement in the Results of Surgical Treatment of Advanced Squamous Esophageal Carcinoma During 15 Consecutive Years

    PubMed Central

    Ando, Nobutoshi; Ozawa, Soji; Kitagawa, Yuko; Shinozawa, Yotaro; Kitajima, Masaki

    2000-01-01

    Objective To document the clinicopathologic characteristics and survival of patients undergoing esophagectomy for squamous carcinoma of the thoracic esophagus, and to examine the factors contributing to improvements in outcome noted in patients with advanced carcinoma. Summary Background Data Japanese and some Western surgeons recently have reported that radical esophagectomy with extensive lymphadenectomy conferred a survival advantage to patients with esophageal carcinoma. The factors contributing to this improvement in results have not been well defined. Methods From 1981 to 1995, 419 patients with carcinoma of the thoracic esophagus underwent esophagectomy at the Keio University Hospital. The clinicopathologic characteristics and survival of patients treated between 1981 and 1987 were compared with those of patients treated between 1988 and 1995. Multivariate analysis using the Cox regression model was carried out to evaluate the impact of 15 variables on survival of patients with p stage IIa to IV disease. Several variables related to prognosis were examined to identify differences between the two time periods. Results The 5-year survival rate for all patients was 40.0%. The 5-year survival rate was 17.7% for p stage IIa to IV patients treated during the earlier period and 37.6% for those treated during the latter period. The Cox regression model revealed seven variables to be important prognostic factors. Of these seven, three (severity of postoperative complications, degree of residual tumor, and number of dissected mediastinal nodes) were found to be significantly different between the earlier and latter periods. Conclusions The survival of patients undergoing surgery for advanced carcinoma (p stage IIa to IV) of the thoracic esophagus has improved during the past 15 years. The authors’ data suggest that this improvement is due mainly to advances in surgical technique and perioperative management. PMID:10903602

  7. [Peptide vaccine therapy with TLR-9 agonist for patients with esophageal squamous cell carcinoma].

    PubMed

    Katsuda, Masahiro; Iwahashi, Makoto; Matsuda, Kenji; Miyazawa, Motoki; Nakamori, Mikihito; Nakamura, Masaki; Naka, Teiji; Ojima, Toshiyasu; Iida, Takeshi; Yamaue, Hiroki

    2011-11-01

    Patients with advanced carcinoma are thought to have an impaired immune surveillance system. Therefore, the potent helper action is required for the induction of an antitumor immune response in such patients. We evaluated the efficacy of CpG-ODN, which is TLR-9 agonist, as cancer vaccine adjuvant through in vitro experiments. We also conducted a phase I clinical trial for patients with advanced esophageal squamous cell carcinoma (ESCC) using peptide vaccine in combination with CpG-B. In vitro experiments showed that CpG-ODN caused various immune-modifications, suggesting an efficacy of CpG-ODN as peptide vaccine adjuvant. Moreover, the immune monitoring data in phase I clinical trial suggested that CpG-B augmented the generation of antigen-specific T cell responses and innate immunity. These data indicated that the vaccination with cancer-testis antigen derived peptide in combination with CpG-B may be useful as a new immunotherapy for patients with advanced ESCC. PMID:22202246

  8. Expression and clinical significance of Apollon in esophageal squamous cell carcinoma

    PubMed Central

    Li, Rong; Chen, Bo-lin; Zhou, Yan-wu; Guo, Ren-wei; Shuai, Meng-ting; Zeng, Jun-xian; Leng, Ai-min

    2016-01-01

    Apollon, an unusually large member of the inhibitors of apoptosis protein family, may be important for oncogenesis development. The aim of the present study was to assess the association between esophageal squamous cell carcinoma (ESCC) and Apollon expression levels, and to highlight the association between Apollon and the occurrence, development and prognosis of ESCC. Apollon expression was detected by immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction in ESCC tissues, adjacent non-cancerous tissues and paired normal tissues respectively, in order to analyze the association between Apollon expression and the clinicopathological features of ESCC. Survival analysis was used to assess the prognostic significance of Apollon expression. It was determined that the mRNA and protein expression levels of Apollon were significantly higher in the carcinoma tissues compared with the adjacent non-cancerous tissues and normal control tissues (P<0.001). There was a significant difference in lymph node involvement and the tumor, nodes, and metastases stage in patients categorized according to different Apollon expression levels. The prognostic significance of Apollon was also determined using the log-rank method. The overexpression of Apollon was associated with shorter overall survival and disease-free survival rates. The present study indicates that Apollon expression is associated with the biological characteristics of ESCC, and may be a valuable prognostic factor and a novel chemotherapeutic target for ESCC treatment. PMID:27432467

  9. Is there a role of whole-body bone scan in patients with esophageal squamous cell carcinoma

    PubMed Central

    2012-01-01

    Background Correct detection of bone metastases in patients with esophageal squamous cell carcinoma is pivotal for prognosis and selection of an appropriate treatment regimen. Whole-body bone scan for staging is not routinely recommended in patients with esophageal squamous cell carcinoma. The aim of this study was to investigate the role of bone scan in detecting bone metastases in patients with esophageal squamous cell carcinoma. Methods We retrospectively evaluated the radiographic and scintigraphic images of 360 esophageal squamous cell carcinoma patients between 1999 and 2008. Of these 360 patients, 288 patients received bone scan during pretreatment staging, and sensitivity, specificity, positive predictive value, and negative predictive value of bone scan were determined. Of these 360 patients, surgery was performed in 161 patients including 119 patients with preoperative bone scan and 42 patients without preoperative bone scan. Among these 161 patients receiving surgery, 133 patients had stages II + III disease, including 99 patients with preoperative bone scan and 34 patients without preoperative bone scan. Bone recurrence-free survival and overall survival were compared in all 161 patients and 133 stages II + III patients, respectively. Results The diagnostic performance for bone metastasis was as follows: sensitivity, 80%; specificity, 90.1%; positive predictive value, 43.5%; and negative predictive value, 97.9%. In all 161 patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0.009, univariately). In multivariate comparison, absence of preoperative bone scan (P = 0.012, odds ratio: 5.053) represented the independent adverse prognosticator for bone recurrence-free survival. In 133 stages II + III patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0

  10. Slug down-regulation by RNA interference inhibits invasion growth in human esophageal squamous cell carcinoma

    PubMed Central

    2011-01-01

    Background Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive carcinomas of the gastrointestinal tract. We assessed the relevance of Slug in measuring the invasive potential of ESCC cells in vitro and in vivo in immunodeficient mice. Methods We utilized RNA interference to knockdown Slug gene expression, and effects on survival and invasive carcinoma were evaluated using a Boyden chamber transwell assay in vitro. We evaluated the effect of Slug siRNA-transfection and Slug cDNA-transfection on E-cadherin and Bcl-2 expression in ESCC cells. A pseudometastatic model of ESCC in immunodeficient mice was used to assess the effects of Slug siRNA transfection on tumor metastasis development. Results The EC109 cell line was transfected with Slug-siRNA to knockdown Slug expression. The TE13 cell line was transfected with Slug-cDNA to increase Slug expression. EC109 and TE13 cell lines were tested for the expression of apoptosis-related genes bcl-2 and metastasis-related gene E-cadherin identified previously as Slug targets. Bcl-2 expression was increased and E-cadherin was decreased in Slug siRNA-transfected EC109 cells. Bcl-2 expression was increased and E-cadherin was decreased in Slug cDNA-transfected TE13 cells. Invasion of Slug siRNA-transfected EC109 cells was reduced and apoptosis was increased whereas invasion was greater in Slug cDNA-transfected cells. Animals injected with Slug siRNA-transfected EC109 cells exhihited fewer seeded nodes and demonstrated more apoptosis. Conclusions Slug down-regulation promotes cell apoptosis and decreases invasion capability in vitro and in vivo. Slug inhibition may represent a novel strategy for treatment of metastatic ESCC. PMID:21599940

  11. The influence of prediagnostic demographic and lifestyle factors on esophageal squamous cell carcinoma survival.

    PubMed

    Thrift, Aaron P; Nagle, Christina M; Fahey, Paul P; Russell, Anne; Smithers, Bernard M; Watson, David I; Whiteman, David C

    2012-09-01

    Demographic and lifestyle factors, in particular tobacco smoking and alcohol, are well established causes of esophageal squamous cell carcinoma (ESCC); however, little is known about the effect of these factors on survival. We included all 301 patients with incident ESCC, recruited into a population-based case-control study of esophageal cancer in Australia. Detailed information about demographic and lifestyle factors was obtained at diagnosis, and deaths were identified using the National Death Index. Median follow-up for all-cause mortality was 6.4 years. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were calculated from Cox proportional hazards models, adjusted for age, sex, pretreatment AJCC tumor stage, treatment and presence of comorbidities. Two hundred and thirteen patients (71%) died during follow-up. High lifetime alcohol consumption was independently associated with poor survival. Relative to life-long nondrinkers and those consuming<1 drink/week, the HRs for those with average consumption of 7-20 drinks/week or ≥21 drinks/week were 2.21 (95% CI=1.27-3.84) and 2.08 (95% CI=1.18-3.69), respectively. There was a suggestion of worse survival among current smokers (HR=1.42, 95% CI=0.89-2.28); however, the risk of early death was greatest among current smokers who reported regularly (≥7 drinks/week) consuming alcohol (HR=3.84, 95% CI=2.02-7.32). Other lifestyle factors putatively associated with risk of developing ESCC were not associated with survival. In addition to increasing disease risk, heavy alcohol consumption may be independently associated with worse survival among patients with ESCC. Future clinical follow-up studies should consider alcohol as a potential prognosticator, in addition to known clinicopathologic factors. PMID:22213172

  12. Genomic Landscape of Somatic Alterations in Esophageal Squamous Cell Carcinoma and Gastric Cancer.

    PubMed

    Hu, Nan; Kadota, Mitsutaka; Liu, Huaitian; Abnet, Christian C; Su, Hua; Wu, Hailong; Freedman, Neal D; Yang, Howard H; Wang, Chaoyu; Yan, Chunhua; Wang, Lemin; Gere, Sheryl; Hutchinson, Amy; Song, Guohong; Wang, Yuan; Ding, Ti; Qiao, You-Lin; Koshiol, Jill; Dawsey, Sanford M; Giffen, Carol; Goldstein, Alisa M; Taylor, Philip R; Lee, Maxwell P

    2016-04-01

    Gastric cancer and esophageal cancer are the second and sixth leading causes of cancer-related death worldwide. Multiple genomic alterations underlying gastric cancer and esophageal squamous cell carcinoma (ESCC) have been identified, but the full spectrum of genomic structural variations and mutations have yet to be uncovered. Here, we report the results of whole-genome sequencing of 30 samples comprising tumor and blood from 15 patients, four of whom presented with ESCC, seven with gastric cardia adenocarcinoma (GCA), and four with gastric noncardia adenocarcinoma. Analyses revealed that an A>C mutation was common in GCA, and in addition to the preferential nucleotide sequence of A located 5 prime to the mutation as noted in previous studies, we found enrichment of T in the 5 prime base. The A>C mutations in GCA suggested that oxidation of guanine may be a potential mechanism underlying cancer mutagenesis. Furthermore, we identified genes with mutations in gastric cancer and ESCC, including well-known cancer genes, TP53, JAK3, BRCA2, FGF2, FBXW7, MSH3, PTCH, NF1, ERBB2, and CHEK2, and potentially novel cancer-associated genes, KISS1R, AMH, MNX1, WNK2, and PRKRIR Finally, we identified recurrent chromosome alterations in at least 30% of tumors in genes, including MACROD2, FHIT, and PARK2 that were often intragenic deletions. These structural alterations were validated using the The Cancer Genome Atlas dataset. Our studies provide new insights into understanding the genomic landscape, genome instability, and mutation profile underlying gastric cancer and ESCC development. Cancer Res; 76(7); 1714-23. ©2016 AACR. PMID:26857264

  13. Genomic characterization of esophageal squamous cell carcinoma from a high-risk population in China

    PubMed Central

    Hu, Nan; Wang, Chaoyu; Ng, David; Clifford, Robert; Yang, Howard H; Tang, Ze-Zhong; Wang, Quan-Hong; Han, Xiao-You; Giffen, Carol; Goldstein, Alisa M; Taylor, Philip R; Lee, Maxwell P

    2009-01-01

    Genomic instability plays an important role in most human cancers. To characterize genomic instability in esophageal squamous cell carcinoma (ESCC), we examined loss of heterozygosity (LOH), copy number (CN) loss, CN gain, and gene expression using the Affymetrix GeneChip Human Mapping 500K (n=30 cases) and Human U133A (n=17 cases) arrays in ESCC cases from a high-risk region of China. We found that genomic instability measures varied widely among cases and separated them into two groups: a high-frequency instability group (two-thirds of all cases with one or more instability category ≥ 10%) and a low-frequency instability group (one-third of cases with instability < 10%). Genomic instability also varied widely across chromosomal arms, with the highest frequency of LOH on 9p (33% of informative single nucleotide polymorphisms (SNPs)), CN loss on 3p (33%), and CN gain on 3q (48%). Twenty-two LOH regions were identified: four on 9p, seven on 9q, four on 13q, two on 17p, and five on 17q. Three CN loss regions – 3p12.3, 4p15.1, and 9p21.3 – were detected. Twelve CN gain regions were found, including six on 3q, one on 7q, four on 8q, and one on 11q. One of the most gene-rich of these CN gain regions was 11q13.1-13.4, where 26 genes also had RNA expression data available. CN gain was significantly correlated with increased RNA expression in over 80% of these genes. Our findings demonstrate the potential utility of combining CN analysis and gene expression data to identify genes involved in esophageal carcinogenesis. PMID:19584285

  14. Three-Dimensional Conformal Radiation Therapy for Esophageal Squamous Cell Carcinoma: Is Elective Nodal Irradiation Necessary?

    SciTech Connect

    Zhao Kuaile; Ma Jinbo; Liu Guang; Wu Kailiang; Shi Xuehui; Jiang Guoliang

    2010-02-01

    Purpose: To evaluate the local control, survival, and toxicity associated with three-dimensional conformal radiotherapy (3D-CRT) for squamous cell carcinoma (SCC) of the esophagus, to determine the appropriate target volumes, and to determine whether elective nodal irradiation is necessary in these patients. Methods and Materials: A prospective study of 3D-CRT was undertaken in patients with esophageal SCC without distant metastases. Patients received 68.4 Gy in 41 fractions over 44 days using late-course accelerated hyperfractionated 3D-CRT. Only the primary tumor and positive lymph nodes were irradiated. Isolated out-of-field regional nodal recurrence was defined as a recurrence in an initially uninvolved regional lymph node. Results: All 53 patients who made up the study population tolerated the irradiation well. No acute or late Grade 4 or 5 toxicity was observed. The median survival time was 30 months (95% confidence interval, 17.7-41.8). The overall survival rate at 1, 2, and 3 years was 77%, 56%, and 41%, respectively. The local control rate at 1, 2, and 3 years was 83%, 74%, and 62%, respectively. Thirty-nine of the 53 patients (74%) showed treatment failure. Seventeen of the 39 (44%) developed an in-field recurrence, 18 (46%) distant metastasis with or without regional failure, and 3 (8%) an isolated out-of-field nodal recurrence only. One patient died of disease in an unknown location. Conclusions: In patients treated with 3D-CRT for esophageal SCC, the omission of elective nodal irradiation was not associated with a significant amount of failure in lymph node regions not included in the planning target volume. Local failure and distant metastases remained the predominant problems.

  15. Preclinical evaluation of afatinib (BIBW2992) in esophageal squamous cell carcinoma (ESCC)

    PubMed Central

    Wong, Chi Hang; Ma, Brigette Buig Yue; Hui, Connie Wun Chun; Tao, Qian; Chan, Anthony Tak Cheung

    2015-01-01

    Esophageal squamous cell carcinoma (ESCC) is the eighth most common cancer worldwide. Epidermal growth factor receptors (EGFR) are often overexpressed in esophageal cancers, thus anti-EGFR inhibitors have been evaluated in ESCC. Afatinib was an irreversible inhibitor of these ErbB family receptors. This study characterized the preclinical activity of afatinib in five ESCC cell lines: HKESC-1, HKESC-2, KYSE510, SLMT-1 and EC-1. ESCC cell lines were sensitive to afatinib with IC50 concentrations at lower micro-molar range (at 72 hour incubation: HKESC-1 = 0.002 μM, HKESC-2 = 0.002 μM, KYSE510 = 1.090 μM, SLMT-1 = 1.161 μM and EC-1 = 0.109 μM) with a maximum growth inhibition over 95%. Afatinib can strongly induce G0/G1 cell cycle arrest in HKESC-2 and EC-1 in a dose- and time-dependent manner. The phosphorylation of ErbB family downstream effectors such as pAKT, pS6 and pMAPK were significantly inhibited in HKESC-2 and EC-1. Apoptosis was observed in both cell lines at 24 hours after exposure to afatinib, as determined by the presence of cleaved PARP. Afatinib could effectively inhibit HKESC-2 tumor growth in mice without obvious toxicity. Afatinib alone has shown excellent growth inhibitory effect on ESCC in both in vitro and in vivo models, however, no synergistic effect was observed when it was combined with chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin. In summary, afatinib can inhibit cell proliferation effectively by arresting the cells in G0/G1 phase, as well as inducing apoptosis in ESCC. These findings warrant further studies of afatinib as therapeutic agent in treating ESCC. PMID:26885448

  16. Comprehensive screening of genes resistant to an anticancer drug in esophageal squamous cell carcinoma

    PubMed Central

    TSUTSUI, MAI; KAWAKUBO, HIROFUMI; HAYASHIDA, TESTSU; FUKUDA, KAZUMASA; NAKAMURA, RIEKO; TAKAHASHI, TSUNEHIRO; WADA, NORIHITO; SAIKAWA, YOSHIRO; OMORI, TAI; TAKEUCHI, HIROYA; KITAGAWA, YUKO

    2015-01-01

    Drug resistance to chemotherapy is a major issue in esophageal cancer management. Drug resistance may be mediated by genetic changes in the tumor; therefore, the identification of gene mutations may lead to better therapeutic outcomes. We used a novel method involving transposons to screen and identify drug-resistant genes. Transposons are DNA sequences that move from one location on the gene to another. A modified piggyBac transposon was designed as an insertion mutagen, and a cytomegalovirus (CMV) promoter sequence was added to induce strong transcription. When the transposon is inserted to the upstream of a certain gene, the gene will be overexpressed while when intserted down or intragenically, it will be downregulated. After establishing a transposon-tagged cell library, we treated cell lines derived from esophageal squamous cell carcinomas (ESCC) [Tohoku esophagus (TE)] with cisplatin (CDDP). We performed splinkerette PCR and TOPO cloning on the resistant colonies. Bacterial colonies were sequenced, and next-generation sequencing was used to identify the overexpressed/downregulated sequences as candidate genes for CDDP resistance. We established 4 cell lines of transposon-tagged cells, TE4, 5, 9 and 15. We treated the two relatively viable cell lines, TE4 and TE15, with CDDP. We identified 37 candidate genes from 8 resistant colonies. Eight genes were overexpressed whilst 29 were downregulated. Among these genes was Janus kinase 2 (JAK2) that is implicated in the progression of myeloproliferative neoplasms. We identified 37 candidate genes responsible for CDDP resistance in the two cell lines derived from ESCC cells. The method is inexpensive, relatively simple, and capable of introducing activating and de-activating mutations in the genome, allowing for drug-resistant genes to be identified. PMID:26202837

  17. BIIB021, a novel Hsp90 inhibitor, sensitizes esophageal squamous cell carcinoma to radiation

    SciTech Connect

    Wang, Xin-Tong; Bao, Ci-Hang; Jia, Yi-Bin; Wang, Nana; Ma, Wei; Liu, Fang; Wang, Cong; Wang, Jian-Bo; Song, Qing-Xu; Cheng, Yu-Feng

    2014-10-03

    Highlights: • BIIB021 downregulated radioresistant proteins in ESCC cell lines. • BIIB021 increased radiation-induced apoptotic cells. • BIIB021 enhanced G{sub 2} arrest in ESCC cell lines. • BIIB021 is a good candidate for radiosensitizer in radiotherapy of ESCC patients. - Abstract: BIIB021 is a novel, orally available inhibitor of heat shock protein 90 (Hsp90) that is currently in phase I/II clinical trials. BIIB021 induces the apoptosis of various types of tumor cells in vitro and in vivo. The aim of this study is to investigate the effect of BIIB021 on the radiosensitivity of esophageal squamous cell carcinoma (ESCC). The results indicated that BIIB021 exhibited strong antitumor activity in ESCC cell lines, either as a single agent or in combination with radiation. BIIB021 significantly downregulated radioresistant proteins including EGFR, Akt, Raf-1 of ESCC cell lines, increased apoptotic cells and enhanced G{sub 2} arrest that is more radiosensitive cell cycle phase. These results suggest that this synthetic Hsp90 inhibitor simultaneously affects multiple pathways involved in tumor development and progression in the ESCC setting and may represent a better strategy for the treatment of ESCC patients, either as a monotherapy or a radiosensitizer.

  18. MMP1 promotes tumor growth and metastasis in esophageal squamous cell carcinoma.

    PubMed

    Liu, Min; Hu, Yi; Zhang, Mei-Fang; Luo, Kong-Jia; Xie, Xiu-Ying; Wen, Jing; Fu, Jian-Hua; Yang, Hong

    2016-07-10

    Matrix metalloproteinases play an essential role in the progression of esophageal squamous cell carcinoma (ESCC). Here, we show that MMP1 expression was markedly increased in a majority of ESCC compared with nontumorous tissue. High expressions of MMP1 were closely associated with lymph node metastasis, microvessel density and advanced TNM stage. Kaplan-Meier and multivariate analyses indicated MMP1 as an independent factor for overall survival in two independent cohorts of 613 patients with ESCC. In vitro studies demonstrated that MMP1 overexpression resulted in enhanced cell viability, abilities of colony formation and cell migration. The knockdown of MMP1 in ESCC cells resulted in the opposite phenomenon. Consistently, in vivo data showed that ectopic expression of MMP1 promoted tumor growth and metastasis. Further study revealed that MMP1 facilitated ESCC through the activation of the PI3K/AKT pathway. Inhibition of the PI3K/AKT pathway by LY294002 significantly attenuated MMP1-mediated cell proliferation and migration. Taken together, our data suggest that MMP1 functions as an oncogene and serves as a prognostic biomarker and a potential therapeutic target in ESCC. PMID:27130665

  19. Functional BCL-2 regulatory genetic variants contribute to susceptibility of esophageal squamous cell carcinoma.

    PubMed

    Pan, Wenting; Yang, Jinyun; Wei, Jinyu; Chen, Hongwei; Ge, Yunxia; Zhang, Jingfeng; Wang, Zhiqiong; Zhou, Changchun; Yuan, Qipeng; Zhou, Liqing; Yang, Ming

    2015-01-01

    B-cell lymphoma-2 (BCL-2) prevents apoptosis and its overexpression could promote cancer cell survival. Multiple functional BCL-2 genetic polymorphisms, such as rs2279115, rs1801018 and rs1564483, have been identified previously and might be involved in cancer development through deregulating BCL-2 expression. Therefore, we examined associations between these three polymorphisms and esophageal squamous cell carcinoma (ESCC) susceptibility as well as its biological function in vivo. Genotypes were determined in two independent case-control sets consisted of 1588 ESCC patients and 1600 controls from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. The impact of the rs2279115 polymorphism on BCL-2 expression was detected using esophagus tissues. Our results demonstrated that the BCL-2 rs2279115 AA genotype was significantly associated with decreased ESCC risk compared with the CC genotype (OR = 0.72, 95% CI = 0.57-0.90, P = 0.005), especially in nonsmokers (OR = 0.42, 95% CI = 0.29-0.59, P = 0.001) or nondrinkers (OR = 0.44, 95% CI = 0.32-0.62, P =  .002). Genotype-phenotype correlation studies demonstrated that subjects with the rs2279115 CA and AA genotypes had a statistically significant decrease of BCL-2 mRNA expression compared to the CC genotype in both normal and cancerous esophagus tissues. Our results indicate that the BCL-2 rs2279115 polymorphism contributes to ESCC susceptibility in Chinese populations. PMID:26132559

  20. Objective evaluation of visibility in virtual chromoendoscopy for esophageal squamous carcinoma using a color difference formula

    NASA Astrophysics Data System (ADS)

    Inoue, Masahito; Miyake, Yoichi; Odaka, Takeo; Sato, Toru; Watanabe, Yoshiyuki; Sakama, Atsunori; Zenbutsu, Satoki; Yokosuka, Osamu

    2010-09-01

    Computed virtual chromoendoscopy with flexible spectral imaging color enhancement (FICE) is a new dyeless imaging technique that enhances mucosal and vascular patterns. However, a method for selecting a suitable wavelength for a particular condition has not been established. The aim of this study is to evaluate the color difference method for quality assessment of FICE images of the intrapapillary capillary loop in magnifying endoscopy for esophageal squamous cell carcinoma. The color difference between 60 microvessels and background mucosa observed using the magnifying endoscope was 8.31+/-2.84 SD under white light and 12.26+/-3.14 (p=0.0031), 11.70+/-4.49 (p=0.0106), and 17.49+/-5.40 (p<0.0001) in FICE modes A, B, and C, respectively. The visibility scores for microvessels observed by medical students were 6.00+/-1.12 points under white light and 11.1+/-2.25 (p<0.0001), 8.65+/-2.06 (p=0.0001), and 12.55+/-2.56 (p<0.0001) in FICE modes A, B, and C, respectively. Furthermore, the measurement of color difference was correlated with the visibility score assigned by medical students (Pearson's correlation coefficient=0.583, p<0.0001) In conclusion, the color difference method corresponds to human vision and is an appropriate method for evaluation of endoscopic images.

  1. A Novel Inflammation-Based Stage (I Stage) in Patients with Resectable Esophageal Squamous Cell Carcinoma

    PubMed Central

    Chen, Peng-Cheng; Feng, Ji-Feng

    2016-01-01

    Background. Inflammation plays a key role in cancer. In the current study, we proposed a novel inflammation-based stage, named I stage, for patients with resectable esophageal squamous cell carcinoma (ESCC). Methods. Three hundred and twenty-three patients with resectable ESCC were enrolled in the current study. The I stage was calculated as follows: patients with high levels of C-reactive protein (CRP) (>10 mg/L), neutrophil-to-lymphocyte ratio (NLR) (>3.5), and platelet-count-to-lymphocyte ratio (PLR) (>150) were defined as I3. Patients with two, one, or no abnormal value were defined as I2, I1, or I0, respectively. The prognostic factors were evaluated by univariate and multivariate analyses. Results. There were 112 patients for I0, 97 patients for I1, 66 patients for I2, and 48 patients for I3, respectively. The 5-year cancer-specific survival (CSS) in patients with I0, I1, I2, and I3 was 50.0%, 30.9%, 18.2%, and 8.3%, respectively (I0 versus I1, P = 0.002; I1 versus I2, P = 0.012; I2 versus I3, P = 0.020). Multivariate analyses revealed that I stage was an independent prognostic factor in patients with resectable ESCC (P < 0.001). Conclusion. The inflammation-based stage (I stage) is a novel and useful predictive factor for CSS in patients with resectable ESCC.

  2. Plasma microRNAs to predict the response of radiotherapy in esophageal squamous cell carcinoma patients

    PubMed Central

    Yu, Qi; Li, Bingxin; Li, Ping; Shi, Zeliang; Vaughn, Amanda; Zhu, Liucun; Fu, Shen

    2015-01-01

    Although microRNAs (miRNAs) play an important role in esophageal squamous cell carcinoma (ESCC), their roles in radiotherapy response remain unexplored. Our study aims to investigate whether plasma miRNAs can be used as predictors of radiotherapy outcome in ESCC patients. We selected nine miRNAs, which were reported to be associated with carcinogenesis or radiobiology of ESCC, as the targets of our study. Plasma miRNA expression was investigated with 24 subjects (pre-, at the first week and post-radiotherapy). Tumor radiographic response and 3-year overall survival were used to evaluate the response. The results showed that the level of miR-16 in the patients with good outcome was significantly higher than that in the patients with poor outcome (P < 0.05, AUC: 0.762) at the post-radiotherapy. We also found that the variation tendency of miRNA expression were related to its radiotherapy response. Moreover, miR-16 levels increased by more than 2-fold following treatment, which were shown to be associated with longer OS (log-rank P = 0.009). In conclusion, miR-16 has considerable clinical value in predicting radiotherapy outcomes for ESCC patients. PMID:26692950

  3. MicroRNA-202 inhibits tumor progression by targeting LAMA1 in esophageal squamous cell carcinoma.

    PubMed

    Meng, Xiangrui; Chen, Xiaoqi; Lu, Peng; Ma, Wang; Yue, Dongli; Song, Lijie; Fan, Qingxia

    2016-05-13

    Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies in the gastrointestinal tract. Emerging studies have indicated that microRNAs (miRNAs) are strongly implicated in the development and progression of ESCC. Here, we focused on the function and the underlying molecular mechanism of miR-202 in ESCC. The results showed that miR-202 was significantly down-regulated in ESCC tissues and cell lines. Overexpression of miR-202 in ECa-109 and KYSE-510 cells markedly suppressed cell proliferation and cell migration, and induced cell apoptosis. Furthermore, laminin α1 (LAMA1) expression was frequently positive in ESCC tissues and inversely correlated with miR-202 expression. Then we demonstrated that miR-202 targeted 3'-untranslated region (UTR) of LAMA1 and inhibited its protein expression. Additionally, LAMA1 overexpression rescued the proliferation inhibition and cell apoptosis elevation induced by miR-202. MiR-202 also inhibited the protein expression of p-FAK and p-Akt, which were all reversed by LAMA1 overexpression. Taken together, these findings suggest that miR-202 may function as a novel tumor suppressor in ESCC by repressing cell proliferation and migration, and its biological effects may attribute the inhibition of LAMA1-mediated FAK-PI3K-Akt signaling. PMID:27045085

  4. Upregulation of SOX4 antagonizes cellular senescence in esophageal squamous cell carcinoma

    PubMed Central

    Han, Rongfei; Huang, Shiying; Bao, Yonghua; Liu, Xin; Peng, Xiaoyu; Chen, Zhiguo; Wang, Qian; Wang, Jiaqi; Zhang, Qiuping; Wang, Tianfu; Zheng, Duo; Yang, Wancai

    2016-01-01

    Senescence, a terminal cell proliferation arrest that is caused by a variety of cellular stresses such as telomere erosion, DNA damage and oncogenic signaling, is classically considered a tumor defense barrier. However, the mechanism by which cancer cells overcome senescence is undetermined. In this study, the gene expression array data of esophageal squamous cell carcinoma (ESCC) was compared with paired normal tissues and showed that a cohort of genes, including proteinases, chemokines and inflammation factors, are upregulated in ESCC, which exhibits the senescence-associated secretory phenotype. In addition, reverse transcription-quantitative polymerase chain reaction was used to demonstrate that gender determining region Y-box 4 (SOX4) is upregulated in ESCC, and that its expression is inversely correlated with senescence markers. In addition, the knockdown of SOX4 expression by short hairpin RNA decreases ESCC cell proliferation and enhances doxorubicin-induced cell senescence. These results reveal the presence of a senescent microenvironment in ESCC, and suggest an important antisenescence role of SOX4 in ESCC progression. PMID:27446439

  5. Long noncoding RNAs are novel potential prognostic biomarkers for esophageal squamous cell carcinoma: an overview

    PubMed Central

    Deng, Han-Yu; Wang, Yun-Cang; Ni, Peng-Zhi; Lin, Yi-Dan

    2016-01-01

    Esophageal squamous cell carcinoma (ESCC) still has a poor prognosis. The prognostic biomarkers of ESCC are not yet well established. Long noncoding RNAs (lncRNAs) have recently been intensively investigated in various cancers including ESCC, and are found to be closely correlated to ESCC. Dysregulated expression of lncRNAs was widely observed in ESCC tumor tissue and was closely related to the tumorigenesis and progression of ESCC. More and more studies have found that lncRNAs were significantly correlated with the prognosis and diagnosis of patients with ESCC. Therefore, all those accumulating evidence indicated that lncRNAs could serve as a prognostic biomarker of ESCC. In this, we summarized the relation between lncRNAs and ESCC as well as the potential biomarker role of lncRNAs in ESCC, especially the prognostic value of lncRNAs. Our current review highlighted the need of further studies to explore the biomarker functions as well as therapeutic values of lncRNAs in ESCC.

  6. Younger women have a better prognosis among patients with esophageal squamous cell carcinoma after esophagectomy

    PubMed Central

    Zhang, Xu; Xie, Hao-Jun; Lin, Peng; Zhang, Lanjun; Rong, Tiehua

    2016-01-01

    Background Epidemiological studies have suggested a potential role for sex hormones in esophageal squamous cell carcinoma (ESCC) etiology. However, the significance of gender as an independent prognostic factor remains uncertain. Our retrospective study was designed to investigate the prognostic role of gender for survival after esophagectomy. Methods Data from 674 patients with ESCC who underwent surgical resection were retrospectively analysed. Age 55 years was selected as a surrogate for menopause. Patients were assigned to age-gender groups: A (female younger than age 55 years), B (female age 55 years and older), C (male younger than age 55 years) and D (male age 55 years and older). Univariate and multivariate analyses were performed to identify prognostic factors for survival. Results There were 520 males and 154 females with median age was 58 years. The 1-, 3-, 5-year survival rates of group A, B, C and D were 93.6%, 70.2%, 61.7% vs. 86.9%, 47.7%, 40.2% vs. 77.8%, 43.9%, 37.0% and 80.3%, 47.9%, 36.6%, respectively (P=0.003). Multivariate analysis suggested that age-gender groups and pTNM staging were independent prognostic factors. Conclusions Among patients with ESCC after esophagectomy, women younger than age 55 years attained a favorable prognosis. PMID:27162661

  7. Socioeconomic status and esophageal squamous cell carcinoma risk in Kashmir, India.

    PubMed

    Dar, Nazir A; Shah, Idrees A; Bhat, Gulzar A; Makhdoomi, Muzamil A; Iqbal, Beenish; Rafiq, Rumaisa; Nisar, Iqra; Bhat, Arshid B; Nabi, Sumaiya; Masood, Akbar; Shah, Sajad A; Lone, Mohd M; Zargar, Showkat A; Islami, Farhad; Boffetta, Paolo

    2013-09-01

    Studies have persistently associated esophageal squamous cell carcinoma (ESCC) risk with low socioeconomic status (SES), but this association is unexplored in Kashmir, an area with a high incidence of ESCC in the northernmost part of India. We carried out a case-control study to assess the association of multiple indicators of SES and ESCC risk in the Kashmir valley. A total number of 703 histologically confirmed ESCC cases and 1664 controls matched to the cases for age, sex, and district of residence were recruited from October 2008 to January 2012. Conditional logistic regression models were used to calculate unadjusted and adjusted odds ratios and 95% confidence intervals. Composite wealth scores were constructed based on the ownership of several appliances using multiple correspondence analyses. Higher education, living in a kiln brick or concrete house, use of liquefied petroleum gas and electricity for cooking, and higher wealth scores all showed an inverse association with ESCC risk. Compared to farmers, individuals who had government jobs or worked in the business sector were at lower risk of ESCC, but this association disappeared in fully adjusted models. Occupational strenuous physical activity was strongly associated with ESCC risk. In summary, we found a strong relationship of low SES and ESCC in Kashmir. The findings need to be studied further to understand the mechanisms through which such SES parameters increase ESCC risk. PMID:23721087

  8. [The expression and significance of hnRNPD in esophageal squamous cell carcinoma cells].

    PubMed

    Geng, Yangyang; Zhang, Lulu; Xu, Miaomiao; Sheng, Wenjiong; Dong, Aijing; Cao, Jinming; Cao, Jianping

    2015-12-01

    Objective To investigate the expression of heterogeneous nuclear ribonucleoprotein D (hnRNPD) in esophageal squamous cell carcinoma (ESCC) tissues and the relationship between hnRNPD expression and the clinicopathological features of ESCC, and to study the effect of down-regulated hnRNPD on the proliferation of ESCC cells and explore its potential mechanism. Methods The expression of hnRNPD protein in ESCC tissues and the normal paracancerous tissues were detected by immunohistochemistry. The siRNA-hnRNPD was transfected into ESCC cells and the silence effect was verified by Western blotting. MTT assay and clone formation assay were used to evaluate the proliferation of ESCC cells after down-regulation of hnRNPD genes. Cell apoptosis was examined by annexin V-phycoerythrin/7-aminoactinomycin D (annexin V-PE/7-AAD) staining and flow cytometry. Results The expression of hnRNPD protein in ESCC tissues was significantly higher than that of the normal paracancerous tissues, and the expression was closely related with neoplasm staging. Down-regulation of hnRNPD inhibited the proliferation and clonality of ESCC cells. Compared with the control group, siRNA targeting hnRNPD significantly promoted cell apoptosis. Conclusion Down-regulation of hnRNPD inhibits the proliferation of ESCC cells by promoting cell apoptosis. PMID:26648300

  9. Pleural lavage with distilled water during surgery for esophageal squamous cell carcinoma.

    PubMed

    Kosuga, Toshiyuki; Shiozaki, Atsushi; Ichikawa, Daisuke; Fujiwara, Hitoshi; Komatsu, Shuhei; Iitaka, Daisuke; Tsujiura, Masahiro; Morimura, Ryo; Takeshita, Hiroki; Nagata, Hiroaki; Okamoto, Kazuma; Nakahari, Takashi; Marunaka, Yoshinori; Otsuji, Eigo

    2011-09-01

    This study aimed to investigate cytocidal effects of hypotonic shock on esophageal squamous cell carcinoma (ESCC) cell lines, and to apply pleural lavage with distilled water to surgery for ESCC. Three human ESCC cell lines, TE5, TE9 and KYSE170 were exposed to distilled water, and morphological changes in ESCC cells were closely observed under a differential interference contrast microscope connected to a high-speed digital video camera. Further, serial cell volume changes after hypotonic shock were measured using a high-resolution flow cytometer. To investigate the cytocidal effects of hypotonic shock on ESCC cells, re-incubation of ESCC cells was performed after hypotonic shock. Additionally, the effects of 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), a Cl- channel blocker, during hypotonic shock were analyzed. Video recordings by high-speed digital camera demonstrated that hypotonic shock with distilled water induced cell swelling followed by cell rupture. Measurements of cell volume changes using a high-resolution flow cytometer indicated that severe hypotonicity with distilled water increased broken fragments of ESCC cells within 5 min. Re-incubation experiments demonstrated cytocidal effects of hypotonic shock on ESCC cells. Treatment of cells with NPPB increased cell volumes by the inhibition of regulatory volume decrease, which is observed during hypotonic shock, and enhanced cytocidal effects. These findings demonstrated the cytocidal effects of hypotonic shock on ESCC cells, and clearly support the efficacy of pleural lavage with distilled water during surgery for ESCC. PMID:21567108

  10. Effects of photodynamic therapy for superficial esophageal squamous cell carcinoma in vivo and in vitro

    PubMed Central

    KAWAZOE, KAORU; ISOMOTO, HAJIME; YAMAGUCHI, NAOYUKI; INOUE, NAOKI; UEHARA, RYOHEI; MATSUSHIMA, KAYOKO; ICHIKAWA, TATSUKI; TAKESHIMA, FUMINAO; NONAKA, TAKASHI; NANASHIMA, ATSUSHI; NAGAYASU, TAKESHI; UEHARA, MASATAKA; ASAHINA, IZUMI; NAKAO, KAZUHIKO

    2010-01-01

    Photodynamic therapy (PDT) is an ablative treatment leading to intracellular photoexcitation and injury. A total of 15 patients with superficial esophageal squamous cell carcinoma (ESCC) without metastasis underwent PDT and 48–72 h after intravenous Photofrin, the patients were treated with a 630-nm excimer dye laser. A total of 13 patients had local tumor recurrence after definitive chemoradiotherapy (CRT) consisting of 5-fluorouracil (5-FU) and cisplatin (CDDP). Of 6 patients, 5 had submucosal ESCC and were treated with S-1. Complete reponse was achieved by 11 patients with initial PDT, but 2 had recurrences. The recurrent/residual tumors were successfully treated with repeated PDT. Two patients with intramucosal ESCC succumbed due to metastatic disease, but 11 patients were disease-free. The 5 patients treated with S-1 remained alive despite submucosal ESCC. PDT was applied to human ESCC cells in vitro in the presence or absence of 5-FU or CDDP. The combination of PDT with 5-FU or CDDP resulted in enhanced cytotoxic effects, thereby reducing the effective dosage of each drug. PDT is a promising treatment option for selected ESCC cases, particularly for local recurrence following CRT. Our experience suggests that PDT is more effective when combined with chemotherapy. PMID:22966398

  11. Correlation of Wnt and NOTCH pathways in esophageal squamous cell carcinoma.

    PubMed

    Moghbeli, Meysam; Abbaszadegan, Mohammad Reza; Golmakani, Ebrahim; Forghanifard, Mohammad Mahdi

    2016-06-01

    There is an inevitable association between cell signaling pathways and tumorigenesis. Wnt and notch pathways play important roles during development and self-renewal. Beside the independent role of such pathways on tumor progression, different cross talks between these pathways through tumorigenesis are emphasized. In this study, we analyzed cross talk between Wnt and NOTCH signaling pathways through assessment of probable correlation between MAML1 and PYGO2 as the main transcription factors of these pathways, respectively in esophageal squamous cell carcinoma (ESCC) patients. Levels of MAML1 and PYGO2 mRNA expression in 48 ESCC patients were compared to the correlated margin normal tissues using real-time polymerase chain reaction (PCR). Eleven out of 48 patients (22.9 %) have shown the concomitant MAML1/PYGO2 over expression in significant correlation with tumor size (p = 0.046) and depth of tumor invasion (p = 0.050). We showed that there is a significant correlation and feedback between these markers during the ESCC progression and metastasis. PMID:27041549

  12. Prognostic value of SATB2 expression in patients with esophageal squamous cell carcinoma.

    PubMed

    Geng, Guo-Jun; Li, Ning; Mi, Yan-Jun; Yu, Xiu-Yi; Luo, Xian-Yang; Gao, Jing; Luo, Qi-Cong; Xie, Jing-Dun; Fa, Xian-En; Jiang, Jie

    2015-01-01

    SATB2, a member of the family of special AT-rich binding proteins, has been shown to affect numerous tumorigenesis. However, the role of SATB2 in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, the SATB2 expression was examined at mRNA and protein levels by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry in ESCC tissues and adjacent non-cancerous tissues. Statistical analyses were applied to test the associations between SATB2 expression, clinicopathologic factors, and prognosis. Western blotting and qRT-PCR showed that the expression levels of SATB2 mRNA and protein were both significantly lower in SATB2 tissues than those in non-cancerous tissues. Immunohistochemistry analysis showed that SATB2 expression was significantly correlated with clinical stage and Histological differentiation. The results of Kaplan-Meier analysis indicated that a low expression level of SATB2 resulted in a significantly poor prognosis of ESCC patients. Importantly, multivariate analysis showed that low SATB2 expression was an independent prognostic factor for ESCC patients. In sum, our data suggest that SATB2 plays an important role in ESCC progression, and that decreased expression of SATB2 in tumor tissues could be used as a potential prognostic marker for patients with ESCC. PMID:25755730

  13. Vanadate-induced antiproliferative and apoptotic response in esophageal squamous carcinoma cell line EC109.

    PubMed

    Yang, Jie; Zhang, Zhuxia; Jiang, Shuyuan; Zhang, Ming; Lu, Jun; Huang, Lihua; Zhang, Tao; Gong, Kerui; Yan, Shaochun; Yang, Zhanjun; Shao, Guo

    2016-01-01

    Vanadate is a transition element that present in nature and was shown to be a nonspecific inhibitor of protein tyrosine phosphatases. It was reported that vanadium (Vd) compounds exhibit antitumor actions in several cancer cell lines. This study aimed to examine the antiproliferative and apoptotic actions of different concentrations of sodium vanadate (NaVd) (+5) in esophageal squamous carcinoma cell line EC109 by determining the protein expression levels of cyclin D1 and caspase-3 following incubation for various times from 15 min up to 4 h. In addition, cell proliferation of EC109 treated with different concentrations (NaVd) was also measured using the MTT assay at 4, 12, 24, and 48 h. The cell cycle of EC109 cells exposed to different concentrations of NaVd was detected using flow cytometry determination at 24 h. Data showed that NaVd greater than 100 µM significantly increased cyclin D1. In contrast, reduced caspase-3 protein expression levels occurred at 50 µM. Cellular proliferation was significantly decreased at 50uM. The cell cycle was arrested at S phase with 100 µM NaVd. Taken together, data indicate that NaVd produced concentration- and time-dependent antitumor actions in EC109 cell line. PMID:27599232

  14. MicroRNA-92b represses invasion-metastasis cascade of esophageal squamous cell carcinoma

    PubMed Central

    Ma, Gang; Jing, Chao; Li, Lin; Huang, Furong; Ding, Fang; Wang, Baona; Lin, Dongmei; Luo, Aiping; Liu, Zhihua

    2016-01-01

    Invasion and metastasis are major contributors to cancer-caused death in patients suffered from esophageal squamous cell carcinoma (ESCC). To explore the microRNAs involved in regulating invasion-metastasis cascade of ESCC, we established two pairs of sublines (30-U/D and 180-U/D) with distinct motility capacity from two ESCC cell lines (KYSE30 and KYSE180). Screening of the differentially expressed microRNAs identified that microRNA-92b-3p (miR-92b) could dramatically inhibit invasion and metastasis of ESCC cells in vitro and in vivo. Subsequent studies showed that miR-92b exerted its inhibitory function through suppressing the expression of integrin αV (ITGAV), which further reduced phosphrylated FAK and impaired Rac1 activation. Moreover, higher expression of miR-92b in ESCC tissues correlated inversely with lymph node metastasis and indicated better prognosis. Together, these results for the first time describe how miR-92b suppresses the motility of ESCC cells and provide a promise for diagnosis or therapy of ESCC invasion and metastasis. PMID:26934001

  15. Preclinical Validation of Talaporfin Sodium-Mediated Photodynamic Therapy for Esophageal Squamous Cell Carcinoma

    PubMed Central

    Ohashi, Shinya; Kikuchi, Osamu; Tsurumaki, Mihoko; Nakai, Yukie; Kasai, Hiroi; Horimatsu, Takahiro; Miyamoto, Shin'ichi; Shimizu, Akira; Chiba, Tsutomu; Muto, Manabu

    2014-01-01

    Photodynamic therapy (PDT) kills cancer cells via a photochemical reaction mediated by an oncotropic photosensitizer. Herein, we performed an experimental preclinical study to validate the anti-tumour effect of talaporfin sodium-mediated PDT (t-PDT) for esophageal squamous cell carcinoma (ESCC) cells. We used human ESCC cells derived from various differentiation grades or resistant to 5-fluorouracil (5-FU). The cytotoxic effect of t-PDT was determined by evaluating cell viability, apoptosis and generation of reactive oxygen species (ROS) and DNA double-strand breaks. Furthermore, the anti-tumour effect of t-PDT was assessed using an anchorage-independent cell-growth assay and xenograft transplantation models. t-PDT induced potent cytotoxicity in ESCC cells independent of their differentiation grade or 5-FU resistance. Moreover, t-PDT induced robust apoptosis, as indicated by cell shrinkage, perinuclear vacuolization, nuclear fragmentation and induction of annexin V-positive cells. This apoptotic response was accompanied by concurrent activation of ROS, and induction of DNA double-strand breakage. Importantly, t-PDT suppressed efficiently anchorage-independent cell growth as well as ESCC-xenografted tumor formation. In aggregate, t-PDT showed anti-tumor potential for ESCC cells with various histological grades or chemoresistance, providing a novel translational rationale of t-PDT for the treatment of ESCC. PMID:25090101

  16. Somatically Acquired LINE-1 Insertions in Normal Esophagus Undergo Clonal Expansion in Esophageal Squamous Cell Carcinoma.

    PubMed

    Doucet-O'Hare, Tara T; Sharma, Reema; Rodić, Nemanja; Anders, Robert A; Burns, Kathleen H; Kazazian, Haig H

    2016-09-01

    Squamous cell carcinoma of the esophagus (SCC) is the most common form of esophageal cancer in the world and is typically diagnosed at an advanced stage when successful treatment is challenging. Understanding the mutational profile of this cancer may identify new treatment strategies. Because somatic retrotransposition has been shown in tumors of the gastrointestinal system, we focused on LINE-1 (L1) mobilization as a source of genetic instability in this cancer. We hypothesized that retrotransposition is ongoing in SCC patients. The expression of L1 encoded proteins is necessary for retrotransposition to occur; therefore, we evaluated the expression of L1 open reading frame 1 protein (ORF1p). Using immunohistochemistry, we detected ORF1p expression in all four SCC cases evaluated. Using L1-seq, we identified and validated 74 somatic insertions in eight tumors of the nine evaluated. Of these, 12 insertions appeared to be somatic, not genetically inherited, and sub-clonal (i.e., present in less than one copy per genome equivalent) in the adjacent normal esophagus (NE), while clonal in the tumor. Our results indicate that L1 retrotransposition is active in SCC of the esophagus and that insertion events are present in histologically NE that expands clonally in the subsequent tumor. PMID:27319353

  17. Contribution of EVX1 in Aggressiveness of Esophageal Squamous Cell Carcinoma.

    PubMed

    Mallak, Afsaneh Javdani; Abbaszadegan, Mohammad Reza; Khorasanizadeh, Pegah Naeemi; Forghanifard, Mohammad Mahdi

    2016-04-01

    Homeobox genes play an overruling role in the regional cell fate determination during development. EVX1 is known as a new target gene of BMP signaling pathway, a group of morphogens which are making the largest subset within the transformation growth factor beta (TGF-β) superfamily. In this study, we aimed to enlighten the expression level of EVX1 in esophageal squamous cell carcinoma (ESCC) and to disclose its apparent roles in maintenance and progression of the disease. The expression level of EVX1 was analyzed in fresh tumoral tissues in comparison with distant tumor-free tissues of 50 ESCC patients using relative comparative real-time PCR. The importance of EVX1 in development and cancer was also reviewed. EVX1 was underexpressed in 70 % of tumor samples. There was a significant correlation between down-regulation of EVX1 and lymph node metastasis of tumor cells (p = 0.027). Furthermore, EVX1 underexpression was significantly correlated with depth of tumor cell invasion (P = 0.037). To the best of our knowledge, this is the first report highlighting EVX1 expression in ESCC to date. The clinicopathological relevance of EVX1 mRNA expression in ESCC targeted this gene as a new independent molecular marker for advanced tumor, which determine the characteristics and behavior of aggressive ESCC. PMID:26552663

  18. The absence of human papillomavirus in esophageal squamous cell carcinoma in East China

    PubMed Central

    Teng, Haohua; Li, Xiaojing; Liu, Xiuping; Wu, Jie; Zhang, Jie

    2014-01-01

    Esophageal squamous cell carcinoma (ESCC) is one of the most common types of tumors worldwide, particularly in China, and human papillomavirus (HPV) is thought to be a potential risk factor for this cancer. To determine whether this is true, we collected 177 formalin-fixed and paraffin-embedded ESCC samples from two hospitals. We screened for 23 different HPV genotypes using a human papillomavirus genotyping kit, which allowed us to amplify the L1 gene by polymerase chain reaction (PCR) and test for 23 HPV subtypes by reverse dot blot (RDB) on a single membrane. We also used immunohistochemistry (IHC) to detect the P16INK4a protein, the expression of which is linked to HPV E7 activity and which is used to diagnose cervical intraepithelial neoplasia. The genotyping results showed that only six samples were weakly positive for HPV: two for HPV16, two for HPV11 and two for HPV35, with no samples showing strong positive signals. The IHC results showed only five samples with diffuse positive staining, with the other samples being completely negative or having only focal positive signals, which were considered as negative. This study demonstrates that the HPV infection rate in ESCC samples is very low, suggesting that HPV is not the etiological cause of ESCC. PMID:25120798

  19. Preclinical validation of talaporfin sodium-mediated photodynamic therapy for esophageal squamous cell carcinoma.

    PubMed

    Ohashi, Shinya; Kikuchi, Osamu; Tsurumaki, Mihoko; Nakai, Yukie; Kasai, Hiroi; Horimatsu, Takahiro; Miyamoto, Shin'ichi; Shimizu, Akira; Chiba, Tsutomu; Muto, Manabu

    2014-01-01

    Photodynamic therapy (PDT) kills cancer cells via a photochemical reaction mediated by an oncotropic photosensitizer. Herein, we performed an experimental preclinical study to validate the anti-tumour effect of talaporfin sodium-mediated PDT (t-PDT) for esophageal squamous cell carcinoma (ESCC) cells. We used human ESCC cells derived from various differentiation grades or resistant to 5-fluorouracil (5-FU). The cytotoxic effect of t-PDT was determined by evaluating cell viability, apoptosis and generation of reactive oxygen species (ROS) and DNA double-strand breaks. Furthermore, the anti-tumour effect of t-PDT was assessed using an anchorage-independent cell-growth assay and xenograft transplantation models. t-PDT induced potent cytotoxicity in ESCC cells independent of their differentiation grade or 5-FU resistance. Moreover, t-PDT induced robust apoptosis, as indicated by cell shrinkage, perinuclear vacuolization, nuclear fragmentation and induction of annexin V-positive cells. This apoptotic response was accompanied by concurrent activation of ROS, and induction of DNA double-strand breakage. Importantly, t-PDT suppressed efficiently anchorage-independent cell growth as well as ESCC-xenografted tumor formation. In aggregate, t-PDT showed anti-tumor potential for ESCC cells with various histological grades or chemoresistance, providing a novel translational rationale of t-PDT for the treatment of ESCC. PMID:25090101

  20. Expression, Tissue Distribution and Function of miR-21 in Esophageal Squamous Cell Carcinoma

    PubMed Central

    Nouraee, Nazila; Van Roosbroeck, Katrien; Vasei, Mohammad; Semnani, Shahriar; Samaei, Nader Mansour; Naghshvar, Farshad; Omidi, Abbas Ali; Calin, George A.; Mowla, Seyed Javad

    2013-01-01

    Objective MiR-21 is an oncomir expressed by malignant cells and/or tumor microenvironment components. In this study we focused on understanding the effects of stromal miR-21 on esophageal malignant cells. Design MiR-21 expression was evaluated in formalin-fixed paraffin-embedded samples from patients with esophageal squamous-cell carcinoma (SCC) by quantitative RT-PCR. MiR-21 tissue distribution was visualized with in situ hybridization. A co-culture system of normal fibroblasts and esophageal cancer cells was used to determine the effects of fibroblasts on miR-21 expression levels, and on SCC cell migration and invasion. Results MiR-21 was overexpressed in SCCs, when compared to the adjacent non-tumor tissues (P = 0.0007), and was mainly localized in the cytoplasm of stromal cells adjacent to malignant cells. Accordingly, miR-21 expression was increased in tumors with high versus low stromal content (P = 0.04). When co-cultured with normal fibroblasts, miR-21 expression was elevated in SCC cells (KYSE-30), while its expression was restricted to fibroblasts when co-cultured with adenocarcinoma cells (OE-33 and FLO-1). MiR-21 was detected in conditioned media of cancer cell lines, illustrating the release of this miRNA into the environment. Co-culturing with normal fibroblasts or addition of fibroblast conditioned media caused a significant increase in cell migration and invasion potency of KYSE-30 cells (P<0.0001). In addition, co-culturing cancer cells with fibroblasts and expression of miR-21 induced the expression of the cancer associated fibroblast (CAF) marker S100A4. Conclusions MiR-21 expression is mostly confined to the SCC stroma and its release from fibroblasts influences the migration and invasion capacity of SCC cells. Moreover, miR-21 may be an important factor in “activating” fibroblasts to CAFs. These findings provide new insights into the role of CAFs and the extracellular matrix in tumor microenvironment formation and in tumor cell

  1. A Phase I Study of LJM716 in Squamous Cell Carcinoma of Head and Neck, or HER2+ Breast Cancer or Gastric Cancer

    ClinicalTrials.gov

    2014-04-21

    HER2 + Breast Cancer, HER2 + Gastric Cancer, Squamous Cell Carcinoma of Head and Neck, Esophageal Squamous Cell Carcinoma; HER2 + Breast Cancer; HER2 + Gastric Cancer; Squamous Cell Carcinoma of Head and Neck; Esophageal Squamous Cell Carcinoma

  2. Epigenetic inactivation of SPINT2 is associated with tumor suppressive function in esophageal squamous cell carcinoma

    SciTech Connect

    Yue, Dongli; Fan, Qingxia; Chen, Xinfeng; Li, Feng; Wang, Liping; Huang, Lan; Dong, Wenjie; Chen, Xiaoqi; Zhang, Zhen; Liu, Jinyan; Wang, Fei; Wang, Meng; Zhang, Bin [The Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan; The Department of Hematology and others

    2014-03-10

    Hepatocyte growth factor activator inhibitor type 2 (SPINT2), a Kunitz-type serine proteinase inhibitor, has been identified as a putative tumor suppressor gene silenced by promoter methylation. We aimed to investigate whether SPINT2 might act as an esophageal squamous cell carcinoma (ESCC) tumor suppressor gene. Four ESCC cell lines, Fifty-two ESCC tissues and twenty-nine neighboring non-cancerous tissues were included in this study. The expression of SPINT2 was monitored by real time PCR. Bisulfite genomic sequencing and methylation-specific PCR were used to analyze methylation status. The effect of SPINT2 on cell proliferation and apoptosis in EC109 and EC9706 cells was observed by CCK-8 assay and flow cytometric analysis. We found that silencing of SPINT2 was associated with promoter methylation in ESCC cell lines. The densely methylated SPINT2 promoter region was confirmed by bisulfite genomic sequencing. Ectopic expression of SPINT2 inhibited cell proliferation through inducing cell apoptosis in vitro. Furthermore, methylation-specific PCR analysis revealed that SPINT2 promoter methylation was prominent in carcinoma tissues (52.08%) compared with neighboring non-cancerous tissues (22.58%). Kaplan–Meier analysis showed that patients with SPINT2 hypermethylation had shorter survival time. The tumor suppressor gene of SPINT2 is commonly silenced by promoter hypermethylation in human ESCC and SPINT2 hypermethylation is correlated with poor overall survival, implicating SPINT2 is an underlying prognostic marker for human ESCC. - Highlights: • We firstly found SPINT2 gene may be transcriptionally repressed by promoter hypermethylation in ESCC cells. • SPINT2 overexpressing cells induced proliferation inhibition through promoting apoptosis. • mRNA expression of SPINT2 was significantly higher in ESCC tissues than in neighboring non-cancerous tissues. • Promoter hypermethylation of SPINT2 is significantly linked to TNM stage and poor overall survival.

  3. Impact of Treatment Modalities on Survival of Patients With Locoregional Esophageal Squamous-Cell Carcinoma in Taiwan.

    PubMed

    Chen, Hui-Shan; Hung, Wei-Heng; Ko, Jiunn-Liang; Hsu, Po-Kuei; Liu, Chia-Chuan; Wu, Shiao-Chi; Lin, Ching-Hsiung; Wang, Bing-Yen

    2016-03-01

    The optimal treatment modality for locoregional esophageal squamous-cell carcinoma (ESCC) is still undetermined. This study investigated the treatment modalities affecting survival of patients with ESCC in Taiwan.Data on 6202 patients who underwent treatment for locoregional esophageal squamous-cell carcinoma during 2008 to 2012 in Taiwan were collected from the Taiwan Cancer Registry. Patients were stratified by clinical stage. The major treatment approaches included definitive chemoradiotherapy, preoperative chemoradiation followed by esophagectomy, esophagectomy followed by adjuvant therapy, and esophagectomy alone. The impact of different treatment modalities on overall survival was analyzed.The majority of patients had stage III disease (n = 4091; 65.96%), followed by stage II (n = 1582, 25.51%) and stage I cancer (n = 529, 8.53%). The 3-year overall survival rates were 60.65% for patients with stage I disease, 36.21% for those with stage II cancer, and 21.39% for patients with stage III carcinoma. Surgery alone was associated with significantly better overall survival than the other treatment modalities for patients with stage I disease (P = 0.029) and was associated with significantly worse overall survival for patients with stage III cancer (P < 0.001). There was no survival risk difference among the different treatment methods for patients with clinical stage II disease.Multimodality treatment is recommended for patients with stage II-III esophageal squamous-cell carcinoma. Patients with clinical stage I disease can be treated with esophagectomy without preoperative therapy. PMID:26962818

  4. Transcription factor AP-1 in esophageal squamous cell carcinoma: Alterations in activity and expression during Human Papillomavirus infection

    PubMed Central

    2009-01-01

    Background Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related deaths in Jammu and Kashmir (J&K) region of India. A substantial proportion of esophageal carcinoma is associated with infection of high-risk HPV type 16 and HPV18, the oncogenic expression of which is controlled by host cell transcription factor Activator Protein-1 (AP-1). We, therefore, have investigated the role of DNA binding and expression pattern of AP-1 in esophageal cancer with or without HPV infection. Methods Seventy five histopathologically-confirmed esophageal cancer and an equal number of corresponding adjacent normal tissue biopsies from Kashmir were analyzed for HPV infection, DNA binding activity and expression of AP-1 family of proteins by PCR, gel shift assay and immunoblotting respectively. Results A high DNA binding activity and elevated expression of AP-1 proteins were observed in esophageal cancer, which differed between HPV positive (19%) and HPV negative (81%) carcinomas. While JunB, c-Fos and Fra-1 were the major contributors to AP-1 binding activity in HPV negative cases, Fra-1 was completely absent in HPV16 positive cancers. Comparison of AP-1 family proteins demonstrated high expression of JunD and c-Fos in HPV positive tumors, but interestingly, Fra-1 expression was extremely low or nil in these tumor tissues. Conclusion Differential AP-1 binding activity and expression of its specific proteins between HPV - positive and HPV - negative cases indicate that AP-1 may play an important role during HPV-induced esophageal carcinogenesis. PMID:19758438

  5. Downregulation of microRNA-382 is associated with poor outcome of esophageal squamous cell carcinoma

    PubMed Central

    Qi, Bo; Lu, Jian-Guo; Yao, Wen-Jian; Chang, Ting-Min; Qin, Xiu-Guang; Ji, Ying-Hua; Wang, Tian-Yun; Liu, Shang-Guo; Li, Han-Chen; Liu, Yu-Zhen; Zhao, Bao-Sheng

    2015-01-01

    AIM: To study the potential prognostic role of microRNA-382 (miR-382) in esophageal squamous cell carcinoma (ESCC). METHODS: Forty six patients were divided into 2 groups according to postoperative survival time: the poor outcome group (28 patients), who showed early metastasis but no recurrence, and died within 1 year after surgery, 12 patients of the group received postoperative chemotherapy treatment that was given after early metastasis happening; the good outcome group (18 patients), who had no clinical metastasis and recurrence, and survived 5 years or more after surgery, all patients did not receive any postoperative treatment. Total RNA was extracted from the patients’ formalin-fixed and paraffin-embedded esophageal cancer tissues. miR-382 level was evaluated using high-throughput real-time quantitative polymerase chain reaction analysis. The correlation between miR-382 level and clinicopathologic features was analyzed through COX regression model, and Kaplan-Meier analysis was used to analyze the relationship between miR-382 level and patient survival time. RESULTS: miR-382 was differentially expressed in the two groups. Overall the average miR-382 level in the ESCC patients with good outcome was 9.8 ± 3.8, while miR-382 level in the ESCC patients with poor outcome was 3.0 ± 0.8. The differences of miR-382 levels between two groups were significant (P < 0.05). Kaplan-Meier analysis results showed that miR-382 expression level generally had a significant reverse-correlation with ESCC patient survival time (P < 0.001), in which the patients with higher expressions of miR-382 had a longer survival time either among individuals with the same tumor stage or among the overall patients. CONCLUSION: miR-382 levels are reverse-correlated with ESCC poor outcomes, suggesting that miR-382 could be a potential predictive biomarker for both prognosis and treatment of ESCC. PMID:26078564

  6. Higher expression of SIRT1 induced resistance of esophageal squamous cell carcinoma cells to cisplatin

    PubMed Central

    Shi, Qintong; Wang, Wengong

    2015-01-01

    Background High expression of Sirtuin type 1 (SIRT1) exists in some cancer cells. However, it is still unclear whether SIRT1 affects the sensitivity of esophageal cancer cells to cisplatin. This study was designed to explore the relationship between SIRT1 expression and resistance of esophageal squamous cell carcinoma (ESCC) cells to cisplatin and reveal the underlying mechanism. Methods The tissue samples of 68 ESCC patients were collected from Nanjing Drum Tower Hospital, China. All the patients had undergone cisplatin based combination chemotherapy. The expression of SIRT1and Noxa in tissue samples were analyzed by quantitative real-time reverse PCR (qRT-PCR) and Western blot. Human ESCC cell line (ECa9706 cells) was cultured and a cisplatin-resistant subline (ECa9706-CisR cells) was established by continuous exposure to cisplatin at different concentrations. The expression of SIRT1 and Noxa in both cell lines was analyzed by qRT-PCR and Western blot. siRNA technology was utilized to down-regulate the SIRT1 expression in ECa9706-CisR cells. The influence of SIRT1 silence on sensitivity of ECa9706-CisR cells to cisplatin was confirmed using CCK-8 assay and flow cytometry. Furthermore, the level change of Noxa after SIRT1 silence in ECa9706-CisR cells was determined by qRT-PCR and Western blot. Result SIRT1 and Noxa expression in chemo-resistant patients was significantly increased and decreased respectively, compared with chemo-sensitive patients. SIRT1 expression in ECa9706-CisR cells was significantly increased with a lower Noxa level, compared with normal ECa9706 cells. Cisplatin 5 µM could cause proliferation inhibition, G2/M phase arrest and apoptosis in ECa9706-CisR cells and these effects could be enhanced dramatically by SIRT1 silencing. Moreover, Noxa expression was increased after treated with SIRT1 siRNA. Conclusions Over-expression of SIRT1 may cause resistance of ESCC cells to cisplatin through the mechanism involved with Noxa expression. PMID

  7. Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population.

    PubMed

    Song, C; Xing, D; Tan, W; Wei, Q; Lin, D

    2001-04-15

    Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism that affects DNA methylation and synthesis. Because germ-line mutations at nucleotides 677 (C-->T) and 1298 (A-->C) in the MTHFR gene cause diminished enzyme activity, and aberrant DNA methylation is oncogenic, we examined the relationship between these two MTHFR polymorphisms and susceptibility to esophageal squamous cell carcinoma (ESCC) in 240 ESCC cases and 360 age- and sex-matched controls in northern CHINA: We found that the allele frequency of MTHFR 677T was significantly higher among cases than among controls (63% versus 41%, P < 0.001). Subjects with the 677TT genotype had a more than 6-fold increased risk of developing ESCC [adjusted odds ratio (OR), 6.18; 95% confidence interval (CI), 3.32-11.51] compared with those who had the 677CC genotype. Furthermore, the elevated ESCC risk associated with the 677 polymorphism was in an allele-dose relationship (trend test, P = 0.0001) with ORs of 1.00, 3.14 (95% CI, 1.94-5.08), and 6.18 (95% CI, 3.32-11.51) for the CC, CT, and TT genotype, respectively, after adjustment for age, sex, smoking status, and the MTHFR 1298 polymorphism. The allele frequency for the MTHFR 1298C was 14% among cases and 17% among controls. The 1298CC genotype was extremely rare in both controls (1.4%) and cases (2.9%) and was also associated with an elevated risk of ESCC (adjusted OR, 4.43; 95% CI, 1.23-16.02) compared with the 1298AA genotype, whereas the 1298AC genotype had no effect on the risk of ESCC. Thus, our findings support the hypothesis that genetic polymorphisms in the MTHFR gene may contribute to susceptibility to carcinogenesis of the esophagus in the at-risk Chinese population. PMID:11309278

  8. Plasma matrix metalloproteinase 1 improves the detection and survival prediction of esophageal squamous cell carcinoma

    PubMed Central

    Chen, Yu-Kuei; Tung, Chun-Wei; Lee, Jui-Ying; Hung, Yi-Chun; Lee, Chien-Hung; Chou, Shah-Hwa; Lin, Hung-Shun; Wu, Ming-Tsang; Wu, I-Chen

    2016-01-01

    This study aimed to identify noninvasive protein markers capable of detecting the presence and prognosis of esophageal squamous-cell carcinoma (ESCC). Analyzing microarray expression data collected from 17-pair ESCC specimens, we identified one protein, matrix metalloproteinase-1 (MMP1), as a possibly useful marker. Plasma MMP1 was then measured by enzyme-linked immunosorbent assay (ELISA) in 210 ESCC patients and 197 healthy controls. ESCC patients had higher mean levels of MMP1 than controls (8.7 ± 7.5 vs. 6.7 ± 4.9 ng/mL, p < 0.0001). Using the highest quartile level (9.67 ng/mL) as cut-off, we found a 9.0-fold risk of ESCC in those with higher plasma MMP1 after adjusting for covariates (95% confidence interval = 2.2, 36.0). Heavy smokers and heavy drinkers with higher plasma MMP1 had 61.4- and 31.0 times the risk, respectively, than non-users with lower MMP1. In the survival analysis, compared to those with MMP1 ≤ 9.67 ng/mL, ESCC patients with MMP1 > 9.67 ng/mL had a 48% increase in the risk of ESCC death (adjusted hazard ratio = 1.48; 95% CI = 1.04–2.10). In conclusion, plasma MMP1 may serve as a noninvasive marker of detecting the presence and predicting the survival of ESCC. PMID:27436512

  9. Expression of Cyclin D1 and P16 in Esophageal Squamous Cell Carcinoma

    PubMed Central

    Dey, Biswajit; Raphael, Vandana; Khonglah, Yookarin; GiriLynrah, Kyrshanlang

    2015-01-01

    BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the lethal cancers with a high incidence rate in Asia. Many genes including cyclin D1 and p16 play important role in its carcinogenesis. We aimed to analyze the expressions of cyclin D1 and p16 with the various clinicopathological characteristics of ESCC. METHODS We examined 30 biopsy samples of ESCC for cyclin D1 and p16 protein expressions using immunohistochemistry. Immunointensity was classified as no immunostaining (-), weakly immunostaining (+), weak immunostaining (++) and strongly positive immunostaining (+++). RESULTS Out of the 30 cases, positive expression of cyclin D1 was detected in 26 cases (86.7%). The percentage of tumors with invasion to the adventitia (88.2%), lymph node metastasis (87.5%), and tumors which were poorly differentiated (92.9%) were higher in cyclin D1 positive tumors than in the cyclin D1 negative tumors. However no significant association was found between cyclin D1 expression and the different clinicopathological parameters.There were 22 cases of ESCC (73.3 %) which showed negativity for p16. The percentage of tumors with invasion to the adventitia (82.4%) and poorly differentiated tumors (92.9%) were higher in the p16 negative tumors than in the p16 positive tumors. There was significant association between the histological grade and p16 expression (p=0.012). However, there were no significant association with regard to site, size and lymph node status of the tumors and p16 expression. CONCLUSION The study shows that alterations of cyclin D1 and p16 play an important role in ESCC. Loss of p16 expression was associated with poor differentiation. PMID:26609350

  10. The Geriatric Nutritional Risk Index Predicts Survival in Elderly Esophageal Squamous Cell Carcinoma Patients with Radiotherapy

    PubMed Central

    Wang, Kunlun; Liu, Yang; You, Jie; Cui, Han; Zhu, Yiwei; Yuan, Ling

    2016-01-01

    The impact of nutritional status on survival among elderly esophageal squamous cell carcinoma (ESCC) patients undergoing radiotherapy is unclear. In this study, we aimed at validating the performance of the geriatric nutritional risk index (GNRI) in predicting overall survival time in elderly ESCC patients with radiotherapy. A retrospective cohort study was conducted on 239 ESCC patients aged 60 and over admitted consecutively from January 2008 to November 2014 in the Department of Radiotherapy, Henan Tumor Hospital (Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan, China. All patients were subjected to nutritional screening using GNRI, and were followed for the occurrence of lymphatic node metastasis, radiation complication and mortality. The Kaplan–Meier method with Log-rank test was used to estimate survival curves. Univariable Cox regression analysis was used to identify variables associated with overall survival time. Among the 239 patients, 184 patients (76.9%) took no nutritional risk, 32 patients (13.4%) took moderate risk of malnutrition, and 23 patients (9.7%) took a high risk of malnutrition. Univariable Cox regression showed that both high nutritional risk group and moderate nutritional risk group were significantly less likely to survive than no nutritional risk patients (hazard ratio (HR) = 1.688, 95% confidence interval (CI) = 1.019–2.798 for moderate risk group, and HR = 2.699, 95% CI = 1.512–4.819 for high risk group, respectively). The GNRI is an independent prognostic factor for overall survival time in elderly ESCC patients with radiotherapy. A GNRI ≤98 can be suggested as an indicator of surviving less. PMID:27196126

  11. Plasma miRNA-506 as a Prognostic Biomarker for Esophageal Squamous Cell Carcinoma

    PubMed Central

    Li, Shu-Ping; Su, Hong-Xin; Zhao, Da; Guan, Quan-Lin

    2016-01-01

    Background MicroRNAs (miRNAs) are responsible for regulating proliferation, differentiation, apoptosis, invasion, and metastasis in tumor cells. miRNA-506 is abnormally expressed in multiple tumors, indicating that it might be oncogenic or tumor-suppressive. However, little is known about the association between miRNA-506 expression and esophageal squamous cell carcinoma (ESCC). Material/Methods We examined the expression of miRNA-506 in the plasma of ESCC patients using quantitative real-time polymerase chain reaction (qRT-PCR) to determine the association between miRNA-506 expression and clinicopathological features of ESCC. ROC curves were produced for ESCC diagnosis by plasma miRNA-506 and the area under curve was calculated to explore its diagnostic value. Results Average miRNA-506 expression levels were remarkably higher in the plasma of ESCC patients than in healthy volunteers (P<0.001). The expression of miRNA-506 in the plasma was closely associated with lymph node status (P=0.004), TNM stage (P=0.031), and tumor length (P<0.001). According to ROC curves, the area under the curve for plasma miRNA-506 was 0.835, indicating statistical significance for ESCC diagnosis by plasma miRNA-506 (P<0.001). Kaplan-Meier analysis showed that patients with high miRNA-506 expression had significantly shorter survival time than those with low miRNA-506 expression. Cox regression analysis demonstrated that T stage, N stage, tumor length, and miRNA-506 expression levels were significantly correlated with prognosis in ESCC patients. Conclusions miRNA-506 can serve as an important molecular marker for diagnosis and prognostic prediction of ESCC. PMID:27345473

  12. Identification of potential plasma biomarkers for esophageal squamous cell carcinoma by a proteomic method.

    PubMed

    Zhao, Jia; Fan, Yu-Xia; Yang, Yang; Liu, Dong-Lei; Wu, Kai; Wen, Feng-Biao; Zhang, Chun-Yang; Zhu, Deng-Yan; Zhao, Song

    2015-01-01

    Among malignant tumors, the mortality rate of esophageal squamous cell carcinoma (ESCC) ranks sixth in the world. Late-stage diagnosis of ESCC increases the mortality. Therefore, more effective biomarkers for early diagnosis of ESCC are necessary. Unfortunately, appropriate biomarkers for clinical diagnosis and prognosis have not been identified yet. However, recent progresses in quantitative proteomics have offered opportunities to identify plasma proteins as biomarkers for ESCC. In the present study, plasma samples were analyzed by differential in-gel electrophoresis (DIGE) and differentially expressed proteins were identified by matrix assisted laser desorption ionization-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF MS). A total of 31 proteins representing 12 unique gene products were identified, in which 16 proteins were up-regulated and 15 down-regulated in tumors. The up-regulated proteins were alpha-2-HS-glycoprotein (AHSG), leucine-rich alpha-2-glycoprotein (LRG), zinc-alpha-2-glycoprotein, alpha-1-antichymotrypsin, complement factor I and complement C4-B, whereas the down-regulated proteins were serum albumin, Ig alpha-2 chain C region, alpha-1-antitrypsin, fibrinogen gamma chain, haptoglobin and hemoglobin subunit alpha. Among all the differentially expressed proteins, AHSG and LRG were validated by ELISA. The results were consistent with the data from the proteomics results, further suggesting that AHSG and LRG may be employed as potential biomarkers for the early diagnosis of ESCC. In summary, this study was the first time to use DIGE combined MALDI-TOF/TOF platform to identify the potential plasma biomarkers for ESCC. The plasma AHSG and LRG showed great potential for ESCC screening. PMID:25973038

  13. DEPTOR suppresses the progression of esophageal squamous cell carcinoma and predicts poor prognosis

    PubMed Central

    Zheng, Xiang; Li, Sheng-Bao; Wei, Zhi-Qiang; Liu, Tao; Cheng, Dong-Liang; Liu, Ping; Song, Kuncheng; Tan, Tao; Zhu, Hua; Guo, Jia-Long

    2016-01-01

    As a naturally occurring inhibitor of mTOR, accumulated evidence has suggested that DEPTOR plays a pivotal role in suppressing the progression of human malignances. However, the function of DEPTOR in the development of esophageal squamous cell carcinoma (ESCC) is still unclear. Here we report that the expression of DEPTOR is significantly reduced in tumor tissues derived from human patients with ESCC, and the downregulation of DEPTOR predicts a poor prognosis of ESCC patients. In addition, we found that the expression of DEPTOR negatively regulates the tumorigenic activities of ESCC cell lines (KYSE150, KYSE510 and KYSE190). Furthermore, ectopic DEPTOR expression caused a significant suppression of the cellular proliferation, migration and invasion of KYSE150 cells, which has the lowest expression level of DEPTOR in the three cell lines. Meanwhile, CRISPR/Cas9 mediated knockout of DEPTOR in KYSE-510 cells significantly promoted cellular proliferation, migration and invasion. In addition, in vivo assays further revealed that tumor growth was significantly inhibited in xenografts with ectopic DEPTOR expression as compared to untreated KYSE150 cells, and was markedly enhanced in DEPTOR knockout KYSE-510 cells. Biochemical studies revealed that overexpression of DEPTOR led to the suppression of AKT/mTOR pathway as evidenced by reduced phosphorylation of AKT, mTOR and downstream SGK1, indicating DEPTOR might control the progression of ESCC through AKT/mTOR signaling pathway. Thus, these findings, for the first time, demonstrated that DEPTOR inhibits the tumorigenesis of ESCC cells and might serve as a potential therapeutic target or prognostic marker for human patients with ESCC. PMID:26893358

  14. Factors Predicting Effectiveness of Neoadjuvant Therapy for Esophageal Squamous Cell Carcinoma.

    PubMed

    Ohkura, Yu; Ueno, Masaki; Iizuka, Toshiro; Haruta, Shusuke; Tanaka, Tsuyoshi; Udagawa, Harushi

    2016-04-01

    The aim of the study was to elucidate pretreatment factors that can predict the outcome of neoadjuvant chemoradiotherapy or chemotherapy (NAC(R)T) and help us choose treatment strategies appropriate for individual patients.Few studies have investigated whether clinical data obtainable before the treatment can predict the efficacy of NAC(R)T.Of 1540 patients treated for esophageal squamous cell carcinoma (ESCC) at our department between January 2000 and June 2014, those who underwent surgical resection of cStage II or more advanced ESCC after NAC(R)T (113 NACRT and 146 NACT patients) were enrolled in this study. Information all available before the treatment was analyzed to extract factors that can predict the effectiveness of NAC(R)T. NAC(R)T was considered effective when Grade 2 or greater treatment efficacy was achieved based on the histological grading system.NACRT was effective in 51 (45%) of 113 patients. The analysis of 35 pretreatment factors showed that female sex (hazard ratio [HR] = 3.650; 1.181-11.236), absence of dyslipidemia (HR = 3.284; 1.341-8.041), and histologically poorly differentiated tumor (HR = 2.431; 1.052-5.619) were factors predicting NACRT effectiveness. On the other hand, NACT was effective in 21 (14%) of 146 patients. The analysis of pretreatment factors showed that absence of dyslipidemia (HR = 10.204; 1.302-83.33) and therapy with docetaxel, cisplatin, and 5-fluorouracil (HR = 2.097; 1.027-4.280) were factors predicting NACT effectiveness.The findings of this study investigating factors that could predict the outcome of NAC(R)T suggest that the prevalence of dyslipidemia influences the outcome of NAC(R)T for ESCC. PMID:27082598

  15. Factors Predicting Effectiveness of Neoadjuvant Therapy for Esophageal Squamous Cell Carcinoma

    PubMed Central

    Ohkura, Yu; Ueno, Masaki; Iizuka, Toshiro; Haruta, Shusuke; Tanaka, Tsuyoshi; Udagawa, Harushi

    2016-01-01

    Abstract The aim of the study was to elucidate pretreatment factors that can predict the outcome of neoadjuvant chemoradiotherapy or chemotherapy (NAC(R)T) and help us choose treatment strategies appropriate for individual patients. Few studies have investigated whether clinical data obtainable before the treatment can predict the efficacy of NAC(R)T. Of 1540 patients treated for esophageal squamous cell carcinoma (ESCC) at our department between January 2000 and June 2014, those who underwent surgical resection of cStage II or more advanced ESCC after NAC(R)T (113 NACRT and 146 NACT patients) were enrolled in this study. Information all available before the treatment was analyzed to extract factors that can predict the effectiveness of NAC(R)T. NAC(R)T was considered effective when Grade 2 or greater treatment efficacy was achieved based on the histological grading system. NACRT was effective in 51 (45%) of 113 patients. The analysis of 35 pretreatment factors showed that female sex (hazard ratio [HR] = 3.650; 1.181–11.236), absence of dyslipidemia (HR = 3.284; 1.341–8.041), and histologically poorly differentiated tumor (HR = 2.431; 1.052–5.619) were factors predicting NACRT effectiveness. On the other hand, NACT was effective in 21 (14%) of 146 patients. The analysis of pretreatment factors showed that absence of dyslipidemia (HR = 10.204; 1.302–83.33) and therapy with docetaxel, cisplatin, and 5-fluorouracil (HR = 2.097; 1.027–4.280) were factors predicting NACT effectiveness. The findings of this study investigating factors that could predict the outcome of NAC(R)T suggest that the prevalence of dyslipidemia influences the outcome of NAC(R)T for ESCC. PMID:27082598

  16. CD68 and interleukin 13, prospective immune markers for esophageal squamous cell carcinoma prognosis prediction

    PubMed Central

    Qin, Yan-Ru; Bi, Jiong; Liu, Hai-Bo; Li, Yan; Cai, Mu-Yan; Ma, Stephanie; Chan, Kwok Wah; Xie, Dan; Guan, Xin-Yuan

    2016-01-01

    Purpose Oncology immunity was reported to play a key role in cancer development and progression, so we investigated the prediction role of several immune markers in esophageal squamous cell carcinoma (ESCC) patients after operation in this study. Patients and Methods 66 primary ESCC tumor tissues and four sets of tissue microarrays including 705 primary ESCC tumor tissues from four centers were collected and analyzed. Expressions of several immune markers in ESCC tumor tissue were detected with immunohistochemistry staining. Their distribution densities were analyzed with InForm™ 2.0.1 software. All statistic analyses were performed with SPSS16.0 and Stata version 10.0. Results Survival analyses assessed by Kaplan-Meier plots and log-rank tests demonstrated that densities of CD68 and interleukin 13 (IL-13) in tumor stroma were positively correlated with the overall survival of ESCC patients after operation (p < 0.01 for CD68, p < 0.001 for IL-13). Further, a model based on tumor stroma densities of CD68 and IL-13 was constructed and it could significantly classify patients with poor or good prognosis. This model could further identify high-risk group and low-risk group at the same Tumor lymph Nodes Metastases (TNM) stage. Lastly, a more accuracy model based on TNM stage, densities of CD68 and IL-13 was constructed to predict the prognosis of ESCC patient after operation. Conclusion Combining the TNM staging system and densities of CD68 and IL-13 could substantially improve the prognosis prediction accuracy of ESCC patient after operation, which might be an excellent tool for selecting patients for individualized therapy in future. PMID:26771842

  17. Microarray expression profile analysis of aberrant long non-coding RNAs in esophageal squamous cell carcinoma.

    PubMed

    Yao, Juan; Huang, Jun-Xing; Lin, Mei; Wu, Zheng-Dong; Yu, Hong; Wang, Peng-Cheng; Ye, Jun; Chen, Ping; Wu, Jing; Zhao, Guo-Jun

    2016-06-01

    Increasing evidence indicates that long non-coding RNA (lncRNA) plays an important role in tumorigenesis. However, the function and regulatory mechanism of lncRNAs are still unclear in esophageal squamous cell carcinoma (ESCC). To address this challenge, we screened lncRNAs expression profiles in 3 pairs of ESCC and matched non-cancerous tissues by microarray assay and identified the relationship between lncRNAs expression in ESCC tissue and clinicopathological characteristics and prognosis of patients with ESCC. We found 182 lncRNAs that were significantly differently expressed in ESCC tissues versus the matched non-cancerous tissues. Gene ontology and pathway analysis results suggested that the primary biological processes of these genes were involved in extracellular matrix, immune responses, cell differentiation and cell proliferation. Through cis and trans analyzing, we found 4 lncRNAs (ENST00000480669, NONHSAT104436, NONHSAT126998 and NONHSAT112918) may play important roles in tumorigenesis of ESCC. The four lncRNAs were checked in 73 patients with ESCC. The results showed that they mainly related to tumor metastasis. Kaplan-Meier survival analysis showed that high expression of NONHSAT104436, NONHSAT126998 and low expression of ENST00000480669 were related to poor 3-year overall survival (P=0.003, 0.032 and 0.040, respectively). Multivariate analysis showed that NONHSAT104436 was an independent prognostic factor (P=0.017). Thus we concluded that, lncRNAs showed differently expression patterns in ESCC versus matched non-cancerous tissues, and aberrantly expressed lncRNA may play important roles in ESCC development and progression. Interestingly, the overexpression of NONHSAT104436 was tightly correlated with distant metastasis and, poor survival rate, which might indicate that NONHSAT104436 might play a very important part in ESCC tumor progression. PMID:27035335

  18. Irradiated fibroblasts promote epithelial–mesenchymal transition and HDGF expression of esophageal squamous cell carcinoma

    SciTech Connect

    Bao, Ci-Hang; Wang, Xin-Tong; Ma, Wei; Wang, Na-Na; Nesa, Effat un; Wang, Jian-Bo; Wang, Cong; Jia, Yi-Bin; Wang, Kai; Tian, Hui; Cheng, Yu-Feng

    2015-03-06

    Recent evidence suggested that nonirradiated cancer-associated fibroblasts (CAFs) promoted aggressive phenotypes of cancer cells through epithelial–mesenchymal transition (EMT). Hepatoma-derived growth factor (HDGF) is a radiosensitive gene of esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the effect of irradiated fibroblasts on EMT and HDGF expression of ESCC. Our study demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of ESCC cells and the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. Scattering of ESCC cells was also accelerated by the supernatant from irradiated fibroblasts. Exposure of ESCC cells to supernatant from irradiated fibroblasts resulted in decreased E-cadherin, increased vimentin in vitro and β-catenin was demonstrated to localize to the nucleus in tumor cells with irradiated fibroblasts in vivo models. The expression of HDGF and β-catenin were increased in both fibroblasts and ESCC cells of irradiated group in vitro and in vivo models. Interestingly, the tumor cells adjoining the stromal fibroblasts displayed strong nuclear HDGF immunoreactivity, which suggested the occurrence of a paracrine effect of fibroblasts on HDGF expression. These data suggested that irradiated fibroblasts promoted invasion, growth, EMT and HDGF expression of ESCC. - Highlights: • Irradiated CAFs accelerated invasiveness and scattering of ESCC cell lines. • Irradiated CAFs promoted EMT of ESCC cells. • Irradiated fibroblasts induced nuclear β-catenin relocalization in ESCC cells. • Irradiated fibroblasts increased HDGF expression in vitro and in vivo.

  19. Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinoma

    PubMed Central

    Mori, Takahiro; Sumii, Makiko; Fujishima, Fumiyoshi; Ueno, Kazuko; Emi, Mitsuru; Nagasaki, Masao; Ishioka, Chikashi; Chiba, Natsuko

    2015-01-01

    BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that is involved in the regulation of cell growth. Recently, many somatic and germline mutations of BAP1 have been reported in a broad spectrum of tumors. In this study, we identified a novel somatic non-synonymous BAP1 mutation, a phenylalanine-to-isoleucine substitution at codon 170 (F170I), in 1 of 49 patients with esophageal squamous cell carcinoma (ESCC). Multiplex ligation-dependent probe amplification (MLPA) of BAP1 gene in this ESCC tumor disclosed monoallelic deletion (LOH), suggesting BAP1 alterations on both alleles in this tumor. The deubiquitinase activity and the auto-deubiquitinase activity of F170I-mutant BAP1 were markedly suppressed compared with wild-type BAP1. In addition, wild-type BAP1 mostly localizes to the nucleus, whereas the F170I mutant preferentially localized in the cytoplasm. Microarray analysis revealed that expression of the F170I mutant drastically altered gene expression profiles compared with expressed wild-type BAP1. Gene-ontology analyses indicated that the F170I mutation altered the expression of genes involved in oncogenic pathways. We found that one candidate, TCEAL7, previously reported as a putative tumor suppressor gene, was significantly induced by wild-type BAP1 as compared to F170I mutant BAP1. Furthermore, we found that the level of BAP1 expression in the nucleus was reduced in 44% of ESCC examined by immunohistochemistry (IHC). Because the nuclear localization of BAP1 is important for its tumor suppressor function, BAP1 may be functionally inactivated in a substantial portion of ESCC. Taken together, BAP1 is likely to function as a tumor suppressor in at least a part of ESCC. PMID:26081045

  20. Associations of ATM Polymorphisms With Survival in Advanced Esophageal Squamous Cell Carcinoma Patients Receiving Radiation Therapy

    SciTech Connect

    Du, Zhongli; Zhang, Wencheng; Zhou, Yuling; Yu, Dianke; Chen, Xiabin; Chang, Jiang; Qiao, Yan; Zhang, Meng; Huang, Ying; Wu, Chen; Xiao, Zefen; Tan, Wen; and others

    2015-09-01

    Purpose: To investigate whether single nucleotide polymorphisms (SNPs) in the ataxia telangiectasia mutated (ATM) gene are associated with survival in patients with esophageal squamous cell carcinoma (ESCC) receiving radiation therapy or chemoradiation therapy or surgery only. Methods and Materials: Four tagSNPs of ATM were genotyped in 412 individuals with clinical stage III or IV ESCC receiving radiation therapy or chemoradiation therapy, and in 388 individuals with stage I, II, or III ESCC treated with surgery only. Overall survival time of ESCC among different genotypes was estimated by Kaplan-Meier plot, and the significance was examined by log-rank test. The hazard ratios (HRs) and 95% confidence intervals (CIs) for death from ESCC among different genotypes were computed by a Cox proportional regression model. Results: We found 2 SNPs, rs664143 and rs664677, associated with survival time of ESCC patients receiving radiation therapy. Individuals with the rs664143A allele had poorer median survival time compared with the rs664143G allele (14.0 vs 20.0 months), with the HR for death being 1.45 (95% CI 1.12-1.89). Individuals with the rs664677C allele also had worse median survival time than those with the rs664677T allele (14.0 vs 23.5 months), with the HR of 1.57 (95% CI 1.18-2.08). Stratified analysis showed that these associations were present in both stage III and IV cancer and different radiation therapy techniques. Significant associations were also found between the SNPs and locosregional progression or progression-free survival. No association between these SNPs and survival time was detected in ESCC patients treated with surgery only. Conclusion: These results suggest that the ATM polymorphisms might serve as independent biomarkers for predicting prognosis in ESCC patients receiving radiation therapy.

  1. Endoscopic Ultrasound for Preoperative Esophageal Squamous Cell Carcinoma: a Meta-Analysis

    PubMed Central

    Huang, Xin-xin; Shan, Hong-bo; Luo, Guang-yu; Li, Yin; Lin, Shi-yong; Wang, Guo-bao; Zhang, Rong; Xu, Guo-liang; Li, Jian-jun

    2016-01-01

    Background Treatment options and prognosis of esophageal squamous cell carcinoma (ESCC) depend on the primary tumor depth (T-staging) and regional lymph node status (N-staging). Endoscopic ultrasound (EUS) has emerged as a useful staging tool, but studies regarding its benefits have been variable. The objective of this study was to evaluate the diagnostic accuracy of EUS for detecting preoperative ESCC. Methods We included in our meta-analysis studies involving EUS-based staging of preoperative ESCC compared with pathological staging. Using a random-effects model, we performed a meta-analysis of the accuracy of EUS by calculating pooled estimates of sensitivity, specificity and the diagnostic odds ratio. In addition, we created a summary receiver operating characteristic (SROC) curve. Results Forty-four studies (n = 2880) met the inclusion criteria. The pooled sensitivity and specificity of T1 were 77% (95%CI: 73 to 80) and 95% (95%CI: 94 to 96). Among the T1 patients, EUS had a pooled sensitivity in differentiating T1a and T1b of 84% (95%CI: 80 to 88) and 83% (95%CI: 80 to 86), and a specificity of 91% (95%CI: 88 to 94) and 89% (95%CI: 86 to 92). To stage T4, EUS had a pooled sensitivity of 84% (95%CI: 79 to 89) and a specificity of 96% (95%CI: 95 to 97). The overall accuracy of EUS for T-staging was 79% (95%CI: 77 to 80), and for N-staging, 71% (95%CI: 69 to 73). Conclusions EUS has good diagnostic accuracy for staging ESCC, which has better performance in T1 sub-staging (T1a and T1b) and advanced disease (T4). PMID:27387830

  2. Whole-Genome Sequencing Reveals Diverse Models of Structural Variations in Esophageal Squamous Cell Carcinoma

    PubMed Central

    Cheng, Caixia; Zhou, Yong; Li, Hongyi; Xiong, Teng; Li, Shuaicheng; Bi, Yanghui; Kong, Pengzhou; Wang, Fang; Cui, Heyang; Li, Yaoping; Fang, Xiaodong; Yan, Ting; Li, Yike; Wang, Juan; Yang, Bin; Zhang, Ling; Jia, Zhiwu; Song, Bin; Hu, Xiaoling; Yang, Jie; Qiu, Haile; Zhang, Gehong; Liu, Jing; Xu, Enwei; Shi, Ruyi; Zhang, Yanyan; Liu, Haiyan; He, Chanting; Zhao, Zhenxiang; Qian, Yu; Rong, Ruizhou; Han, Zhiwei; Zhang, Yanlin; Luo, Wen; Wang, Jiaqian; Peng, Shaoliang; Yang, Xukui; Li, Xiangchun; Li, Lin; Fang, Hu; Liu, Xingmin; Ma, Li; Chen, Yunqing; Guo, Shiping; Chen, Xing; Xi, Yanfeng; Li, Guodong; Liang, Jianfang; Yang, Xiaofeng; Guo, Jiansheng; Jia, JunMei; Li, Qingshan; Cheng, Xiaolong; Zhan, Qimin; Cui, Yongping

    2016-01-01

    Comprehensive identification of somatic structural variations (SVs) and understanding their mutational mechanisms in cancer might contribute to understanding biological differences and help to identify new therapeutic targets. Unfortunately, characterization of complex SVs across the whole genome and the mutational mechanisms underlying esophageal squamous cell carcinoma (ESCC) is largely unclear. To define a comprehensive catalog of somatic SVs, affected target genes, and their underlying mechanisms in ESCC, we re-analyzed whole-genome sequencing (WGS) data from 31 ESCCs using Meerkat algorithm to predict somatic SVs and Patchwork to determine copy-number changes. We found deletions and translocations with NHEJ and alt-EJ signature as the dominant SV types, and 16% of deletions were complex deletions. SVs frequently led to disruption of cancer-associated genes (e.g., CDKN2A and NOTCH1) with different mutational mechanisms. Moreover, chromothripsis, kataegis, and breakage-fusion-bridge (BFB) were identified as contributing to locally mis-arranged chromosomes that occurred in 55% of ESCCs. These genomic catastrophes led to amplification of oncogene through chromothripsis-derived double-minute chromosome formation (e.g., FGFR1 and LETM2) or BFB-affected chromosomes (e.g., CCND1, EGFR, ERBB2, MMPs, and MYC), with approximately 30% of ESCCs harboring BFB-derived CCND1 amplification. Furthermore, analyses of copy-number alterations reveal high frequency of whole-genome duplication (WGD) and recurrent focal amplification of CDCA7 that might act as a potential oncogene in ESCC. Our findings reveal molecular defects such as chromothripsis and BFB in malignant transformation of ESCCs and demonstrate diverse models of SVs-derived target genes in ESCCs. These genome-wide SV profiles and their underlying mechanisms provide preventive, diagnostic, and therapeutic implications for ESCCs. PMID:26833333

  3. Predicting the molecular role of MEIS1 in esophageal squamous cell carcinoma.

    PubMed

    Rad, Abolfazl; Farshchian, Moein; Forghanifard, Mohammad Mahdi; Matin, Maryam M; Bahrami, Ahmad Reza; Geerts, Dirk; A'rabi, Azadeh; Memar, Bahram; Abbaszadegan, Mohammad Reza

    2016-02-01

    The three amino acid loop extension (TALE) class myeloid ecotropic viral integration site 1 (MEIS1) homeobox gene is known to play a crucial role in normal and tumor development. In contrast with its well-described cancer stemness properties in hematopoietic cancers, little is known about its role in solid tumors like esophageal squamous cell carcinoma (ESCC). Here, we analyzed MEIS1 expression and its clinical relevance in ESCC patients and also investigated its correlation with the SOX2 self-renewal master transcription factor in the ESCC samples and in the KYSE-30 ESCC cell line. MEIS1 mRNA and protein expression were significantly decreased in ESCC disease (P < 0.05). The inverse correlation between MEIS1 mRNA expression and tumor cell metastasis to the lymph nodes (P = 0.004) was significant. Also, MEIS1 protein levels inversely correlated to lymph node involvement (P = 0.048) and high tumor stage (stages III/IV, P = 0.030). The low levels of DNA methylation in the MEIS1 promoter showed that this suppression does not depend on methylation. We showed that downregulation of EZH2 restored MEIS1 expression significantly. Also, we investigated that MEIS1 downregulation is concomitant with increased SOX2 expression. To the best of our knowledge, this is the first report on the MEIS1 gene in ESCC. The inverse correlation of MEIS1 with metastasis, tumor staging, and the role of EZH2 in methylation, together with its correlation with stemness factor SOX2 expression, led us to predict cancer stemness properties for MEIS1 in ESCC. PMID:26314854

  4. Genomic Analyses Reveal Mutational Signatures and Frequently Altered Genes in Esophageal Squamous Cell Carcinoma

    PubMed Central

    Zhang, Ling; Zhou, Yong; Cheng, Caixia; Cui, Heyang; Cheng, Le; Kong, Pengzhou; Wang, Jiaqian; Li, Yin; Chen, Wenliang; Song, Bin; Wang, Fang; Jia, Zhiwu; Li, Lin; Li, Yaoping; Yang, Bin; Liu, Jing; Shi, Ruyi; Bi, Yanghui; Zhang, Yanyan; Wang, Juan; Zhao, Zhenxiang; Hu, Xiaoling; Yang, Jie; Li, Hongyi; Gao, Zhibo; Chen, Gang; Huang, Xuanlin; Yang, Xukui; Wan, Shengqing; Chen, Chao; Li, Bin; Tan, Yongkai; Chen, Longyun; He, Minghui; Xie, Sha; Li, Xiangchun; Zhuang, Xuehan; Wang, Mengyao; Xia, Zhi; Luo, Longhai; Ma, Jie; Dong, Bing; Zhao, Jiuzhou; Song, Yongmei; Ou, Yunwei; Li, Enming; Xu, Liyan; Wang, Jinfen; Xi, Yanfeng; Li, Guodong; Xu, Enwei; Liang, Jianfang; Yang, Xiaofeng; Guo, Jiansheng; Chen, Xing; Zhang, Yanbo; Li, Qingshan; Liu, Lixin; Li, Yingrui; Zhang, Xiuqing; Yang, Huanming; Lin, Dongxin; Cheng, Xiaolong; Guo, Yongjun; Wang, Jun; Zhan, Qimin; Cui, Yongping

    2015-01-01

    Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets. PMID:25839328

  5. The implications and mechanisms of the extra-nuclear nucleolin in the esophageal squamous cell carcinomas.

    PubMed

    Qi, Jiafeng; Li, Huiling; Liu, Nanbo; Xing, Yutong; Zhou, Gang; Wu, Yao; Liu, Yuanhang; Chen, Wenxia; Yue, Jie; Han, Bater; Kang, Shirong; Wu, Xu

    2015-03-01

    In recent decades, the multi-functional protein nucleolin (NCL) has been reported to express outside the nucleus of many cancer cells. However, the expression and role of the extra-nuclear NCL in esophageal squamous cell carcinoma (ESCC) were not well characterized. Here, NCL was detected by immunohistochemistry and Western blotting in 60 ESCC tissues. Further, the associations of NCL, EGFR, CXCR4 and Ki67 were analyzed by in vitro assays. Our results showed that NCL expression in all 40 cases of ESCC tissues with metastasis was extensively located in the nucleus, cytoplasm and cell membrane (extra-nucleus), while NCL expression in all 20 cases of ESCC without metastasis was merely limited into the nucleus (intra-nucleus).The extra-nuclear NCL expression was positively correlated with the expression of EGFR, CXCR4 and Ki67 and serves as an independent prognostic factor for ESCC patients. In vitro, NCL siRNA (si-NCL) efficaciously affected the expression of EGF or SDF-1-induced p-AKT, p-ERK and Ki67. Also, NCL siRNA inhibited the capacity of migration and invasion of ECA109 cells. In conclusions, our study suggests that NCL is implicated in the initiation and transduction of EGFR and CXCR4 signaling and further up-regulates Ki67 expression to modulate the biological behaviors of ESCC. Clinically, the extra-nuclear NCL expression can be used as an important indicator to determine metastasis and predict the prognosis, which help develop new therapeutic strategies against ESCC. PMID:25631630

  6. Whole-Genome Sequencing Reveals Diverse Models of Structural Variations in Esophageal Squamous Cell Carcinoma.

    PubMed

    Cheng, Caixia; Zhou, Yong; Li, Hongyi; Xiong, Teng; Li, Shuaicheng; Bi, Yanghui; Kong, Pengzhou; Wang, Fang; Cui, Heyang; Li, Yaoping; Fang, Xiaodong; Yan, Ting; Li, Yike; Wang, Juan; Yang, Bin; Zhang, Ling; Jia, Zhiwu; Song, Bin; Hu, Xiaoling; Yang, Jie; Qiu, Haile; Zhang, Gehong; Liu, Jing; Xu, Enwei; Shi, Ruyi; Zhang, Yanyan; Liu, Haiyan; He, Chanting; Zhao, Zhenxiang; Qian, Yu; Rong, Ruizhou; Han, Zhiwei; Zhang, Yanlin; Luo, Wen; Wang, Jiaqian; Peng, Shaoliang; Yang, Xukui; Li, Xiangchun; Li, Lin; Fang, Hu; Liu, Xingmin; Ma, Li; Chen, Yunqing; Guo, Shiping; Chen, Xing; Xi, Yanfeng; Li, Guodong; Liang, Jianfang; Yang, Xiaofeng; Guo, Jiansheng; Jia, JunMei; Li, Qingshan; Cheng, Xiaolong; Zhan, Qimin; Cui, Yongping

    2016-02-01

    Comprehensive identification of somatic structural variations (SVs) and understanding their mutational mechanisms in cancer might contribute to understanding biological differences and help to identify new therapeutic targets. Unfortunately, characterization of complex SVs across the whole genome and the mutational mechanisms underlying esophageal squamous cell carcinoma (ESCC) is largely unclear. To define a comprehensive catalog of somatic SVs, affected target genes, and their underlying mechanisms in ESCC, we re-analyzed whole-genome sequencing (WGS) data from 31 ESCCs using Meerkat algorithm to predict somatic SVs and Patchwork to determine copy-number changes. We found deletions and translocations with NHEJ and alt-EJ signature as the dominant SV types, and 16% of deletions were complex deletions. SVs frequently led to disruption of cancer-associated genes (e.g., CDKN2A and NOTCH1) with different mutational mechanisms. Moreover, chromothripsis, kataegis, and breakage-fusion-bridge (BFB) were identified as contributing to locally mis-arranged chromosomes that occurred in 55% of ESCCs. These genomic catastrophes led to amplification of oncogene through chromothripsis-derived double-minute chromosome formation (e.g., FGFR1 and LETM2) or BFB-affected chromosomes (e.g., CCND1, EGFR, ERBB2, MMPs, and MYC), with approximately 30% of ESCCs harboring BFB-derived CCND1 amplification. Furthermore, analyses of copy-number alterations reveal high frequency of whole-genome duplication (WGD) and recurrent focal amplification of CDCA7 that might act as a potential oncogene in ESCC. Our findings reveal molecular defects such as chromothripsis and BFB in malignant transformation of ESCCs and demonstrate diverse models of SVs-derived target genes in ESCCs. These genome-wide SV profiles and their underlying mechanisms provide preventive, diagnostic, and therapeutic implications for ESCCs. PMID:26833333

  7. Genome-wide profiling of DNA methylation and gene expression in esophageal squamous cell carcinoma

    PubMed Central

    Chen, Chen; Peng, Hao; Huang, Xiaojie; Zhao, Ming; Li, Zhi; Yin, Ni; Wang, Xiang; Yu, Fenglei; Yin, Bangliang; Yuan, Yunchang; Lu, Qianjin

    2016-01-01

    Esophageal squamous cell carcinoma (ESCC) is the leading cause of cancer-related death worldwide. Previous studies have suggested that DNA methylation involved in the development of ESCC. However, the precise mechanisms underlying the regulation and maintenance of the methylome as well as their relationship with ESCC remain poorly understood. Herein, we used methylated DNA immunoprecipitation sequencing (MeDIP-Seq) and RNA-Seq to investigate whole-genome DNA methylation patterns and the genome expression profiles in ESCC samples. The results of MeDIP-Seq analyses identified differentially methylated regions (DMRs) covering almost the entire genome with sufficient depth and high resolution. The gene ontology (GO) analysis showed that the DMRs related genes belonged to several different ontological domains, such as cell cycle, adhesion, proliferation and apoptosis. The RNA-Seq analysis identified a total of 6150 differentially expressed genes (3423 up-regulated and 2727 down-regulated). The significant GO terms showed that these genes belonged to several molecular functions and biological pathways. Moreover, the bisulfite-sequencing of genes MLH1, CDH5, TWIST1 and CDX1 confirmed the methylation status identified by MeDIP-Seq. And the mRNA expression levels of MLH1, TWIST1 and CDX1 were consistent with their DNA methylation profiles. The DMR region of MLH1 was found to correlate with survival. The identification of whole-genome DNA methylation patterns and gene expression profiles in ESCC provides new insight into the carcinogenesis of ESCC and represents a promising avenue through which to investigate novel therapeutic targets. PMID:26683359

  8. Genome-wide profiling of DNA methylation and gene expression in esophageal squamous cell carcinoma.

    PubMed

    Chen, Chen; Peng, Hao; Huang, Xiaojie; Zhao, Ming; Li, Zhi; Yin, Ni; Wang, Xiang; Yu, Fenglei; Yin, Bangliang; Yuan, Yunchang; Lu, Qianjin

    2016-01-26

    Esophageal squamous cell carcinoma (ESCC) is the leading cause of cancer-related death worldwide. Previous studies have suggested that DNA methylation involved in the development of ESCC. However, the precise mechanisms underlying the regulation and maintenance of the methylome as well as their relationship with ESCC remain poorly understood. Herein, we used methylated DNA immunoprecipitation sequencing (MeDIP-Seq) and RNA-Seq to investigate whole-genome DNA methylation patterns and the genome expression profiles in ESCC samples. The results of MeDIP-Seq analyses identified differentially methylated regions (DMRs) covering almost the entire genome with sufficient depth and high resolution. The gene ontology (GO) analysis showed that the DMRs related genes belonged to several different ontological domains, such as cell cycle, adhesion, proliferation and apoptosis. The RNA-Seq analysis identified a total of 6150 differentially expressed genes (3423 up-regulated and 2727 down-regulated). The significant GO terms showed that these genes belonged to several molecular functions and biological pathways. Moreover, the bisulfite-sequencing of genes MLH1, CDH5, TWIST1 and CDX1 confirmed the methylation status identified by MeDIP-Seq. And the mRNA expression levels of MLH1, TWIST1 and CDX1 were consistent with their DNA methylation profiles. The DMR region of MLH1 was found to correlate with survival. The identification of whole-genome DNA methylation patterns and gene expression profiles in ESCC provides new insight into the carcinogenesis of ESCC and represents a promising avenue through which to investigate novel therapeutic targets. PMID:26683359

  9. Protein and gene expression characteristics of heterogeneous nuclear ribonucleoprotein H1 in esophageal squamous cell carcinoma

    PubMed Central

    Sun, Yu-Lin; Liu, Fei; Liu, Fang; Zhao, Xiao-Hang

    2016-01-01

    AIM To investigate the expression characteristics of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) mRNA and protein in cell lines and tissues of esophageal squamous cell carcinoma (ESCC). METHODS Western blotting was used to assess the expression of HNRNPH1 protein in seven ESCC cell lines and 30 paired fresh tissue specimens. The subcellular localization of HNRNPH1 was determined by immunofluorescence in ESCC cells. The RNA sequencing data from 87 patients with ESCC were obtained from the cancer genome atlas (TCGA), and the expression and clinical characteristics analysis of different transcript variants of HNRNPH1 were evaluated in this dataset. In addition, immunohistochemistry was carried out to detect the expression of HNRNPH1 protein in 125 patients. RESULTS The expression of HNRNPH1 protein varied across different ESCC cell lines. It was exclusively restricted to the nucleus of the ESCC cells. There are two transcript variants of the HNRNPH1 gene. Variant 1 was constitutively expressed, and its expression did not change during tumorigenesis. In contrast, levels of variant 2 were low in non-tumorous tissues and were dramatically increased in ESCC (P = 0.0026). The high levels of variant 2 were associated with poorer differentiated tumors (P = 0.0287). Furthermore, in paired fresh tissue specimens, HNRNPH1 protein was overexpressed in 73.3% (22/30) of neoplastic tissues. HNRNPH1 was significantly upregulated in ESCC, with strong staining in 43.2% (54/125) of tumor tissues and 22.4% (28/125) of matched non-cancerous tissues (P = 0.0005). Positive HNRNPH1 expression was significantly associated with poor tumor differentiation degree (P = 0.0337). CONCLUSION The different alternative transcript variants of HNRNPH1 exhibited different expression changes during tumorigenesis. Its mRNA and protein were overexpressed in ESCC and associated with poorer differentiation of tumor cells. These findings highlight the potential of HNRNPH1 in the therapy and diagnosis

  10. Pemetrexed plus dendritic cells as third-line therapy for metastatic esophageal squamous cell carcinoma

    PubMed Central

    Zhang, Bin; Li, Rui; Chang, Chun-Xiao; Han, Yong; Shi, Sheng-Bin; Tian, Jing

    2016-01-01

    This study was conducted to evaluate the toxicity and efficacy of pemetrexed plus dendritic cells (DCs) when administered as third-line treatment for metastatic esophageal squamous cell carcinoma (ESCC). All patients in the study group had previously failed first-line treatment with 5-fluorouracil and cisplatin-based regimens, as well as second-line treatment with taxane-based regimens. A total of 31 patients were treated with pemetrexed (500 mg/m2) plus DCs on day 1, every 3 weeks. DCs were given for one cycle of 21 days. Thirty patients were evaluated for their response. No patient had a complete response, three patients (10.0%) had a partial response, ten patients (33.3%) had stable disease, and 17 patients (56.7%) had progressive disease. The overall response rate was 10.0%. The median progression-free survival (PFS) time was 2.9 months (95% CI, 2.7–3.2), and the median overall survival (OS) time was 7.1 months (95% CI, 6.4–7.9). The median PFS and OS times among patients with high and low levels of miR-143 expression in their blood serum were significantly different: median PFS times =3.2 months (95% CI, 2.9–3.4) and 2.7 months (95% CI, 2.4–3.0), respectively (P=0.017), and median OS times =7.8 months (95% CI, 6.8–8.9) and 6.3 months (95% CI, 5.3–7.3), respectively (P=0.036). No patient experienced Grade 4 toxicity. Combined third-line treatment with pemetrexed and DCs was marginally effective and well tolerated in patients with advanced ESCC. Serum miR-143 levels are a potential biomarker for predicting the efficacy of pemetrexed plus DCs in the treatment of ESCC. PMID:27418834

  11. Plasma miRNA-506 as a Prognostic Biomarker for Esophageal Squamous Cell Carcinoma.

    PubMed

    Li, Shu-Ping; Su, Hong-Xin; Zhao, Da; Guan, Quan-Lin

    2016-01-01

    BACKGROUND MicroRNAs (miRNAs) are responsible for regulating proliferation, differentiation, apoptosis, invasion, and metastasis in tumor cells. miRNA-506 is abnormally expressed in multiple tumors, indicating that it might be oncogenic or tumor-suppressive. However, little is known about the association between miRNA-506 expression and esophageal squamous cell carcinoma (ESCC). MATERIAL AND METHODS We examined the expression of miRNA-506 in the plasma of ESCC patients using quantitative real-time polymerase chain reaction (qRT-PCR) to determine the association between miRNA-506 expression and clinicopathological features of ESCC. ROC curves were produced for ESCC diagnosis by plasma miRNA-506 and the area under curve was calculated to explore its diagnostic value. RESULTS Average miRNA-506 expression levels were remarkably higher in the plasma of ESCC patients than in healthy volunteers (P<0.001). The expression of miRNA-506 in the plasma was closely associated with lymph node status (P=0.004), TNM stage (P=0.031), and tumor length (P<0.001). According to ROC curves, the area under the curve for plasma miRNA-506 was 0.835, indicating statistical significance for ESCC diagnosis by plasma miRNA-506 (P<0.001). Kaplan-Meier analysis showed that patients with high miRNA-506 expression had significantly shorter survival time than those with low miRNA-506 expression. Cox regression analysis demonstrated that T stage, N stage, tumor length, and miRNA-506 expression levels were significantly correlated with prognosis in ESCC patients. CONCLUSIONS miRNA-506 can serve as an important molecular marker for diagnosis and prognostic prediction of ESCC. PMID:27345473

  12. Coexpression of periostin and EGFR in patients with esophageal squamous cell carcinoma and their prognostic significance

    PubMed Central

    Jia, Wei; Wang, Wei; Ji, Chu-shu; Niu, Jun-yang; Lv, Ya-jing; Zhou, Hang-cheng; Hu, Bing

    2016-01-01

    Background Both periostin (PN) and epidermal growth factor receptor (EGFR) can predict the prognosis of several carcinomas alone. However, coexpression of PN and EGFR in esophageal squamous cell carcinoma (ESCC) still remains unknown. We aimed to clarify their relationship with clinicopathological factors and prognostic significance of their coexpression in ESCC. Patients and methods In this single-center retrospective study, immunohistochemistry was performed to evaluate the expression of PN and EGFR in ESCC and paracarcinomatous tissues of 83 patients. The quantitative expression levels of PN and EGFR were examined in two ESCC and tumor-adjacent tissues. The levels of PN and EGFR expression were correlated with clinicopathological parameters by the χ2 or Kruskal–Wallis method. Spearman’s rank correlation test was performed to determine the relationship between PN and EGFR expression levels. Kaplan–Meier and Cox regression analyses were used to detect the prognostic factors of disease-free survival (DFS) and overall survival (OS). Results The high expression of PN protein in ESCC tissues was significantly associated with tumor length (P=0.044), differentiation grade (P=0.003), venous invasion (P=0.010), invasion depth (P=0.007), lymphatic metastasis (P=0.000), and tumor stage (P=0.000). The high expression of EGFR protein in ESCC tissues was only significantly related to lymphatic metastasis (P=0.000), invasion depth (P=0.022), and tumor stage (P=0.000). Kaplan–Meier analysis showed that high expression of PN was closely correlated to reduced OS (P=0.000) and DFS (P=0.000), which was consistent with EGFR expression. Cox regression analysis identified PN and EGFR as independent poor prognostic factors of OS and DFS in the ESCC patients (P<0.05). Moreover, the risk of death for the ESCC patients with low expression of two biomarkers and high expression of single biomarker was 0.243 times (P=0.000) and 0.503 times (P=0.030), respectively, than that for

  13. Factors associated with the presence of multiple Lugol-voiding lesions in patients with esophageal squamous-cell carcinoma.

    PubMed

    Katada, C; Muto, M; Tanabe, S; Higuchi, K; Sasaki, T; Azuma, M; Ishido, K; Katada, N; Sakuramoto, S; Yamashita, K; Masaki, T; Nakayama, M; Okamoto, M; Koizumi, W

    2014-07-01

    Multicentric squamous dysplasia of the esophagus is characterized by multiple Lugol-voiding lesions (LVLs) on Lugol chromoendoscopy. Multiple LVLs are associated with a very high risk of multiple cancers arising in the esophagus as well as the head and neck. To gain insight into the pathogenesis of multiple LVLs of the esophageal mucosa, we studied risk factors for the development of such lesions in 76 patients who had a current or previous diagnosis of esophageal squamous cell carcinoma. All patients underwent Lugol chromoendoscopy of the esophageal mucosa. The history of tobacco and alcohol use was documented. Polymorphisms of the aldehyde dehydrogenase type 2 (ALDH2) gene were identified by polymerase chain reaction using sequence-specific primers. Clinical factors related to multiple LVLs were analyzed. All patients with multiple LVLs were drinkers. On univariate analysis, male sex (odds ratio [OR] 15, 95% confidence interval [CI] 1.84-122.45: P = 0.011), presence of the ALDH2-2 allele (OR 4.5, 95% CI 1.55-13.24: P = 0.006), and smoking index ≥1000 (OR 2.6, 95% CI 1.02-6.6: P = 0.045) were associated with multiple LVLs. On multivariate analysis, male sex (OR 10.02, 95% CI 1.13-88.44: P = 0.038) and presence of the ALDH2-2 allele (OR 4.56, 95% CI 1.4-14.82: P = 0.012) were associated with multiple LVLs. Among drinkers, a daily alcohol intake of ≥100 g pure ethanol with the ALDH2-2 allele (OR 17.5, 95% CI 1.97-155.59: P = 0.01) and a daily alcohol intake of <100 g pure ethanol with the ALDH2-2 allele (OR 8.85, 95% CI 1.68-46.69: P = 0.01) more strongly correlated with multiple LVLs than did a daily alcohol intake of <100 g pure ethanol without the ALDH2-2 allele, whereas a daily alcohol intake of ≥100 g pure ethanol without the ALDH2-2 allele (OR 4.0, 95% CI 0.54-29.81: P = 0.18) did not. In conclusion, male sex and the ALDH2-2 allele are associated with an increased risk for multiple LVLs of the esophageal mucosa in patients with esophageal

  14. Adherence to Mediterranean-style dietary pattern and risk of esophageal squamous cell carcinoma: a case-control study in Iran

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The benefit of adherence to a Mediterranean-style dietary pattern in relation to the risk of esophageal squamous cell carcinoma (ESCC) has not been investigated among non-Mediterranean high-risk populations. The objective of the present study was to examine the association of compliance with the Med...

  15. Genome-wide analysis of the effect of esophageal squamous cell carcinoma on human umbilical vein endothelial cells.

    PubMed

    Jin, Guoguo; Yang, Yi; Liu, Hangfan; Liu, Kangdong; Zhao, Jimin; Chen, Xinhuan; Zhang, Xiaoyan; Zhang, Yanyan; Lu, Jing; Dong, Ziming

    2016-07-01

    A large volume of data indicates that controlling tumor-associated angiogenesis is a promising therapy against cancer. However, angiogenesis is a complex process, little is known about the differential gene expression in the process of normal endothelial cell differentiation toward tumor vascular endothelial cells induced by tumor microenvironment. The aim of this study is to investigate the effect of tumor microenvironment simulated by the supernatant of esophageal squamous cancer cells (KYSE70) on normal endothelial cells (HUVECs) at the whole genome level. The gene expression profile was studied through gene ontology and signal pathway analysis. Compared with the normal HUVECs, a total of 3769 differentially expressed genes in induced HUVECs were detected, including 1609 upregulated genes and 2160 downregulated genes. Moreover, the microarray data analysis showed that 11 significant biological processes and 10 significant signaling pathways changed most, which are associated with angiogenesis and cell differentiation. According to the different expression levels in the microarrays and their functions, four differentially expressed genes involved in tumor angiogenesis and cell differentiation (IL6, VEGFA, S1PR1, TYMP) were selected and analyzed by qRT-PCR. The qRT-PCR results were consistent with the microarray data. Furthermore, we simulated the tumor microenvironment by human esophageal carcinoma tissue homogenate to investigate its effect on HUVECs, the qRT-PCR results indicated that the above genes were highly expressed in HUVECs after induction by esophageal carcinoma tissue homogenate. In conclusion, tumor microenvironment impact on normal endothelial cells differentiated toward tumor vascular endothelial cells, and the selected genes, which are associated with tumor angiogenesis, would be anti-angiogenesis targets against esophageal carcinoma. PMID:27222202

  16. The tumor-suppressive role of BATF2 in esophageal squamous cell carcinoma.

    PubMed

    Han, Tianci; Wang, Zhiyong; Yang, Yang; Shu, Tianci; Li, Weinan; Liu, Dali; Li, Peiwen; Qi, Ruiqun; Ren, Yi; Li, Li; Liu, Hong; Zhang, Shuguang; Zhang, Lin

    2015-09-01

    BATF2 has been found to be decreased in a variety of human malignancies, while its clinical significance and functional roles in esophageal squamous cell carcinoma (ESCC) remain unknown. Herein, the aim of this study was to investigate the expression pattern and to explore the potential functions of BATF2 in ESCC tissues and cell lines. BATF2 mRNA and protein expression levels in human tissues and human ESCC cell lines were evaluated by quantitative real‑time polymerase chain reaction (qRT-PCR), western blotting (WB) and immunohistochemical (IHC) analyses. BATF2 was upregulated by transfection of the pcDNA3.1‑BATF2 plasmid into KYSE-410 cells. MTT and Transwell assays were used to investigate the effects of BATF2 on cellular proliferation and invasion. Survival curves were plotted using Kaplan-Meier plots and log-rank tests. Cox's proportional hazards regression model was used to analyze univariate and multivariate survival. The results showed that, compared to the matched non-tumor tissues from 36 ESCC patients, 80.56% (29/36) of the tumor tissues presented downregulation of BATF2 by WB analysis (P<0.001). The results of IHC in 104 patients who underwent surgery for ESCC showed that the expression of BATF2 was closely related to tumor differentiation (P=0.023) and lymph node metastasis (P=0.027), while there was no significant correlation with age (P=0.574), gender (P=0.357), tumor location (P=0.721) and TNM stage (P=0.126) of the patients. Pathological grade (P=0.027), clinical stage (P=0.000), lymph node metastasis (P=0.002) and BATF2 expression (P=0.028) were identified as independent prognostic factors for overall survival (OS). In the in vitro studies, upregulation of BATF2 expression significantly inhibited the proliferation and invasive ability of the human ESCC KYSE-410 cells. In conclusion, as a tumor suppressor, BATF2 serves as a prognostic biomarker of ESCC and it may be a potential therapeutic target for ESCC treatment. PMID:26135942

  17. Diagnostic and predictive significance of serum microRNA-7 in esophageal squamous cell carcinoma.

    PubMed

    Dong, Wei; Li, Baosheng; Wang, Juan; Song, Yipeng; Zhang, Zicheng; Fu, Chengrui; Zhang, Peiliang

    2016-03-01

    MicroRNA-7 has been reported to participate in tumorigenesis and progression by several signaling pathways in various tumors. However, its potential as a serum diagnostic factor and predictive biomarker for esophageal squamous cell carcinoma (ESCC) has not been studied. Serum samples were collected from 105 pathologically proven ESCC patients and 30 age- and gender-matched healthy controls. All patients were treated with concurrent chemoradiotherapy (CRT). Real‑time polymerase chain reaction was carried out to measure the serum miR-7 expression level. The data were compared among radio-sensitive and radio-resistant groups, and healthy volunteers to elucidate the diagnostic and predictive value of miR-7 expression. Finally, in vitro experiments are used to clarify the mechanisms of the miR-7. In the present study, we found that the serum miR-7 level of ESCC patients was 4.74-fold lower as compared with healthy subjects, indicating that serum miR-7 expression could be an excellent diagnostic factor. The serum miR-7 expression level for these responsive patients was 2.34‑fold higher than that for non-responsive patients, indicating it as a valuable biomarker for predicting treatment response of ESCC patients to concurrent chemoradiation treatment. We also found that miR-7 levels are strongly correlated with tumor length and the status of lymph node metastasis (P<0.05). In contrast, the responsiveness of therapy is significantly correlated with CEA (P<0.05), Cyfra21-1 (P<0.05), serum miR-7 level (P<0.05) and myelosuppression (P<0.01). In addition, the experimental data also suggest that miR-7 can interfere with EGFR mRNA translation. In ESCC patients, serum miR-7 has the potential to serve as a noninvasive biomarker of diagnosis and predicting treatment responses to concurrent chemoradiation therapy. ESCC patients with lower Cyfra21-1 and CEA, higher miR-7 and severe myelosuppression were much more sensitive to CRT. In addition, miR-7 may function by interfering

  18. SILAC-based quantitative proteomic approach to identify potential biomarkers from the esophageal squamous cell carcinoma secretome

    PubMed Central

    Kashyap, Manoj Kumar; Harsha, HC; Renuse, Santosh; Pawar, Harsh; Sahasrabuddhe, Nandini A; Kim, Min-Sik; Marimuthu, Arivusudar; Keerthikumar, Shivakumar; Muthusamy, Babylakshmi; Kandasamy, Kumaran; Subbannayya, Yashwanth; Prasad, Thottethodi Subrahmanya Keshava; Mahmood, Riaz; Chaerkady, Raghothama; Meltzer, Stephen J; Kumar, Rekha V; Rustgi, Anil K

    2010-01-01

    The identification of secreted proteins that are differentially expressed between non-neoplastic and esophageal squamous cell carcinoma (ESCC) cells can provide potential biomarkers of ESCC. We used a SILAC-based quantitative proteomic approach to compare the secretome of ESCC cells with that of non-neoplastic esophageal squamous epithelial cells. Proteins were resolved by SDS-PAGE and tandem mass spectrometry analysis (LC-MS/MS) of in-gel trypsindigested peptides was carried out on a high-accuracy qTOF mass spectrometer. In total, we identified 441 proteins in the combined secretomes, including 120 proteins with ≥ 2-fold upregulation in the ESCC secretome vs. that of non-neoplastic esophageal squamous epithelial cells. In this study, several potential protein biomarkers previously known to be increased in ESCC including matrix metalloproteinase 1, transferrin receptor and transforming growth factor beta-induced 68 kDa were identified as overexpressed in the ESCC-derived secretome. In addition, we identified several novel proteins that have not been previously reported to be associated with ESCC. Among the novel candidate proteins identified, protein disulfide isomerase family a member 3 (PDIA3), GDP dissociation inhibitor 2 (GDI2) and lectin galactoside binding soluble 3 binding protein (LGALS3BP) were further validated by immunoblot analysis and immunohistochemical labeling using tissue microarrays. This tissue microarray analysis showed overexpression of protein disulfide isomerase family a member 3, GDP dissociation inhibitor 2 and lectin galactoside binding soluble 3 binding protein in 93, 93 and 87% of 137 ESCC cases, respectively. Hence, we conclude that these potential biomarkers are excellent candidates for further evaluation to test their role and efficacy in the early detection of ESCC. PMID:20686364

  19. Radiotherapy With or Without Concurrent Chemotherapy for Lymph Node Recurrence After Radical Surgery of Thoracic Esophageal Squamous Cell Carcinoma

    SciTech Connect

    Lu Jincheng; Kong Cheng; Tao Hua

    2010-11-01

    Purpose: To retrospectively compare the outcomes of patients with lymph node recurrence after radical surgery of esophageal cancer, when given radiotherapy with or without concurrent chemotherapy. Methods and Materials: Between January 1996 and December 2005, the data from 73 patients with lymph node recurrence after radical surgery of thoracic esophageal squamous cell carcinoma were retrospectively reviewed. The patients were separated into two groups: radiochemotherapy (RC, 31 patients) and radiotherapy alone (RA, 42 patients). Patients in the RC group received at least two cycles of 5-fluorouracil/cisplatin chemotherapy concurrently with radiotherapy. Results: The median duration of follow-up was 11 months (range, 2-48). The overall survival rate for all patients was 46.7% and 4.7% at 1 and 3 years, respectively. The median overall survival time was 9 months (95% confidence interval, 6.96-11.04) and 17 months (95% confidence interval, 13.61-20.39) for RA and RC groups, respectively. The survival rate at 1 and 3 years was 62.5% and 10.5% in the RC group and 33.8% and 0% in the RA group (p = .0049, log-rank test; hazard ratio for death, 0.52; 95% confidence interval, 0.30-0.92). Acute toxicities were more frequent in the RC group than in the RA group. No significant differences were found in the late toxicity profiles between the two groups. Conclusion: The results of the present retrospective analysis suggest that RC should be considered an effective and well-tolerated treatment of patients with thoracic esophageal squamous cell carcinoma and postoperative lymph node recurrence.

  20. Differences in displacement of the proximal and distal ends of mid-upper thoracic esophageal squamous cell carcinoma

    PubMed Central

    QIU, GUOQIN; WEN, DENGSHUN; DU, XIANGHUI; SHENG, LIMING; ZHOU, XIA; JI, YONGLING; BAO, WUAN; ZHANG, DANHONG; CHENG, LEI

    2016-01-01

    In the present study, clips were used as markers to evaluate displacement differences between proximal and distal ends of esophageal tumors and to test whether their internal target volume (ITV) margins should be determined separately. A total of 23 patients with mid-upper thoracic esophageal squamous-cell carcinoma, a tumor length of ≤8 cm and an esophageal lumen suitable for endoscopic ultrasonography were recruited for the present study. Clips were implanted endoscopically at the proximal and distal ends of the esophageal tumor (upper and lower clips). In a further exploratory study on 16 of the patients, a third clip was placed at the distal esophagus 2 cm above the gastro-esophageal junction (GEJ) (cardiac clip). The clips were contoured for all 10 phases of the four-dimensional computed tomography and the maximum displacements of the clip centroids among different breathing phases in left-right (LR), superior-inferior (SI) and anterior-posterior (AP) directions were marked as x, y and z, respectively. The ITV margins that covered 95% of the LR, SI and AP motion were 2.89, 5.00 and 2.36 mm, respectively. Axial displacement (y) was greater than radial displacement (x, z; P<0.05). It was also revealed that LR(x), SI(y) and AP(z) displacement of cardiac clips was greater than that of upper or lower clips (P<0.05). Differences in the axial and radial displacement of the upper and lower clips indicated that axial and radial ITV margins should be determined separately. However, further study is required on patients in whom the distal tumor end is located in proximity to the GEJ. PMID:27330787

  1. Overexpression of Ku80 correlates with aggressive clinicopathological features and adverse prognosis in esophageal squamous cell carcinoma

    PubMed Central

    WANG, SHUAI; WANG, ZHOU; YANG, YU; SHI, MO; SUN, ZHENGUO

    2015-01-01

    Ku80, a subunit of the heterodymeric Ku protein, is clearly implicated in nonhomologous end joining DNA repair, chemoresistance and radioresistance in malignant tumors. In the present study, the clinicopathological significance of Ku80 in esophageal squamous cell carcinoma (ESCC) was investigated. The expression levels of Ku80 were determined by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry in ESCC specimens and normal esophageal mucosa. The mRNA and protein levels of Ku80 were significantly higher in ESCC tissues than in normal esophageal mucosa, and were significantly associated with tumor differentiation, local invasion, lymph node metastasis and tumor-node-metastasis (TNM) stage. However, overexpression of Ku80 mRNA and protein levels were not significantly correlated with age, gender, tumor site or tumor size. Cox proportional hazards regression model demonstrated that tumor local invasion, lymph node metastasis, TNM stage and Ku80 mRNA and protein levels were independent risk factors indicating the overall survival of patients with ESCC. The present study demonstrated that aberrant Ku80 overexpression is observed in ESCC. In addition, high expression levels of Ku80 are associated with adverse clinicopathological features and unfavorable prognosis in ESCC patients. PMID:26722230

  2. Targeting oncogenic PLCE1 by miR-145 impairs tumor proliferation and metastasis of esophageal squamous cell carcinoma

    PubMed Central

    Peng, Hao; Jin, Ting-Ting; Zhang, Shu-Mao; Liu, Chun-Xia; Yang, Lan; Shen, Yao-Yuan; Li, Shu-Gang; Li, Na; Li, Yong; Hu, Jian-Ming; Jiang, Jin-Fang; Suo, Jing; Qi, Yan; Liang, Wei-Hua; Wang, Liang-Hai; Dang, Hong-Wei; Li, Li; Cao, Wei-Wei; Wei, Yutao; Yin, Laibo; Wu, Chuan-Yue; Yuan, Xiang-Lin; Zhou, Hong; Zheng, Yu; Chen, Yun-Zhao; Li, Feng

    2016-01-01

    Phospholipase C epsilon 1 (PLCE1) is a susceptibility gene in esophageal squamous cell carcinoma (ESCC). Nevertheless, the role of PLCE1 in ESCC tumorigenesis has not been elucidated. In this study, we determined the function of PLCE1 and its regulatory microRNA (miRNA) in ESCC. PLCE1 protein was excessively expressed in ESCC and precancerous lesions compared with that in normal tissues. High PLCE1 expression levels in ESCC were significantly linked with poor overall survival. Knockdown of PLCE1 promoted the apoptosis, cytokine-induced apoptosis, and sensitivity of cancer cells to chemotherapeutic drugs but abrogated the proliferation and EMT phenotype of ESCC in vitro. Notably, miR-145 was newly identified as a potent repressor of PLCE1 expression by directly targeting the 3′UTR of PLCE1. MiR-145 also inhibited cell proliferation, migration, and metastasis, as well as controlled the cytoskeleton dynamics of esophageal cancer. Moreover, miR-145 was expressed at low levels in a large cohort of patients with ESCC and was inversely correlated with PLCE1 protein expression in cancer cells and tissues. These findings demonstrate that PLCE1 functions as tumor promoter in ESCC and can be suppressed by miR-145 through inhibition of PLCE1 translation. Hence, delivery of PLCE1-targeting miR-145 is a potential therapeutic approach for esophageal cancer. PMID:26657507

  3. Esophagitis may not be a Major Precursor Lesion for Esophageal Squamous Cell Carcinoma in a High Incidence Area in North-Eastern Iran.

    PubMed

    Abedi-Ardekani, B; Sotoudeh, M; Aghcheli, K; Semnani, S; Shakeri, R; Taghavi, N; Nasrollahzadeh, D; Fahimi, S; Islami, F; Marjani, H; Malekzadeh, R

    2011-03-01

    BACKGROUND Esophageal squamous cell carcinoma (ESCC) is usually detected in advanced stages resulting in a very poor prognosis. Early diagnosis needs identification of clinically relevant precancerous lesions which could become the target of screening and early treatment. Our aim was to check whether esophagitis could serve as a relevant histological precursor of ESCC in Northern Iran. METHODS During 2001-2005, all adult patients who were referred to Atrak clinic for upper gastrointestinal endoscopy and biopsy were enrolled. Atrak clinic is a major center for upper gastrointestinal cancer research in eastern Golestan. All subjects had been complaining of upper GI symptoms and were under further investigation to rule out cancer. Biopsies from the endoscopically normal mid-esophagus and also just above the esophago-gastric junction were obtained in all subjects whose esophagus appeared normal during endoscopy and from endoscopically normal appearing mucosa at the proximal vicinity of any detected mass. Microscopic examinations for the verification of the presence or absence of esophagitis was performed by independant histological examination of the samples by two pathologists. All the discrepant diagnoses were resolved in joint diagnostic sessions. RESULTS During the study period 836 patients were enrolled including 419 non cancer patients (endoscopy clinic controls), 387 cancer patients, and 30 subjects with clinical diagnosis of malignancy referred for histological reconfirmation of diagnosis by repeated biopsy. Mild or marked mid-esophagitis was diagnosed in 39 (9.3%), 47 (12.5%) and 12 (40%) of endoscopy clinic controls, cancer patients and those who were suspicious for upper gastrointestinal malignancies. CONCLUSION Our observation does not show evidence for esophagitis to be a predisposing factor for ESCC in Gonbad region In North Eastern Iran. PMID:25197529

  4. Esophagitis may not be a Major Precursor Lesion for Esophageal Squamous Cell Carcinoma in a High Incidence Area in North-Eastern Iran

    PubMed Central

    Abedi-Ardekani, B; Sotoudeh, M; Aghcheli, K; Semnani, S; Shakeri, R; Taghavi, N; Nasrollahzadeh, D; Fahimi, S; Islami, F; Marjani, H; Malekzadeh, R

    2011-01-01

    BACKGROUND Esophageal squamous cell carcinoma (ESCC) is usually detected in advanced stages resulting in a very poor prognosis. Early diagnosis needs identification of clinically relevant precancerous lesions which could become the target of screening and early treatment. Our aim was to check whether esophagitis could serve as a relevant histological precursor of ESCC in Northern Iran. METHODS During 2001–2005, all adult patients who were referred to Atrak clinic for upper gastrointestinal endoscopy and biopsy were enrolled. Atrak clinic is a major center for upper gastrointestinal cancer research in eastern Golestan. All subjects had been complaining of upper GI symptoms and were under further investigation to rule out cancer. Biopsies from the endoscopically normal mid-esophagus and also just above the esophago-gastric junction were obtained in all subjects whose esophagus appeared normal during endoscopy and from endoscopically normal appearing mucosa at the proximal vicinity of any detected mass. Microscopic examinations for the verification of the presence or absence of esophagitis was performed by independant histological examination of the samples by two pathologists. All the discrepant diagnoses were resolved in joint diagnostic sessions. RESULTS During the study period 836 patients were enrolled including 419 non cancer patients (endoscopy clinic controls), 387 cancer patients, and 30 subjects with clinical diagnosis of malignancy referred for histological reconfirmation of diagnosis by repeated biopsy. Mild or marked mid-esophagitis was diagnosed in 39 (9.3%), 47 (12.5%) and 12 (40%) of endoscopy clinic controls, cancer patients and those who were suspicious for upper gastrointestinal malignancies. CONCLUSION Our observation does not show evidence for esophagitis to be a predisposing factor for ESCC in Gonbad region In North Eastern Iran. PMID:25197529

  5. Clinical Study of Time Optimizing of Endoscopic Photodynamic Therapy on Esophageal and/or Gastric Cardiac Cancer

    ClinicalTrials.gov

    2015-12-10

    Stage I Esophageal Adenocarcinoma; Stage II Esophageal Adenocarcinoma; Stage III Esophageal Adenocarcinoma; Stage I Esophageal Squamous Cell Carcinoma; Stage II Esophageal Squamous Cell Carcinoma; Stage III Esophageal Squamous Cell Carcinoma

  6. Squamous Cell Carcinoma (SCC)

    MedlinePlus

    ... A A Squamous cell carcinoma typically develops in sun-damaged skin in fair-skinned patients. Overview Squamous ... skin cancer. Squamous cell carcinoma usually occurs on sun-damaged skin, especially in light-skinned individuals with ...

  7. Interleukin-6 as a potential molecular target in esophageal squamous cell carcinoma

    PubMed Central

    ZHAO, ZHI-FEI; LI, JIAN-XIONG; YE, RUI; WU, XUAN; GAO, LING-LING; NIU, BAO-LONG

    2016-01-01

    Knowledge of potential tumor markers may improve chemotherapeutic efficacy. Interleukin-6 (IL-6) expression in local tumor tissues is associated with cancer progression and poor prognosis in variety of cancer types. The aim of the present study was to investigate the role and potential application of IL-6 in determining the prognosis of esophageal carcinoma. KYSE170 and TE13 esophageal cancer cell lines were used to conduct cell- and animal-based experiments investigating biological changes and tumor behavior. Immunohistochemical analysis revealed that 70–80% of cancer cells exhibited positive staining for IL-6, compared with <15% of non-malignant epithelial cells. These immunohistochemical results were consistent with the mRNA expression levels detetced. The IL-6 silencing vector significantly reduced invasion and proliferation of the two cell lines and attenuated tumor growth in xenograft mouse models (P<0.05). The IL-6 silencing vector markedly reduced the presence of Ki-67 (a typical proliferation marker) and microvessel density, indicating that downregulation of IL-6 levels may greatly affect tumor growth and inhibition. The IL-6 silencing vector increased E-cadherin and matrix metalloproteinase (MMP)-9 expression levels in the two esophageal carcinoma cell lines. This vector also regulated the release of IL-6 in cell supernatant and serum in KYSE170- and TE13-tumor-bearing mice. The secretion of vascular endothelial growth factor and cluster of differentiation 31 (a nuclear protein) immunoreactive molecules were also reduced by the IL-6 silencing vector. Therefore, IL-6 may be an important trigger in the progression of angiogenesis and endothelial tube formation within the tumor, and targeting IL-6 may be a promising strategy for the treatment of esophageal cancer. PMID:26893670

  8. Regulatory Role of miR-203 in Occurrence and Progression of Kazakh Esophageal squamous cell carcinoma

    PubMed Central

    Hu, Jian Ming; Chang, Ai Min; Chen, Yun Zhao; Yuan, Xiang Lin; Li, Feng

    2016-01-01

    Esophageal carcinoma is one of the most common malignant tumors and the Kazakh national minority (ethnic) in Xinjiang (northwest of China) has been reported to be one of the highest incidence of Esophageal squamous cell carcinoma (ESCC) in the world. MicroRNA-203 (miR-203) was described as a tumor-suppressive miRNA in several cancers, but little study about the role of miR-203 in Kazakh ESCC. Therefore, we aimed to investigate the role of miR-203 in the occurrence and progression of Kazakh ESCC. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect miR-203 expression, and immunohistochemistry (IHC) was used to examine P63 expression. The expression level of miR-203 in ESCC was significantly lower than that of cancer adjacent normal (CAN) samples (P < 0.05). Whereas the expression level of P63 in ESCC was significantly higher than that of CAN samples (P < 0.05), an inverse association between the expression of P63 and miR-203 was found but was not statistically significant (P > 0.05). These findings suggest that miR-203 is a tumor suppressor gene that plays an important role in inhibiting the occurrence of Kazakh ESCC in Xinjiang, China. PMID:27029934

  9. Upregulation of MAGEA4 correlates with poor prognosis in patients with early stage of esophageal squamous cell carcinoma

    PubMed Central

    Tang, Wei-Wei; Liu, Zi-Hao; Yang, Tong-Xin; Wang, Han-Jin; Cao, Xiu-Feng

    2016-01-01

    Esophageal cancer is a common type of cancer in the People’s Republic of China. Many genes have been reported to be linked with it. Melanoma antigen gene family A (MAGEA) genes are frequently highly expressed in various types of carcinoma. However, the specific role of MAGEA gene expression in esophageal squamous cell carcinoma (ESCC) still remains unclear. MAGEA4 is a member of MAGEA genes. We aimed to investigate the expression and prognosis of MAGEA4 expression in ESCC. MAGEA4 messenger RNA expression levels of 120 pairs of tumor and nontumor tissues of patients with ESCC were measured by quantitative real-time polymerase chain reaction. The results showed that MAGEA4 messenger RNA was significantly elevated in tumor tissues of patients with ESCC compared to nontumor ones. In addition, overexpression of MAGEA4 messenger RNA was significantly correlated with poorer overall survival (P=0.018) in early stage of patients with ESCC (I–IIA). In conclusion, MAGEA4 played an important role in the early stage of ESCC and overexpression of MAGEA4 was expected to become a potential prognostic marker for patients with early stage of ESCC. PMID:27478386

  10. Serum miR-1297: a promising diagnostic biomarker in esophageal squamous cell carcinoma.

    PubMed

    Wang, Cong; Li, Qingbao; Liu, Fang; Chen, Xuan; Nesa, Effat Un; Guan, Shanghui; Liu, Bowen; Han, Lihui; Tan, Bingxu; Wang, Ding; Chen, Pengxiang; Liu, Xiaoyue; Zhang, Han; Sun, Ying; Cheng, Yufeng

    2016-09-01

    We aimed to value the diagnostic potential of serum miR-1297 in esophageal squamous cell cancer (ESCC). Its expression level was detected in 156 pairs of patients with ESCC and healthy volunteers using quantitative real-time polymerase chain reaction (qRT-PCR) method. It was statistically decreased in ESCC patients compared with healthy controls. AUC based on serum miR-1297 was 0.840 ± 0.035 in discovery group and 0.837 ± 0.034 in validation group. Further analysis on early-stage patients revealed that the AUC was 0.819 ± 0.053 in discovery group and 0.814 ± 0.044 in validation group. Its sensitivity and specificity were promising. In conclusion, serum miR-1297 can serve as an ideal indicator for the diagnosis of ESCC. PMID:27152453

  11. DNA polymorphism and risk of esophageal squamous cell carcinoma in a population of North Xinjiang, China

    PubMed Central

    Ma, Wen-Jing; Lv, Guo-Dong; Zheng, Shu-Tao; Huang, Cong-Gai; Liu, Qing; Wang, Xing; Lin, Ren-Yong; Sheyhidin, Ilyar; Lu, Xiao-Mei

    2010-01-01

    AIM: To investigate the role of metabolic enzyme and DNA repair genes in susceptibility of esophageal squamous cell carcinoma (ESCC). METHODS: A case-control study was designed with 454 samples from 128 ESCC patients and 326 gender, age and ethnicity-matched control subjects. Genotypes of 69 single nucleotide polymorphisms (SNPs) of metabolic enzyme (aldehyde dehydrogenase-2, ALDH2; alcohol dehydrogenase-1 B, ADHB1; Cytochrome P450 2A6, CYP2A6) and DNA repair capacity genes (excision repair cross complementing group 1, ERCC1; O6-methylguanine DNA methyltransferase, MGMT; xeroderma pigmentosum group A, XPA; xeroderma pigmentosum group A, XPD) were determined by the Sequenom MassARRAY system, and results were analyzed using unconditional logistic regression adjusted for age, gender. RESULTS: There was no association between the variation in the ERCC1, XPA, ADHB1 genes and ESCC risk. Increased risk of ESCC was suggested in ALDH2 for frequency of presence C allele of SNP [Rs886205: 1.626 (1.158-2.284)], XPD for C allele [Rs50872: 1.482 (1.058-2.074)], and MGMT for A allele [Rs11016897: 1.666 (1.245-2.228)]. Five variants of MGMT were associated with a protective effect on ESCC carcinogenesis, including C allele [Rs7069143: 0.698 (0.518-0.939)], C allele [Rs3793909: 0.653 (0.429-0.995)], A allele [Rs12771882: 0.719 (0.524-0.986)], C allele [Rs551491: 0.707 (0.529-0.945)], and A allele [Rs7071825: 0.618 (0.506-0.910)]. At the genotype level, increased risk of ESCC carcinogenesis was found in homozygous carriers of the ALDH2 Rs886205 [CC vs TT, odds ratios (OR): 3.116, 95% CI: 1.179-8.234], MGMT Rs11016879 (AA vs GG, OR: 3.112, 95% CI: 1.565-6.181), Rs12771882 (AA vs GG, OR: 2.442, 95% CI: 1.204-4.595), and heterozygotes carriers of the ALDH2 Rs886205 (CT vs TT, OR: 3.930, 95% CI: 1.470-10.504), MGMT Rs11016879 (AG vs GG, OR: 3.933, 95% CI: 2.216-6.982) and Rs7075748 (CT vs CC, OR: 1.949, 95% CI: 1.134-3.350), respectively. Three variants were associated with a protective

  12. Phase II trial of biweekly docetaxel, cisplatin, and 5-fluorouracil chemotherapy for advanced esophageal squamous cell carcinoma.

    PubMed

    Tanaka, Yoshihiro; Yoshida, Kazuhiro; Yamada, Atsuko; Tanahashi, Toshiyuki; Okumura, Naoki; Matsuhashi, Nobuhisa; Yamaguchi, Kazuya; Miyazaki, Tatsuhiko

    2016-06-01

    The prognosis of esophageal cancer patients is still unsatisfactory. Although a docetaxel, cisplatin, and 5-Fu (DCF) regimen has been reported, it is often difficult to accomplish because of severe toxicity. Therefore, we developed a new biweekly DCF (Bi-DCF) regimen and previously reported the recommended dose in a phase I dose-escalation study. We then performed a phase II study of Bi-DCF for advanced esophageal squamous cell carcinoma (SCC). Patients with clinical stage II/III were eligible. Patients received 2 courses of chemotherapy: docetaxel 35 mg/m(2) with cisplatin 40 mg/m(2) on days 1 and 15 and 400 mg/m(2) 5-fluorouracil on days 1-5 and 15-19 every 4 weeks. After completion of the chemotherapy, patients received esophagectomy. The primary endpoint was the completion rate of protocol treatment. Thirty-two patients were enrolled. The completion rate of protocol treatment (completion of two courses of preoperative chemotherapy and R0 surgery) was 100 %. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (31.3 %). No treatment-related death was observed, and the incidence of operative morbidity was tolerable. The overall response rate after the chemotherapy was 90.3 %. This Bi-DCF regimen was well tolerated and highly active. This trial was registered with the University Hospital Medical Information Network (No. UMIN 000014625). PMID:26896963

  13. HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway.

    PubMed

    Ge, Xiao-Song; Ma, Hua-Juan; Zheng, Xiao-Hui; Ruan, Hong-Lian; Liao, Xiao-Yu; Xue, Wen-Qiong; Chen, Yuan-Bin; Zhang, Ying; Jia, Wei-Hua

    2013-12-01

    Long non-coding RNAs (LncRNAs) have been recently found to be pervasively transcribed in the genome and critical regulators of the epigenome. HOTAIR, as a well-known LncRNA, has been found to play important roles in several tumors. Herein, the clinical application value and biological functions of HOTAIR were focused and explored in esophageal squamous cell carcinoma (ESCC). It was found that there was a great upregulation of HOTAIR in ESCC compared to their adjacent normal esophageal tissues. Meanwhile, patients with high HOTAIR expression have a significantly poorer prognosis than those with low expression. Moreover, HOTAIR was further validated to promote migration and invasion of ESCC cells in vitro. Then some specific molecules with great significance were investigated after HOTAIR overexpression using microarray and quantitative real time-polymerase chain reaction (qPCR). WIF-1 playing an important role in Wnt/β-catenin signaling pathway was selected and further tested by immunehistochemistry. Generally, inverse correlation between HOTAIR and WIF-1 expression was demonstrated both in ESCC cells and tissues. Mechanistically, HOTAIR directly decreased WIF-1 expression by promoting its histone H3K27 methylation in the promoter region and then activated the Wnt/β-catenin signaling pathway. This newly identified HOTAIR/WIF-1 axis clarified the molecular mechanism of ESCC cell metastasis and represented a novel therapeutic target in patients with ESCC. PMID:24118380

  14. Radiation-induced autophagy promotes esophageal squamous cell carcinoma cell survival via the LKB1 pathway.

    PubMed

    Lu, Chi; Xie, Conghua

    2016-06-01

    Radiotherapy is an important treatment modality for esophageal cancer; however, the clinical efficacy of radiotherapy is limited by tumor radioresistance. In the present study, we explored the hypothesis that radiation induces tumor cell autophagy as a cytoprotective adaptive response, which depends on liver kinase B1 (LKB1) also known as serine/threonine kinase 11 (STK11). Radiation-induced Eca-109 cell autophagy was found to be dependent on signaling through the LKB1 pathway, and autophagy inhibitors that disrupted radiation-induced Eca-109 cell autophagy increased cell cycle arrest and cell death in vitro. Inhibition of autophagy also reduced the clonogenic survival of the Eca-109 cells. When treated with radiation alone, human esophageal carcinoma xenografts showed increased LC3B and p-LKB1 expression, which was decreased by the autophagy inhibitor chloroquine. In vivo inhibition of autophagy disrupted tumor growth and increased tumor apoptosis when combined with 6 Gy of ionizing radiation. In summary, our findings elucidate a novel mechanism of resistance to radiotherapy in which radiation-induced autophagy, via the LKB1 pathway, promotes tumor cell survival. This indicates that inhibition of autophagy can serve as an adjuvant treatment to improve the curative effect of radiotherapy. PMID:27109915

  15. Type-specific detection of human papillomaviruses in Kazakh esophageal squamous cell carcinoma by genotyping both E6 and L1 genes with MALDI-TOF mass spectrometry

    PubMed Central

    Dong, Hong-Chao; Cui, Xiao-Bin; Wang, Liang-Hai; Li, Man; Shen, Yao-Yuan; Zhu, Jian-Bo; Li, Cheng-Fang; Hu, Jian-Ming; Li, Shu-Gang; Yang, Lei; Zhang, Wen-Jie; Chen, Yun-Zhao; Li, Feng

    2015-01-01

    Background: Many studies have suggested a relationship between human papillomavirus (HPV) infection and the risk of esophageal squamous cell carcinoma (ESCC). However, findings are inconclusive, potentially because of geographic heterogeneity and variations in detection methods. Objectives: We sought to further investigate the prevalence of HPV with a new detection method, the MassARRAY Sequenom technique, in esophageal squamous cell carcinomas occurring in patients belonging to Kazakh populations in Xinjiang, China. Study design: In the present study, a novel genotyping method for detecting 30 HPV genotypes, specifically by genotyping both the HPV E6 and L1 genes with multiplex PCR using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) (PCR-MS) was first adopted to evaluate HPV genotypes in 89 esophageal cancer samples and 49 matched adjacent normal esophageal tissues. Results: Six HPV genotypes (HPV6, HPV16, HPV33, HPV39, HPV51, and HPV82) were present in at least 51.7% of the esophageal carcinoma tissues, which was significantly greater than 28.6% prevalence among controls (P < 0.05). HPV16 was the most common of all the genotypes investigated (HPV16 prevalence in carcinoma tissue: 49.4%; odds ratio 3.02, 95% confidence interval 1.39-6.53). HPV-positive ESCC patients were generally younger than HPV-negative patients (P = 0.04). In addition, HPV infection was more common in cases of well-differentiated and shallower invasive depth. Conclusions: Based on this new detection method, our findings reiterate the possibility that HPV infection (especially HPV16) may be involved in the etiology of esophageal carcinoma in the Kazakh populations and that HPV E6 gene positivity may be associated with prognosis of patients. PMID:26722514

  16. A COX-2 inhibitor enhances the antitumor effects of chemotherapy and radiotherapy for esophageal squamous cell carcinoma.

    PubMed

    Yusup, Gulbostan; Akutsu, Yasunori; Mutallip, Muradil; Qin, Wei; Hu, Xin; Komatsu-Akimoto, Aki; Hoshino, Isamu; Hanari, Naoyuki; Mori, Mikito; Akanuma, Naoki; Isozaki, Yuka; Matsubara, Hisahiro

    2014-04-01

    Cyclooxygenase-2 (COX-2) is a key enzyme of prostaglandin (PG) synthesis that has been demonstrated to be overexpressed in several types of cancers. The function of COX-2 in tumor progression has been recently elucidated. In tumors in which COX-2 is overexpressed, the antitumor effects are suppressed. We examined the effects of celecoxib, a COX-2 inhibitor, in enhancing the antitumor effects of chemotherapy and radiotherapy for esophageal squamous cell carcinoma (ESCC) by reducing the COX-2 activity. We used the human esophageal squamous cell lines TE2 and T.Tn treated with celecoxib and 5-FU/radiation, after which cell viability assays were performed. Changes in the expressions of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) mRNA and PGE2 were also measured. In addition, apoptotic changes, and the invasion and migration activity in both the celecoxib and 5-FU treated cells were evaluated. The experiments showed that T.Tn and TE2 proliferation was strongly inhibited by the combination of 5-FU/radiation and the COX-2 inhibitor. Inhibiting the COX-2 activity induced a reduction in PGE2 levels in TE2/T.Tn cells. Following treatment with the COX-2 inhibitor and 5-FU, the OPRT expression was upregulated and the DPD expression was downregulated in the resistant cells. In addition, the combination treatment with the COX-2 inhibitor and 5-FU markedly inhibited both the cell invasion and migration activity. Therefore, COX-2 inhibitors can be useful enhancers of antitumor drugs and radiotherapy for ESCC. PMID:24535229

  17. Intraepithelial p63-dependent expression of distinct components of cell adhesion complexes in normal esophageal mucosa and squamous cell carcinoma.

    PubMed

    Thépot, Amélie; Hautefeuille, Agnès; Cros, Marie-Pierre; Abedi-Ardekani, Behnoush; Pétré, Aurélia; Damour, Odile; Krutovskikh, Vladimir; Hainaut, Pierre

    2010-11-01

    TP63 gene is a member of TP53 tumor suppressor gene family that encodes several protein isoforms involved in the process of epithelial stratification and in epithelial-mesenchyme interactions. TP63 is amplified in a significant proportion of squamous cell carcinoma of the esophagus (ESCC), resulting in the hyper-expression of DeltaNp63 as the major p63 isoform. To better understand the contribution of this high expression to tumorigenesis, we have analyzed the impact of intraepithelial p63 expression on the expression of cell adhesion complexes in normal esophagus and in ESCC cell lines. Cells expressing p63 showed an adhesion pattern characterized by lack of tight junctions and presence of adherens junctions. Cell differentiation was accompanied by a decrease in p63 and by a shift to adhesion patterns involving tight junctions. Silencing of p63 mRNA in ESCC cell lines resulted in a similar shift, characterized by increased expression of component of tight junctions, decreased cell-to-cell communication and downregulation of cell proliferation. These results indicate that DeltaNp63 may contribute to esophageal squamous carcinogenesis by maintaining cell adhesion patterns compatible with cell proliferation. PMID:20127860

  18. A Retrospective Comparison of Taxane and Fluorouracil-based Chemoradiotherapy in Patients with Inoperable Esophageal Squamous Cell Carcinoma

    PubMed Central

    Sun, Xiaojiang; Han, Shuiyun; Gu, Feiying; Lin, Gang; Wang, Zhun; Wang, Yuezhen; Xu, Yaping

    2016-01-01

    Purpose: To retrospectively compare taxane-based with fluorouracil-based chemoradiotherapy in terms of toxicity profiles, efficacy and survival in patients with inoperable esophageal cancer. Methods and Materials: We analyzed retrospectively 179 consecutive patients who were unresectable or medically unfit for surgery between March 2009 and November 2014. Eight-three patients were included in the taxane group and 96 cases were in the fluorouracil group. Results: The overall response rate (ORR) in the taxane group was higher than fluorouracil group, but was not significantly different (71.6% vs. 63.5%, respectively, P=0.255). In total, 53.0% (44/83) of the patients in the taxane group had progressive disease versus 54.2% (52/96) in the fluorouracil group (not significantly different (P=0.758)). There was no significant difference in overall response rate, progression free survival and overall survival, as well as treatment-related death. In terms of non-hematological toxicity, patients in the taxane group experienced a lower incidence of ≥ grade 3 esophageal perforation or fistula (4.8% vs. 13.5%, P=0.047) and pneumonia (4.8% vs. 9.7%, P=0.242). Regarding hematological toxicity, thrombocytopenia in the taxane group was significantly lower (4.8% vs. 13.5%, P=0.047), but there was a trend towards a higher rate of ≥ grade 3 leukopenia (34.9% vs.26.0%, P=0.196). Conclusions: Chemoradiation with taxane-based regimens is well tolerated, with potentially promising efficacy, and could become a good alternative treatment in a first line setting for patients with inoperable esophageal squamous cell carcinoma. PMID:27326249

  19. Dietary intake of minerals and risk of esophageal squamous cell carcinoma: results from the Golestan Cohort Study123

    PubMed Central

    Hashemian, Maryam; Poustchi, Hossein; Abnet, Christian C; Boffetta, Paolo; Dawsey, Sanford M; Brennan, Paul J; Pharoah, Paul; Etemadi, Arash; Kamangar, Farin; Sharafkhah, Maryam; Hekmatdoost, Azita; Malekzadeh, Reza

    2015-01-01

    Background: Dietary factors have been hypothesized to affect the risk of esophageal cancer via different mechanisms, but the intake of minerals is understudied and the evidence is conflicting. Objective: The objective was to evaluate the associations of dietary intake of minerals with risk of esophageal squamous cell carcinoma (ESCC). Design: We used data from the Golestan Cohort Study, which was launched in a high-risk region for esophageal cancer in Iran. Participants were enrolled in 2004–2008 and were followed to 2014. Intakes of minerals were assessed with a validated food-frequency questionnaire. A Cox proportional hazards model was used to estimate HRs and 95% CIs of ESCC for dietary intakes of selected minerals. Results: We identified 201 ESCC cases among 47,405 subjects. Calcium intake was significantly inversely associated with the risk of ESCC (HR per 100-mg/d increase: 0.88; 95% CI: 0.81, 0.96; P = 0.005; quartile 4 vs. quartile 1 HR: 0.49; 95% CI: 0.29, 0.82; P-trend = 0.013). Zinc intake was also inversely associated with ESCC, but the quartile association did not reach significance (HR per 1-mg/d increase: 0.87; 95% CI: 0.77, 0.98; P = 0.027; quartile 4 vs. quartile 1 HR: 0.56; 95% CI: 0.28, 1.12; P-trend = 0.097). The relations between dietary intakes of selenium, magnesium, and copper and risk of ESCC were nonlinear (P-nonlinear trend = 0.001, 0.016, and 0.029, respectively). There was no relation between dietary intake of manganese and the risk of ESCC. Conclusion: The results suggest that higher intakes of calcium and zinc are associated with a lower risk of ESCC in a high-risk region of Iran. PMID:26016858

  20. MicroRNA-373 promotes migration and invasion in human esophageal squamous cell carcinoma by inhibiting TIMP3 expression.

    PubMed

    Liu, Wenzhi; Li, Mengkao; Chen, Xiangming; Zhang, Dakai; Wei, Lin; Zhang, Zicheng; Wang, Shuang; Meng, Li; Zhu, Shan; Li, Baosheng

    2016-01-01

    Esophageal squamous cell carcinoma (ESCC) is the predominant pathological type of esophageal carcinoma in Asia. MicroRNAs (miRNAs) are a class of 19-22-nucleotide non-coding RNAs acting on target mRNAs that function as either oncogenes or anti-oncogenes. It has been confirmed that miR-373 expression varies among different tumor types. However, its mechanism is still unclear in ESCC. In our current study, we found that miR-373 expression was upregulated in ESCC tissues compared with matched adjacent normal tissues, as well as in the plasma of ESCC patients compared with that of healthy volunteers. Overexpression of miR-373 in ECA109 cells enhanced proliferation, G1-phase cell proportion, migration, and invasion. On the other hand, suppression of miR-373 in KYSE410 cells decreased proliferation, G1-phase cell proportion, migration, and invasion and also improved cell apoptosis. Moreover, we found that TIMP3, which was reported to suppress invasion and metastasis of ESCC, was a direct target of miR-373. Overexpression of miR-373 in ECA109 caused a reduction of TIMP3 mRNA and protein, whereas suppression of miR-373 in KYSE410 led to an increase of TIMP3 mRNA and protein. Introducing TIMP3 in miR-373 over-expressed cells or knocking down TIMP3 in miR-373 suppressed cells could partially abrogate the effect of miR-373 on migration and invasion. Therefore, these results prove that as an oncogene, miRNA-373 would be an important and reliable biomarker for ESCC diagnosis and treatment by targeting TIMP3. PMID:27073718

  1. Continuous Taurocholic Acid Exposure Promotes Esophageal Squamous Cell Carcinoma Progression Due to Reduced Cell Loss Resulting from Enhanced Vascular Development

    PubMed Central

    Sato, Sho; Yamamoto, Hiroto; Mukaisho, Ken-ichi; Saito, Shota; Hattori, Takanori; Yamamoto, Gaku; Sugihara, Hiroyuki

    2014-01-01

    Background Refluxogenic effects of smoking and alcohol abuse may be related to the risk of esophageal squamous cell carcinoma (ESCC). The present study attempts to clarify the effects of continuous taurocholic acid (TCA) exposure, which is neither mutagenic nor genotoxic, on ESCC progression. Methods A squamous carcinoma cell line (ESCC-DR) was established from a tumor induced in a rat model of gastroduodenal reflux. ESCC-DR cells were incubated with 2 mM TCA for ≥2 months. The effects of continuous TCA exposure were evaluated in vitro on cell morphology, growth, and invasion and in vivo on xenograft tumor growth in nude mice. Moreover, the mean level of secreted transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) proteins in cell culture supernatants and mRNA synthesis of TGF-β1 and VEGF-A of ESCC cells were measured. The angiogenic potential was further examined by a migration assay using human umbilical vein endothelial cells (HUVECs). Results Continuous TCA exposure induced marked formation of filopodia in vitro. Expression levels of angiogenic factors were significantly higher in the cells treated with TCA than in control cells. Tumor xenografts derived from cells pre-exposed to TCA were larger and more vascularized than those derived from control cells. In addition, TCA exposure increased HUVEC migration. Conclusion Continuous TCA exposure enhanced ESCC progression due to reduced cell loss in vivo. Cell loss was inhibited by TCA-induced vascular endothelial cell migration, which was mediated by TGF-β1 and VEGF-A released from ESCC cells. PMID:24551170

  2. Evaluation of the 7th edition of the TNM classification in patients with resected esophageal squamous cell carcinoma

    PubMed Central

    Wang, Jia; Wu, Nan; Zheng, Qing-Feng; Yan, Shi; Lv, Chao; Li, Shao-Lei; Yang, Yue

    2014-01-01

    AIM: To evaluate the prognostic factors and tumor stages of the 7th edition TNM classification for esophageal cancer. METHODS: In total, 1033 patients with esophageal squamous cell carcinoma (ESCC) who underwent surgical resection with or without (neo)adjuvant therapy between January 2003 and June 2012 at the Thoracic Surgery Department II of the Beijing Cancer Hospital, Beijing, China were included in this study. The following eligibility criteria were applied: (1) squamous cell carcinoma of the esophagus or gastroesophageal junction identified by histopathological examination; (2) treatment with esophagectomy plus lymphadenectomy with curative intent; and (3) complete pathologic reports and follow-up data. Patients who underwent non-curative (R1) resection and patients who died in hospital were excluded. Patients who received (neo)adjuvant therapy were also included in this analysis. All patients were restaged using the 7th edition of the Union for International Cancer Control and the American Joint Committee on Cancer TNM staging systems. Univariate and multivariate analyses were performed to identify the prognostic factors for survival. Survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to evaluate differences between the subgroups. RESULTS: Of the 1033 patients, 273 patients received (neo)adjuvant therapy, and 760 patients were treated with surgery alone. The median follow-up time was 51.6 mo (range: 5-112 mo) and the overall 5-year survival rate was 36.4%. Gender, “pT” and “pN” descriptors, (neo)adjuvant therapy, and the 7th edition TNM stage grouping were independent prognostic factors in the univariate and multivariate analyses. However, neither histologic grade nor cancer location were independent prognostic factors in the univariate and multivariate analyses. The 5-year stage-based survival rates were as follows: IA, 84.9%; IB, 70.9%; IIA, 56.2%; IIB, 43.3%; IIIA, 37.9%; IIIB, 23.3%; IIIC,12.9% and IV, 3

  3. Abnormal Localization and Tumor Suppressor Function of Epithelial Tissue-Specific Transcription Factor ESE3 in Esophageal Squamous Cell Carcinoma.

    PubMed

    Wang, Li; Xing, Jie; Cheng, Rui; Shao, Ying; Li, Peng; Zhu, Shengtao; Zhang, Shutian

    2015-01-01

    Esophageal cancer is one of the most common malignant cancers worldwide. The molecular mechanism of esophageal squamous cell carcinoma (ESCC) is still poorly understood. ESE3 is a member of the Ets transcription family, which is only expressed in epithelial tissues and acts as a tumor suppressor gene in prostate cancer. Our study aim was to confirm whether ESE3 is involved in the carcinogenesis of ESCC. Immunohistochemical analysis revealed that ESE3 was mainly located in cell nuclei of normal tissues and the cytoplasm in ESCC tissues. Immunofluorescence and western blot analyses of the normal esophageal cell line HEEpiC and ESCC cell lines EC9706 TE-1, KYSE150, and KYSE410 confirmed these results. pEGFP-ESE3 and pcDNA3.1-V5/HisA-ESE3 plasmids were constructed for overexpression of ESE3 in EC9706 and KYSE150 cells. The stably transfected cells showed restoration of the nuclear localization of ESE3. EC9706 cells with re-localization of ESE3 to the nucleus showed inhibition of proliferation, colony formation, migration, and invasion. To explore the possible mechanism of the differences in localization of ESE3 in normal esophageal cells and ESCC cells, ESCC cell lines were treated with the nuclear export inhibitor leptomycin B, transcription inhibitor actinomycin D, PKC inhibitor sphinganine, P38 MAPK inhibitor SB202190, and CK II inhibitor TBCA. These reagents were chosen according to the well-known mechanisms of protein translocation. However, the localization of ESE3 was unchanged after these treatments. The sequence of ESE3 cDNA in ESCC cells was identical to the standard sequence of ESE3 in the NCBI Genebank database, indicating that there was no mutation in the coding region of ESE3 in ESCC. Taken together, our study suggests that ESE3 plays an important role in the carcinogenesis of ESCC through changes in subcellular localization and may act as a tumor suppressor gene in ESCC, although the mechanisms require further study. PMID:25950810

  4. Evaluation of tumor metastasis-associated markers for molecular classification in patients with esophageal squamous cell carcinoma

    PubMed Central

    Huang, Jun-Xing; Yao, Juan; Lin, Mao-Song; Lin, Mei; Xiao, Wei; Yu, Hong; Chen, Ping; Qian, Rong-Yu

    2015-01-01

    This study aims to ascertain the relationship of tumor metastasis-associated markers cyclin D1, connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) with the clinicopathologic features and prognosis of patients with esophageal squamous cell carcinoma (ESCC), and to investigate their value in ESCC molecular classification. The expression of cyclin D1, CTGF and VEGF in 100 specimens from patients and 20 from normal esophageal mucosa were detected by immunohistochemistry. The relationship of their expression with prognosis of the patients with ESCC was evaluated by Cox regression model and Kaplan-Meier survival curve analysis. High levels of expression of cyclin D1, CTGF, and VEGF were observed in 61 (61%), 53 (53%), 49 (49%) cases, respectively. Univariate survival analysis indicated that the levels of expression of cyclin D1, CTGF and VEGF were associated with survival (all P-value < 0.05). Multivariate analysis indicated that cyclin D1 and VEGF were independent prognostic factors affecting the three-year survival rate of patients (P = 0.001, 0.017, respectively). Furthermore, high level expression of cyclin D1, CTGF and VEGF in stage I patients was found associated with poor three-year survival rate (all P-value < 0.05). The prognosis probably was favorable for patients with low expression of cyclin D1 even in stage III, or VEGF even in stage IV. Tumor metastasis-associated markers such as cyclin D1 and VEGF may be independent prognostic factors affecting survival rate of postoperative ESCC patients. It is possible to judge prognosis better and tailor treatments to each individual patient when these markers were applied to ESCC molecular classification. PMID:26629095

  5. Body mass index and long‐term risk of death from esophageal squamous cell carcinoma in a Chinese population

    PubMed Central

    Wang, Shao‐Ming; Fan, Jin‐Hu; Jia, Meng‐Meng; Yang, Zhao; Zhang, Yu‐Qing; Taylor, Philip R.

    2016-01-01

    Abstract Background Studies based on Western populations have found that body mass index (BMI) is positively related to the risk of esophageal adenocarcinoma but inversely associated with esophageal squamous cell carcinoma (ESCC). Little reliable evidence exists of an association between BMI and ESCCin China, where ESCC incidence is high but BMI is low. Methods We evaluated the BMI‐ESCC association in a population‐based prospective study of 29 446 Chinese aged 40–69 with 27 years of follow‐up. China‐specific BMI cut‐offs (underweight < 18.5, healthy ≥ 18.5 to <24, overweight ≥ 24 to <28, and obese ≥ 28) and quartile categories were used to define BMI subgroups. Adjusted hazard ratios (HRs) and confidence intervals (CIs) for death from ESCC by BMI subgroups were calculated using Cox proportional hazards models. Results During a median follow‐up duration of 21.2 years (555 439 person‐years), 2436 ESCC deaths were identified. BMI was protective for death from ESCC with an HR of 0.97 (95% CI 0.95–0.99) for each unit increase in BMI. Relative to healthy weight, HRs for BMI were 1.21 (95% CI 1.02–1.43) for the underweight group and 0.87 (95% CI 0.78–0.98) for the overweight. Categorical quartile analyses found people with BMIs in the Q3 and Q4 groups had 16% and 13% reductions in the risk of ESCC, respectively. Gender‐specific analyses found that clear effects were evident in women only. Conclusions Higher BMI was associated with a reduced risk of ESCC in aChinese population. PMID:27385979

  6. Multiple region whole-exome sequencing reveals dramatically evolving intratumor genomic heterogeneity in esophageal squamous cell carcinoma

    PubMed Central

    Cao, W; Wu, W; Yan, M; Tian, F; Ma, C; Zhang, Q; Li, X; Han, P; Liu, Z; Gu, J; Biddle, F G

    2015-01-01

    Cancer is a disease of genome instability and genomic alterations; now, genomic heterogeneity is rapidly emerging as a defining feature of cancer, both within and between tumors. Motivation for our pilot study of tumor heterogeneity in esophageal squamous cell carcinoma (ESCC) is that it is not well studied, but the highest incidences of esophageal cancers are found in China and ESCC is the most common type. We profiled the mutations and changes in copy number that were identified by whole-exome sequencing and array-based comparative genomic hybridization in multiple regions within an ESCC from two patients. The average mutational heterogeneity rate was 90% in all regions of the individual tumors in each patient; most somatic point mutations were nonsynonymous substitutions, small Indels occurred in untranslated regions of genes, and copy number alterations varied among multiple regions of a tumor. Independent Sanger sequencing technology confirmed selected gene mutations with more than 88% concordance. Phylogenetic analysis of the somatic mutation frequency demonstrated that multiple, genomically heterogeneous divergent clones evolve and co-exist within a primary ESCC and metastatic subclones result from the dispersal and adaptation of an initially non-metastatic parental clone. Therefore, a single-region sampling will not reflect the evolving architecture of a genomically heterogeneous landscape of mutations in ESCC tumors and the divergent complexity of this genomic heterogeneity among patients will complicate any promise of a simple genetic or epigenetic diagnostic signature in ESCC. We conclude that any potential for informative biomarker discovery in ESCC and targeted personalized therapies will require a deeper understanding of the functional biology of the ontogeny and phylogeny of the tumor heterogeneity. PMID:26619400

  7. MicroRNA-218 inhibits the proliferation and metastasis of esophageal squamous cell carcinoma cells by targeting BMI1

    PubMed Central

    WANG, TING; CHEN, TENGFEI; NIU, HUA; LI, CHANG; XU, CHUN; LI, YUANYUAN; HUANG, RUI; ZHAO, JUN; WU, SHUYAN

    2015-01-01

    MicroRNAs (miRNAs or miRs) play a pivotal role in esophageal carcinogenesis either as oncogenes or as tumor suppressor genes. In the present study, we found that the expression level of miR-218 was significantly reduced in esophageal squamous cell carcinoma (ESCC) tissues and ESCC cell lines. Moreover, its expression was found to correlate with the clinicopathological stage of ESCC; miR-218 expression was lower in the stage III tissue samples than in the stage I and II tissue samples. Furthermore, the decreased expression of miR-218 was found to be associated with an enhanced ESCC cell proliferation and metastasis. Western blot analysis and luciferase reporter assay revealed that miR-218 decreased BMI1 expression by binding to the putative binding sites in its 3′-untranslated region (3′-UTR). The BMI1 mRNA expression levels were markedly increased and negatively correlated with the miR-218 expression level in the ESCC tissues. Functional analyses revealed that the restoration of miR-218 expression inhibited ESCC cell proliferation, migration and invasion and promoted apoptosis. The knockdown of BMI1 by siRNA showed the same phenocopy as the effect of miR-218 on ESCC cells, indicating that BMI1 was a major target of miR-218. In the present study, our findings confirm miR-218 as a tumor suppressor and identify BMI1 as a novel target of miR-218 in ESCC. Therefore, miR-218 may prove to be a useful biomarker for monitoring the initiation and development of ESCC, and may thus be an effective therapeutic target in ESCC. PMID:25999024

  8. Postoperative Radiation Therapy With or Without Concurrent Chemotherapy for Node-Positive Thoracic Esophageal Squamous Cell Carcinoma

    SciTech Connect

    Chen, Junqiang; Pan, Jianji; Liu, Jian; Li, Jiancheng; Zhu, Kunshou; Zheng, Xiongwei; Chen, Mingqiang; Chen, Ming; Liao, Zhongxing

    2013-07-15

    Purpose: To retrospectively compare the efficacy of radiation therapy (RT) and chemotherapy plus RT (CRT) for the postoperative treatment of node-positive thoracic esophageal squamous cell carcinoma (TESCC) and to determine the incidence and severity of toxic reactions. Methods and Materials: We retrospectively reviewed data from 304 patients who had undergone esophagectomy with 3-field lymph node dissection for TESCC and were determined by postoperative pathology to have lymph node metastasis without distant hematogenous metastasis. Of these patients, 164 underwent postoperative chemotherapy (cisplatin 80 mg/m{sup 2}, average days 1-3, plus paclitaxel 135 mg/m{sup 2}, day 1; 21-day cycle) plus RT (50 Gy), and 140 underwent postoperative RT alone. Results: The 5-year overall survival rates for the CRT and RT groups were 47.4% and 38.6%, respectively (P=.030). The distant metastasis rate, the mixed (regional lymph node and distant) metastasis rate, and the overall recurrence rate were significantly lower in the CRT group than in the RT group (P<.05). However, mild and severe early toxic reactions, including neutropenia, radiation esophagitis, and gastrointestinal reaction, were significantly more common in the CRT group than in the RT group (P<.05). No significant differences in incidence of late toxic reactions were found between the 2 groups. Conclusions: Our results show that in node-positive TESCC patients, postoperative CRT is significantly more effective than RT alone at increasing the overall survival and decreasing the rates of distant metastasis, mixed metastasis, and overall recurrence. Severe early toxic reactions were more common with CRT than with RT alone, but patients could tolerate CRT.

  9. Pralatrexate and Oxaliplatin in Treating Patients With Unresectable or Metastatic Esophageal, Stomach, or Gastroesophageal Junction Cancer

    ClinicalTrials.gov

    2016-01-11

    Adenocarcinoma of the Gastroesophageal Junction; Esophageal Undifferentiated Carcinoma; Gastric Adenocarcinoma; Gastric Squamous Cell Carcinoma; Recurrent Esophageal Adenocarcinoma; Recurrent Esophageal Squamous Cell Carcinoma; Recurrent Gastric Carcinoma; Stage IIIB Esophageal Adenocarcinoma; Stage IIIB Esophageal Squamous Cell Carcinoma; Stage IIIB Gastric Cancer; Stage IIIC Esophageal Adenocarcinoma; Stage IIIC Esophageal Squamous Cell Carcinoma; Stage IIIC Gastric Cancer; Stage IV Esophageal Adenocarcinoma; Stage IV Esophageal Squamous Cell Carcinoma; Stage IV Gastric Cancer; Undifferentiated Gastric Carcinoma

  10. Apoptotic effect of gambogic acid in esophageal squamous cell carcinoma cells via suppression of the NF-κB pathway

    PubMed Central

    LIU, WEN-YUE; WU, XU; LIAO, CHENG-QUAN; SHEN, JIE; LI, JUN

    2016-01-01

    Despite extensive investigations of therapeutic improvements for surgical techniques, chemotherapy and chemoradiotherapy, esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive forms of cancer, and the prognosis for patients with advanced ESCC remains poor. Therefore, effective therapies are urgently required in order to improve the prognosis of patients with ESCC. TE-1 cells were treated with gambogic acid (GA), and then subjected to western blot analysis, TUNEL assay and caspase activity analysis. GA significantly induced apoptosis in ESCC TE-1 cells. In addition, the antitumor activity of GA was accompanied by the decreased expression of phosphorylated-protein kinase B (p-AKT) and nuclear factor of κ light polypeptide gene enhancer in B-cells 1 (NF-κB). The inhibition of protein kinase B (AKT) and NF-κB activation by chemical inhibitors augmented the apoptotic effect responses to GA in the TE-1 cells. The pan-caspase inhibitor z-VAD-fmk (zVAD) decreased GA-induced apoptosis. Furthermore, zVAD attenuated GA-induced growth inhibition in TE-1 cells. GA induced apoptosis in ESCC TE-1 via suppression of NF-κB pathway. The findings of the present study may provide a novel insight into ESCC treatment. PMID:27284372

  11. Integrin α5 promotes tumor progression and is an independent unfavorable prognostic factor in esophageal squamous cell carcinoma.

    PubMed

    Xie, Jian-Jun; Guo, Jin-Cheng; Wu, Zhi-Yong; Xu, Xiu-E; Wu, Jian-Yi; Chen, Bo; Ran, Li-Qiang; Liao, Lian-Di; Li, En-Min; Xu, Li-Yan

    2016-02-01

    The integrin family plays a major role in complex biological events such as differentiation, development, wound healing, and the altered adhesive and invasive properties of tumor cells. The expression and function of integrin α5 in esophageal squamous cell carcinoma (ESCC) are not clear. Here, by using tissue microarrays and immunohistochemical method, integrin α5 expression was retrospectively evaluated in 147 samples of human ESCC. Results showed that expression of integrin α5 was heterogeneous and varied from negative to intense expression in a membrane and cytoplasmic distribution manner. High expression of integrin α5 was significantly correlated with lymph node metastasis (P = .042) and tumor size (P = .042). Kaplan-Meier analysis revealed that high expression of integrin α5 was related to poor overall survival of ESCC patients (P = .018). Multivariate analysis suggested that integrin α5 expression status was an independent prognostic factor for ESCC (P = .003). Moreover, integrin α5 expression was associated with the survival of patients with lymph node metastasis (P = .020), but did not influence the survival of patients without lymph node metastasis. Finally, we found that RNAi-mediated knockdown of integrin α5 led to decreased growth, migration, and invasion of ESCC cells. Combined, integrin α5 might play important roles in the progression of ESCC. Integrin α5 is a novel biomarker to predict the prognosis of ESCC patients. PMID:26772401

  12. Fibroblast growth factor receptor 1 gene amplification is associated with poor survival in patients with resected esophageal squamous cell carcinoma

    PubMed Central

    Kim, Dae Joon; Lee, Chang-Geol; Hur, Jin; Chung, Hyunsoo; Park, Jun Chul; Jung, Da Hyun; Shin, Sung Kwan; Lee, Sang Kil; Lee, Yong Chan; Kim, Hye Ryun; Moon, Yong Wha; Kim, Joo Hang; Shim, Young Mog; Jewell, Susan S.; Kim, Hyunki; Choi, Yoon-La; Cho, Byoung Chul

    2015-01-01

    To investigate the frequency and the prognostic impact of fibroblast growth factor receptor 1 (FGFR1) gene amplification in 526 curatively resected esophageal squamous cell carcinoma (ESCC). Using fluorescent in situ hybridization, high amplification was defined by an FGFR1/centromer 8 ratio is ≥ 2.0, or average number of FGFR1 signals/tumor cell nucleus ≥ 6.0, or percentage of tumor cells containing ≥ 15 FGFR1 signals or large cluster in ≥ 10%. Low amplification was defined by ≥ 5 FGFR1 signals in ≥ 50%. FGFR2 and FGFR3 mutations were assessed by direct sequencing in 388 cases and no mutation was detected. High and low amplification were detected in 8.6% and 1.1%, respectively. High FGFR1 amplification had significantly shorter disease-free survival (34.0 vs 158.5 months P=0.019) and overall survival (52.2 vs not reached P=0.022) than low/no amplification group. After adjusting for sex, smoking, stage, histology, and adjuvant treatment, high FGFR1 amplification had a greater risk of recurrence (adjusted hazard ratio [AHR], 1.6; P=0.029) and death (AHR, 1.53; P=0.050). High amplification was significantly higher in current smokers than former and never-smokers (Ptrend<0.001) and increased proportional to smoking dosage. High FGFR1 amplification is a frequent oncogenic alteration and an independent poor prognostic factor in resected ESCC. PMID:25537505

  13. Downregulation of cell division cycle 25 homolog C reduces the radiosensitivity and proliferation activity of esophageal squamous cell carcinoma.

    PubMed

    Yin, Yachao; Dou, Xiaoyan; Duan, Shimiao; Zhang, Lei; Xu, Quanjing; Li, Hongwei; Li, Duojie

    2016-09-30

    Radiation therapy is one of the most important methods of contemporary cancer treatment. Cells in the G2 and M phases are more sensitive to radiation therapy, and cell division cycle 25 homolog C (CDC25C) is essential in shifting the cell cycle between these two phases. In this study, the knockdown of CDC25C in human esophageal squamous carcinoma EC9706 cells was mediated by transfecting shRNA against human CDC25C-subcloning into pGV248. The levels of CDC25C mRNA and protein expression were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting, respectively. Moreover, cell proliferation and radiosensitivity were measured. Stable CDC25C-knockdown EC9706 cell lines were successfully established. Furthermore, the proliferation of both control and CDC25C-shRNA-EC9706 cells was inhibited after the cells were treated with increasing X-ray doses, and the proliferation of the control cells was affected more significantly (p<0.05). Moreover, cell colony formation assays allowed us to reach the same conclusion. Taken together, our experiments demonstrated that the knockdown of CDC25C can reduce both the radiotherapy sensitivity and the proliferation activity of EC9706 cells. Thus, CDC25C might be a potential biomarker for radiotherapy treatment. PMID:27188256

  14. SU-E-I-85: Exploring the 18F-Fluorodeoxyglucose PET Characteristics in Staging of Esophageal Squamous Cell Carcinoma

    SciTech Connect

    Ma, C; Yin, Y

    2014-06-01

    Purpose: The aim of this study was to explore the characteristics derived from 18F-fluorodeoxyglucose (18F-FDG) PET image and assess its capacity in staging of esophageal squamous cell carcinoma (ESCC). Methods: 26 patients with newly diagnosed ESCC who underwent 18F-FDG PET scan were included in this study. Different image-derived indices including the standardized uptake value (SUV), gross tumor length, texture features and shape feature were considered. Taken the histopathologic examination as the gold standard, the extracted capacities of indices in staging of ESCC were assessed by Kruskal-Wallis test and Mann-Whitney test. Specificity and sensitivity for each of the studied parameters were derived using receiver-operating characteristic curves. Results: 18F-FDG SUVmax and SUVmean showed statistically significant capability in AJCC and TNM stages. Texture features such as ENT and CORR were significant factors for N stages(p=0.040, p=0.029). Both FDG PET Longitudinal length and shape feature Eccentricity (EC) (p≤0.010) provided powerful stratification in the primary ESCC AJCC and TNM stages than SUV and texture features. Receiver-operating-characteristic curve analysis showed that tumor textural analysis can capability M stages with higher sensitivity than SUV measurement but lower in T and N stages. Conclusion: The 18F-FDG image-derived characteristics of SUV, textural features and shape feature allow for good stratification AJCC and TNM stage in ESCC patients.

  15. miR-502 medaited histone methyltransferase SET8 expression is associated with outcome of esophageal squamous cell carcinoma.

    PubMed

    Wang, Cuiju; Wu, Jianhua; Zhao, Yue; Guo, Zhanjun

    2016-01-01

    The histone methyltransferase SET8, whose expression is regulated by miR-502 though the binding site in the 3' UTR of SET8, implicated in cancer development. Single nucleotide polymorphism (SNP) of rs16917496 located in the miR-502 and SET8 binding site was analyzed in esophageal squamous cell carcinoma (ESCC) patients, the SET8 C/C genotype was independently associated with longer post-operative survival by multivariate analysis (relative risk, 2.250; 95% CI, 1.041-4.857; p = 0.039). Moreover, the reduced SET8 expression mediated by SET8 C/C genotype was associated with longer ESCC survival. Functional assay indicated that the SET8 knock down could inhibit proliferation and promote apoptosis of ESCC cells. The subsequent assay also showed the markedly inhibition of ESCC cell migration and invasion by SET8 knock down. Our data suggested that the altering SET8 expression, which is mediated at least partly by miR-502 through changing the binding affinity between miR-502 and SET8 3' UTR, could modify the ESCC outcome by inhibiting the proliferation and invasion as well as promoting the apoptosis of ECSS cell. Our data indicated that SET8 was a new target for ESCC therapy. PMID:27605386

  16. Local production of the chemokines CCL5 and CXCL10 attracts CD8+ T lymphocytes into esophageal squamous cell carcinoma

    PubMed Central

    Ping, Yu; Wang, Liping; Chen, Xinfeng; Wang, Dan; Cao, Ling; Zhao, Song; Li, Bing; Kalinski, Pawel; Thorne, Stephen H.; Zhang, Bin; Zhang, Yi

    2015-01-01

    Esophageal squamous cell carcinoma (ESCC) is a very common malignant tumor with poor prognosis in China. Chemokines secreted by tumors are pivotal for the accumulation of CD8+ T lymphocytes within malignant lesions in several types of cancers, but the exact mechanism underlying CD8+ T lymphocyte homing is still unknown in ESCC. In this study, we revealed that, compared with marginal tissues, the expression of both chemokine (C-C motif) ligand 5 (CCL5) and (C-X-C motif) ligand 10 (CXCL10) was upregulated in ESCC tissues. CCL5 expression was positively associated with the overall survival of patients. Meanwhile, RT-PCR data showed that the expression of CCL5 and CXCL10 was positively correlated with the local expressions of the CD8+ T lymphocyte markers (CD8 and Granzyme B) in tumor tissues. Correspondingly, CD8+ T lymphocytes were more frequently CCR5- and CXCR3-positive in tumor than in peripheral blood. Transwell analysis showed both CCL5 and CXCL10 were important for the chemotactic movement of CD8+ T lymphocytes. Our data indicate that CCL5 and CXCL10 serve as the key chemokines to recruit CD8+ T lymphocytes into ESCC tissue and may play a role in patient survival. PMID:26317795

  17. Enhanced expression of early mitotic inhibitor-1 predicts a poor prognosis in esophageal squamous cell carcinoma patients

    PubMed Central

    GUAN, CHENGQI; ZHANG, JIANFENG; ZHANG, JIANGUO; SHI, HUI; NI, RUNZHOU

    2016-01-01

    Early mitotic inhibitor-1 (Emi1), as a key cell cycle regulatory gene, induces S phase and mitotic entry by controlling anaphase-promoting complex substrates. Emi1 overexpression may be a prognostic factor for patients with invasive breast cancer. However, its expression and clinical significance in esophageal squamous cell carcinoma (ESCC) remain unknown. In the present study, Emi1 was overexpressed in ESCC samples, contrarily to their neighboring normal tissues. The expression of Emi1 was correlated with histological differentiation (P=0.032), lymphatic metastasis (P=0.006) and Ki-67 expression (P=0.028). Multivariate analysis indicated that the presence of lymphatic metastasis and the protein expression levels of Emi1 and Ki-67 were all independent prognostic factors for ESCC patients (P=0.042, 0.018 and 0.001, respectively). In vitro, however, the expression of Emi1 was upregulated in the ECA109 cell line following release from serum starvation. In addition, depletion of endogenous Emi1 by small interfering RNA could effectively reduce cell proliferation. Thus, the present data indicated that Emi1 expression was upregulated in ESCC tissues and correlated with poor survival in ESCC patients, and suggested that Emi1 may be an independent prognostic factor for ESCC patients. PMID:27347110

  18. High Expression of LAMP3 Is a Novel Biomarker of Poor Prognosis in Patients with Esophageal Squamous Cell Carcinoma.

    PubMed

    Liao, Xiaoyu; Chen, Yuanbin; Liu, Deqing; Li, Fangfang; Li, Xizhao; Jia, Weihua

    2015-01-01

    Lysosomal-associated membrane protein 3 (LAMP3), identified as a molecular marker of mature dendritic cells, is one of the LAMP family members. Its expression was induced by hypoxia, and was associated with hypoxia mediated metastasis in breast and cervical cancers. However, epithelial expression of LAMP3 and its prognostic value in esophageal squamous cell carcinoma (ESCC) is still unknown. In the current study, mRNA expression of LAMP3 in 157 ESCC tissues and 50 adjacent normal tissues was detected by quantitative real-time PCR (qRT-PCR). LAMP3 protein expression in 46 paired cancerous and normal tissues was detected by immunohistochemistry (IHC). Then, DNA copy number was examined to observe its potential correlation with mRNA expression. The results showed that both mRNA and protein expression level of LAMP3 was significantly higher in cancerous tissues compared with normal controls (p < 0.001). LAMP3 DNA copy number was amplified in 70% of ESCC tissues and positive correlated with mRNA expression (p = 0.037). Furthermore, patients with higher LAMP3 expression had worse overall survival (HR = 1.90, 95% CI = 1.17-3.09, p = 0.010) and disease-free survival (HR = 1.80, 95% CI = 1.18-2.74, p = 0.006). In conclusion, our results suggest that epithelial LAMP3 expression is an independent prognostic biomarker for ESCC. PMID:26263981

  19. miR-502 medaited histone methyltransferase SET8 expression is associated with outcome of esophageal squamous cell carcinoma

    PubMed Central

    Wang, Cuiju; Wu, Jianhua; Zhao, Yue; Guo, Zhanjun

    2016-01-01

    The histone methyltransferase SET8, whose expression is regulated by miR-502 though the binding site in the 3′ UTR of SET8, implicated in cancer development. Single nucleotide polymorphism (SNP) of rs16917496 located in the miR-502 and SET8 binding site was analyzed in esophageal squamous cell carcinoma (ESCC) patients, the SET8 C/C genotype was independently associated with longer post-operative survival by multivariate analysis (relative risk, 2.250; 95% CI, 1.041–4.857; p = 0.039). Moreover, the reduced SET8 expression mediated by SET8 C/C genotype was associated with longer ESCC survival. Functional assay indicated that the SET8 knock down could inhibit proliferation and promote apoptosis of ESCC cells. The subsequent assay also showed the markedly inhibition of ESCC cell migration and invasion by SET8 knock down. Our data suggested that the altering SET8 expression, which is mediated at least partly by miR-502 through changing the binding affinity between miR-502 and SET8 3′ UTR, could modify the ESCC outcome by inhibiting the proliferation and invasion as well as promoting the apoptosis of ECSS cell. Our data indicated that SET8 was a new target for ESCC therapy. PMID:27605386

  20. Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations.

    PubMed

    Wu, Chen; Wang, Zhaoming; Song, Xin; Feng, Xiao-Shan; Abnet, Christian C; He, Jie; Hu, Nan; Zuo, Xian-Bo; Tan, Wen; Zhan, Qimin; Hu, Zhibin; He, Zhonghu; Jia, Weihua; Zhou, Yifeng; Yu, Kai; Shu, Xiao-Ou; Yuan, Jian-Min; Zheng, Wei; Zhao, Xue-Ke; Gao, She-Gan; Yuan, Zhi-Qing; Zhou, Fu-You; Fan, Zong-Min; Cui, Ji-Li; Lin, Hong-Li; Han, Xue-Na; Li, Bei; Chen, Xi; Dawsey, Sanford M; Liao, Linda; Lee, Maxwell P; Ding, Ti; Qiao, You-Lin; Liu, Zhihua; Liu, Yu; Yu, Dianke; Chang, Jiang; Wei, Lixuan; Gao, Yu-Tang; Koh, Woon-Puay; Xiang, Yong-Bing; Tang, Ze-Zhong; Fan, Jin-Hu; Han, Jing-Jing; Zhou, Sheng-Li; Zhang, Peng; Zhang, Dong-Yun; Yuan, Yuan; Huang, Ying; Liu, Chunling; Zhai, Kan; Qiao, Yan; Jin, Guangfu; Guo, Chuanhai; Fu, Jianhua; Miao, Xiaoping; Lu, Changdong; Yang, Haijun; Wang, Chaoyu; Wheeler, William A; Gail, Mitchell; Yeager, Meredith; Yuenger, Jeff; Guo, Er-Tao; Li, Ai-Li; Zhang, Wei; Li, Xue-Min; Sun, Liang-Dan; Ma, Bao-Gen; Li, Yan; Tang, Sa; Peng, Xiu-Qing; Liu, Jing; Hutchinson, Amy; Jacobs, Kevin; Giffen, Carol; Burdette, Laurie; Fraumeni, Joseph F; Shen, Hongbing; Ke, Yang; Zeng, Yixin; Wu, Tangchun; Kraft, Peter; Chung, Charles C; Tucker, Margaret A; Hou, Zhi-Chao; Liu, Ya-Li; Hu, Yan-Long; Liu, Yu; Wang, Li; Yuan, Guo; Chen, Li-Sha; Liu, Xiao; Ma, Teng; Meng, Hui; Sun, Li; Li, Xin-Min; Li, Xiu-Min; Ku, Jian-Wei; Zhou, Ying-Fa; Yang, Liu-Qin; Wang, Zhou; Li, Yin; Qige, Qirenwang; Yang, Wen-Jun; Lei, Guang-Yan; Chen, Long-Qi; Li, En-Min; Yuan, Ling; Yue, Wen-Bin; Wang, Ran; Wang, Lu-Wen; Fan, Xue-Ping; Zhu, Fang-Heng; Zhao, Wei-Xing; Mao, Yi-Min; Zhang, Mei; Xing, Guo-Lan; Li, Ji-Lin; Han, Min; Ren, Jing-Li; Liu, Bin; Ren, Shu-Wei; Kong, Qing-Peng; Li, Feng; Sheyhidin, Ilyar; Wei, Wu; Zhang, Yan-Rui; Feng, Chang-Wei; Wang, Jin; Yang, Yu-Hua; Hao, Hong-Zhang; Bao, Qi-De; Liu, Bao-Chi; Wu, Ai-Qun; Xie, Dong; Yang, Wan-Cai; Wang, Liang; Zhao, Xiao-Hang; Chen, Shu-Qing; Hong, Jun-Yan; Zhang, Xue-Jun; Freedman, Neal D; Goldstein, Alisa M; Lin, Dongxin; Taylor, Philip R; Wang, Li-Dong; Chanock, Stephen J

    2014-09-01

    We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 × 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 × 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 × 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC. PMID:25129146

  1. Zoledronic acid suppresses metastasis of esophageal squamous cell carcinoma cells through upregulating the tight junction protein occludin.

    PubMed

    Lin, Canfeng; Xin, Shubo; Qin, Xin; Li, Haijun; Lin, Lianxing; You, Yanjie

    2016-08-01

    We have previously demonstrated the radio-sensitizing effect of zoledronic acid (ZOL), a third generation bisphosphonate, on human esophageal squamous cell carcinoma (ESCC) cells. Here we show that ZOL suppresses metastatic progression of ESCC cells mainly through up-regulating the tight junction protein occludin. Exposure to ZOL at lower concentrations dramatically reduced migration and invasion of ESCC cells. In addition, ZOL treatment decreased the expression of mesenchymal markers, vimentin and N-cadherin, while increased the expression of the tight junction protein occludin. Moreover, ectopic expression of Slug, a well-known transcriptional repressor of occludin, partially but significantly abrogated the effect of ZOL on occludin expression and subsequently rescued the malignant metastatic phenotype, suggesting that Slug is one of the mediators underlying the anti-metastatic effect of ZOL. The present study is the first to report the significance of ZOL on ESCC metastasis. These data are promising for the future application of this drug regimen in patients with ESCC. PMID:26204820

  2. Tooth loss and lack of regular oral hygiene are associated with higher risk of esophageal squamous cell carcinoma

    PubMed Central

    Abnet, Christian C.; Kamangar, Farin; Islami, Farhad; Nasrollahzadeh, Dariush; Brennan, Paul; Aghcheli, Karim; Merat, Shahin; Pourshams, Akram; Marjani, Haj Amin; Ebadati, Abdolhakim; Sotoudeh, Masoud; Boffetta, Paolo; Malekzadeh, Reza; Dawsey, Sanford M.

    2008-01-01

    We tested the association between tooth loss and oral hygiene and the risk of esophageal squamous cell carcinoma (ESCC) in people living in a high risk area of Iran. We used a case-control study of pathologically-confirmed ESCC cases (N=283) and controls (N=560) matched on sex, age, and neighborhood. Subjects with ESCC had significantly more decayed, missing, or filled teeth with a median (interquartile range) of 31 (23-32) compared to controls 28 (2-32) (P=0.0045). And subjects with ESCC were significantly more likely than controls to fail to practice regular oral hygiene, 78% versus 58%. In multivariate adjusted conditional logistic regression models having 32 decayed, missing, or filled teeth compared to ≤15 conferred an OR (95% CI) of 2.10 (1.19-3.70). Compared to daily tooth brushing, practicing no regular oral hygiene conferred an OR (95% CI) of 2.37 (1.42-3.97). Restricting the analysis to subjects that had never smoked tobacco did not materially alter these results. We found significant associations between two markers of poor oral hygiene, a larger number of decayed, missing, or filled teeth and lack of daily tooth brushing, and risk of ESCC in a population at high risk for ESCC where many cases occur in never smokers. Our results are consistent with several previous analyses in other high risk populations. PMID:18990747

  3. PIM1 polymorphism and PIM1 expression as predisposing factors of esophageal squamous cell carcinoma in the Asian population

    PubMed Central

    Wu, Yuan-Bo; Lu, Di; He, Zhi-Feng; Jin, Chan-Guan

    2016-01-01

    Our study aimed to identify the association between a PIM1 polymorphism and PIM1 expression levels with clinicopathological features of esophageal squamous cell carcinoma (ESCC). A total of 168 patients with ESCC were recruited as the case group, and 180 healthy individuals were included as the control group. Polymerase chain reaction-direct sequencing was employed to analyze all genotypes containing the PIM1 −1 882 A>T mutation. Immunohistochemistry was used to detect PIM1 expression. The distributions of genotype AA and allele A of PIM1 −1 882 A>T were higher in the case group than in the control group (both P<0.05). AT + TT carriers had a lower risk of ESCC than AA carriers (P<0.05). PIM1 polymorphism was related to the invasion depth, degree of differentiation, and lymphatic metastasis of ESCC (P<0.05). PIM1 expression was associated with lymphatic metastasis of ESCC and PIM1 polymorphism (both P<0.05). PIM1 −1 882 A>T and the overexpression of PIM1 were associated with the clinicopathological features of ESCC, and PIM1 −1 882 A>T may help to reduce the risk of ESCC in the Asian population. PMID:27274285

  4. Characterization of gene rearrangements resulted from genomic structural aberrations in human esophageal squamous cell carcinoma KYSE150 cells.

    PubMed

    Hao, Jia-Jie; Gong, Ting; Zhang, Yu; Shi, Zhi-Zhou; Xu, Xin; Dong, Jin-Tang; Zhan, Qi-Min; Fu, Song-Bin; Wang, Ming-Rong

    2013-01-15

    Chromosomal rearrangements and involved genes have been reported to play important roles in the development and progression of human malignancies. But the gene rearrangements in esophageal squamous cell carcinoma (ESCC) remain to be identified. In the present study, array-based comparative genomic hybridization (array-CGH) was performed on the ESCC cell line KYSE150. Eight disrupted genes were detected according to the obviously distinct unbalanced breakpoints. The splitting of these genes was validated by dual-color fluorescence in-situ hybridization (FISH). By using rapid amplification of cDNA ends (RACE), genome walking and sequencing analysis, we further identified gene disruptions and rearrangements. A fusion transcript DTL-1q42.2 was derived from an intrachromosomal rearrangement of chromosome 1. Highly amplified segments of DTL and PTPRD were self-rearranged. The sequences on either side of the junctions possess micro-homology with each other. FISH results indicated that the split DTL and PTPRD were also involved in comprising parts of the derivative chromosomes resulted from t(1q;9p;12p) and t(9;1;9). Further, we found that regions harboring DTL (1q32.3) and PTPRD (9p23) were also splitting in ESCC tumors. The data supplement significant information on the existing genetic background of KYSE150, which may be used as a model for studying these gene rearrangements. PMID:23026210

  5. Downregulation of p70S6K Enhances Cell Sensitivity to Rapamycin in Esophageal Squamous Cell Carcinoma.

    PubMed

    Lu, Zhaoming; Peng, Kezheng; Wang, Ning; Liu, Hong-Min; Hou, Guiqin

    2016-01-01

    It has been demonstrated that mTOR/p70S6K pathway was abnormally activated in many cancers and rapamycin and its analogs can restrain tumor growth through inhibiting this pathway, but some tumors including esophageal squamous cell carcinoma (ESCC) appear to be insensitive to rapamycin in recent studies. In the present study, we explored the measures to improve the sensitivity of ESCC cells to rapamycin and identified the clinical significance of the expression of phosphorylated p70S6K (p-p70S6K). The results showed that, after downregulating the expression of p70S6K and p-p70S6K by p70S6K siRNA, the inhibitory effects of rapamycin on cell proliferation, cell cycle, and tumor growth were significantly enhanced in vitro and in vivo. Furthermore, p-p70S6K had strong positive expression in ESCC tissues and its expression was closely related to lymph node metastasis and the TNM staging. These results indicated that p-p70S6K may participate in the invasion and metastasis in the development of ESCC and downregulation of the expression of p-p70S6K could improve the sensitivity of cells to rapamycin in ESCC. PMID:27595116

  6. Exploration of potential roles of a new LOXL2 splicing variant using network knowledge in esophageal squamous cell carcinoma.

    PubMed

    Wu, Bing-Li; Lv, Guo-Qing; Zou, Hai-Ying; Du, Ze-Peng; Wu, Jian-Yi; Zhang, Pi-Xian; Xu, Li-Yan; Li, En-Min

    2014-01-01

    LOXL2 (lysyl oxidase-like 2), an enzyme that catalyzes oxidative deamination of lysine residue, is upregulated in esophageal squamous cell carcinoma (ESCC). A LOXL2 splice variant LOXL2-e13 and its wild type were overexpressed in ESCC cells followed by microarray analyses. In this study, we explored the potential role and molecular mechanism of LOXL2-e13 based on known protein-protein interactions (PPIs), following microarray analysis of KYSE150 ESCC cells overexpressing a LOXL2 splice variant, denoted by LOXL2-e13, or its wild-type counterpart. The differentially expressed genes (DEGs) of LOXL2-WT and LOXL2-e13 were applied to generate individual PPI subnetworks in which hundreds of DEGs interacted with thousands of other proteins. These two DEG groups were annotated by Functional Annotation Chart analysis in the DAVID bioinformatics database and compared. These results found many specific annotations indicating the potential specific role or mechanism for LOXL2-e13. The DEGs of LOXL2-e13, comparing to its wild type, were prioritized by the Random Walk with Restart algorithm. Several tumor-related genes such as ERO1L, ITGA3, and MAPK8 were found closest to LOXL2-e13. These results provide helpful information for subsequent experimental identification of the specific biological roles and molecular mechanisms of LOXL2-e13. Our study also provides a work flow to identify potential roles of splice variants with large scale data. PMID:25254241

  7. A truncated splice variant of human lysyl oxidase-like 2 promotes migration and invasion in esophageal squamous cell carcinoma.

    PubMed

    Zou, Hai-Ying; Lv, Guo-Qing; Dai, Li-Hua; Zhan, Xiu-Hui; Jiao, Ji-Wei; Liao, Lian-Di; Zhou, Tai-Mei; Li, Chun-Quan; Wu, Bing-Li; Xu, Li-Yan; Li, En-Min

    2016-06-01

    Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family, which plays an important role in extracellular matrix protein biosynthesis and tumor progression. In the present study, we identified a novel splice variant, LOXL2Δ72, which encodes a peptide having the same N- and C-termini as wild-type LOXL2 (LOXL2WT), but lacks 72 nucleotides encoding 24 amino acids. LOXL2Δ72 had dramatically reduced enzymatic activity, and was no longer secreted. However, LOXL2Δ72 promoted greater cell migration and invasion than LOXL2WT. Furthermore, a dual luciferase reporter assay indicated that LOXL2Δ72 activates distinct signal transduction pathways compared to LOXL2WT, consistent with cDNA microarray data showing different expression levels of cell migration- and invasion-related genes induced following over-expression of each LOXL2 isoform. In particular, LOXL2Δ72 distinctly promoted esophageal squamous cell carcinoma (ESCC) cell migration via up-regulating the C-C motif chemokine ligand 28 (CCL28). Our results suggest that the new LOXL2 splice variant contributes to tumor progression by novel molecular mechanisms different from LOXL2WT. PMID:27063404

  8. Stemness and chemotherapeutic drug resistance induced by EIF5A2 overexpression in esophageal squamous cell carcinoma

    PubMed Central

    Yang, Hong; Li, Xiao-dong; Zhou, Ying; Ban, Xiaojiao; Zeng, Ting-ting; Li, Lei; Zhang, Bao-zhu; Yun, Jingping; Xie, Dan; Guan, Xin-Yuan; Li, Yan

    2015-01-01

    Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies of the digestive tract in East Asian countries. Multimodal therapies, including adjuvant chemotherapy and neo-adjuvant chemotherapy, have become more often used for patients with advanced ESCC. However, the chemotherapy effect is often limited by patients' drug resistance. This study demonstrated that EIF5A2 (eukaryotic translation initiation factor 5A2) overexpression induced stemness and chemoresistance in ESCC cells. We showed that EIF5A2 overexpression in ESCC cells resulted in increased chemoresistance to 5-fluorouracil (5-FU), docetaxel and taxol. In contrast, shRNAs suppressing eIF5A2 increased tumor sensitivity to these chemotherapeutic drugs. In addition, EIF5A2 overexpression was correlated with a poorer overall survival in patients with ESCC who underwent taxane-based chemotherapy after esophagectomy (P < 0.05). Based on these results, we suggest that EIF5A2 could be a predictive biomarker for selecting appropriate chemo-treatment for ESCC patients and EIF5A2 inhibitors might be considered as combination therapy to enhance chemosensitivity in patients with ESCC. PMID:26317793

  9. Insulin-like growth factor binding protein-3 is a new predictor of radiosensitivity on esophageal squamous cell carcinoma

    PubMed Central

    Luo, Li-Ling; Zhao, Lei; Wang, Ying-Xue; Tian, Xiao-Peng; Xi, Mian; Shen, Jing-Xian; He, Li-Ru; Li, Qiao-Qiao; Liu, Shi-Liang; Zhang, Peng; Xie, Dan; Liu, Meng-Zhong

    2015-01-01

    Insulin-like growth factor binding protein-3 (IGFBP-3) plays an essential role in radiosensitivity of esophageal squamous cell carcinoma (ESCC). However, the underlying mechanism is not completely understood. Here, we observed that IGFBP-3 had favorable impact on the tumorigenicity of ESCC cells in nude mice by using an in vivo imaging system (IVIS) to monitor tumor growth treated with ionizing radiation (IR). Downregulation of IGFBP-3 expression enhanced tumor growth, inhibited anti-proliferative and apoptotic activity and result in IR resistance in vivo. Cell cycle antibody array suggested that silencing IGFBP-3 promoted transition from G0/G1 to S phase, perhaps though influencing Smad3 dephosphorylation and retinoblastoma protein (Rb) phosphorylation. Downregulation of P21 and P27, and upregulation of p-P27 (phospho-Thr187), cyclin-dependent kinase 2 (CDK2), and cyclin E1 might contribute to the G0/G1 to S phase transition promoted by IGFBP-3. Our results suggest that Smad3-P27/P21-cyclin E1/CDK2-phosphorylated retinoblastoma protein pathways might be involved in this IGFBP-3 mediated radiosensitivity transition in ESCC. PMID:26670461

  10. Monitoring disease progression and treatment efficacy with circulating tumor cells in esophageal squamous cell carcinoma: A case report

    PubMed Central

    Qiao, Yuan-Yuan; Lin, Kai-Xuan; Zhang, Ze; Zhang, Da-Jin; Shi, Cheng-He; Xiong, Ming; Qu, Xiu-Hua; Zhao, Xiao-Hang

    2015-01-01

    This study investigated whether changes in circulating tumor cell (CTC) numbers reflect tumor progression and treatment efficacy in esophageal squamous cell carcinoma (ESCC). A 47-year-old male patient with ESCC is presented in this case study. The patient was evaluated for a series of serum tumor markers and subjected to radiological examinations before and after surgery and during follow-up over the course of five years. In addition, the CTCs in 7.5 mL of peripheral blood were enriched by magnetic-activated cell sorting negative selection and identified by immunofluorescence staining. Serum tumor markers remained within normal ranges and were discordant with imaging scans during the follow-up. Initially, one CTC was detected in the peripheral blood sample, and 14 were observed seven days after the operation. After 12 wk, subcutaneous metastases and bone metastases occurred, and the number of CTCs increased to 84. After 48 wk, lung metastases were noted, and the CTC level was 21. At 104 wk, the number of CTCs was 14, and disease recurrence was detected by positron emission tomography-computed tomography. The CTC counts were in accord with the imaging studies at several time points. The additional information provided by CTC enumeration could thus facilitate monitoring of disease status and treatment efficacy and provide support for treatment decisions. PMID:26167094

  11. Downregulation of p70S6K Enhances Cell Sensitivity to Rapamycin in Esophageal Squamous Cell Carcinoma

    PubMed Central

    Lu, Zhaoming; Peng, Kezheng; Wang, Ning; Liu, Hong-Min

    2016-01-01

    It has been demonstrated that mTOR/p70S6K pathway was abnormally activated in many cancers and rapamycin and its analogs can restrain tumor growth through inhibiting this pathway, but some tumors including esophageal squamous cell carcinoma (ESCC) appear to be insensitive to rapamycin in recent studies. In the present study, we explored the measures to improve the sensitivity of ESCC cells to rapamycin and identified the clinical significance of the expression of phosphorylated p70S6K (p-p70S6K). The results showed that, after downregulating the expression of p70S6K and p-p70S6K by p70S6K siRNA, the inhibitory effects of rapamycin on cell proliferation, cell cycle, and tumor growth were significantly enhanced in vitro and in vivo. Furthermore, p-p70S6K had strong positive expression in ESCC tissues and its expression was closely related to lymph node metastasis and the TNM staging. These results indicated that p-p70S6K may participate in the invasion and metastasis in the development of ESCC and downregulation of the expression of p-p70S6K could improve the sensitivity of cells to rapamycin in ESCC. PMID:27595116

  12. Detection of Circulating Tumor Cells by Fluorescent Immunohistochemistry in Patients with Esophageal Squamous Cell Carcinoma: Potential Clinical Applications.

    PubMed

    Li, Shu-Ping; Guan, Quan-Lin; Zhao, Da; Pei, Guang-Jun; Su, Hong-Xin; Du, Lan-Ning; He, Jin-Xiang; Liu, Zhao-Chen

    2016-01-01

    BACKGROUND Circulating tumor cells (CTCs) are tumor cells that leave the primary tumor site and enter the bloodstream, where they can spread to other organs; they are very important in the diagnosis, treatment, and prognosis of malignant tumors. However, few studies have investigated CTCs in esophageal squamous cell carcinoma (ESCC). The aim of this study was to investigate the CTCs in blood of ESCC patients and its potential relevance to clinicopathological features and prognosis. MATERIAL AND METHODS CTCs were acquired by a negative enrichment method that used magnetic activated cell sorting (MACSTM). Fluorescent immunohistochemistry (IHC) was used to identify the CTCs. Then, the positive CTC patients with ESCC were analyzed, after which the relationship between CTCs and clinicopathologic features was evaluated. RESULTS In the present study, 62 out of 140 (44.3%) patients with ESCC were positive for CTCs. The positive rate of CTCs was significantly related with stage of ESCC patients (P=0.013). However, there was no relationship between CTC status and age, sex, smoking tumor history, tumor location, differentiation of tumor, lymphatic invasion, or lymph venous invasion (P>0.05). Kaplan-Meier analysis showed that patients positive for CTCs had significantly shorter survival time than patients negative for CTCs. Multivariate analysis demonstrated that stage and CTC status were significant prognostic factors for patients with ESCC. CONCLUSIONS CTCs positivity is an independent prognostic biomarker that indicates a worse prognosis for patients with ESCC. PMID:27184872

  13. Transcriptome profiling of esophageal squamous cell carcinoma reveals a long noncoding RNA acting as a tumor suppressor

    PubMed Central

    Li, Jiagen; Tian, Liqing; Liu, Wei; Liu, Lihui; Luo, Jianjun; He, Jie; Chen, Runsheng

    2015-01-01

    Esophageal Squamous Cell Carcinoma (ESCC) is among the most common malignant cancers worldwide. In the past, extensive efforts have been made to characterize the involvement of protein-coding genes in ESCC tumorigenesis but few for long noncoding RNAs (lncRNAs). To investigate the transcriptome profile and functional relevance of lncRNAs, we performed an integrative analysis of a customized combined lncRNA-mRNA microarray and RNA-seq data on ESCCs and matched normal tissues. We identified numerous lncRNAs that were differentially expressed between the normal and tumor tissues, termed “ESCC-associated lncRNAs (ESCALs)”, of which, the majority displayed restricted expression pattern. Also, a subset of ESCALs appeared to be associated with ESCC patient survival. Gene set enrichment analysis (GSEA) further suggested that over half of the ESCALs were positively- or negatively-associated with metastasis. Among these, we identified a novel nuclear-retained lncRNA, named Epist, which is generally highly expressed in esophagus, and which is down-regulated during ESCC progression. Epist over-expression and knockdown studies further suggest that Epist inhibits the metastasis, acting as a tumor suppressor in ESCC. Collectively, our analysis of the ESCC transcriptome identified the potential tumor suppressing lncRNA Epist, and provided a foundation for future efforts to identify functional lncRNAs for cancerous therapeutic targeting. PMID:26158411

  14. IL-17A promotes migration and tumor killing capability of B cells in esophageal squamous cell carcinoma

    PubMed Central

    Lu, Lin; Weng, Chengyin; Mao, Haibo; Fang, Xisheng; Liu, Xia; Wu, Yong; Cao, Xiaofei; Li, Baoxiu; Chen, Xiaojun; Gan, Qinquan; Xia, Jianchuan; Liu, Guolong

    2016-01-01

    We have previously reported that the accumulation of IL-17-producing cells could mediate tumor protective immunity by promoting the migration of NK cells, T cells and dendritic cells in esophageal squamous cell carcinoma (ESCC) patients. However, there were no reports concerning the effect of IL-17A on tumor infiltrating B cells. In this study, we investigated the accumulation of CD20+ B cells in the ESCC tumor nests and further addressed the effect of IL-17A on the migration and cytotoxicity of B cells. There was positive correlation between the levels of CD20+ B cells and IL-17+ cells. IL-17A could promote the ESCC tumor cells to produce more chemokines CCL2, CCL20 and CXCL13, which were associated with the migration of B cells. In addition, IL-17A enhanced the IgG-mediated antibody and complement mediated cytotoxicity of B cells against tumor cells. IL-17A-stimulated B cells gained more effective direct killing capability through enhanced expression of Granzyme B and FasL. The effect of IL-17A on the migration and cytotoxicity of B cells was IL-17A pathway dependent, which could be inhibited by IL-17A inhibitor. This study provides further understanding of the roles of IL-17A in humoral response, which may contribute to the development of novel tumor immunotherapy strategy. PMID:26942702

  15. Involved-field radiotherapy for esophageal squamous cell carcinoma: theory and practice.

    PubMed

    Li, Minghuan; Zhang, Xiaoli; Zhao, Fen; Luo, Yijun; Kong, Li; Yu, Jinming

    2016-01-01

    Esophageal carcinoma (EC) is characterized by a high rate of lymph node metastasis and its spread pattern is not always predictable. Chemoradiotherapy has an important role in the treatment of EC in both the inoperable and the pre-operative settings. However, regarding the target volume for radiation, different clinical practices exist. Theoretically, in addition to the clinical target volume administered to the gross lesion, it might seem logical to deliver a certain dose to the uninvolved regional lymph node area at risk for microscopic disease. However, in practice, it is difficult because of the intolerance of normal tissue to radiotherapy (RT), particularly if all regions containing the cervical, mediastinal, and upper abdominal nodes are covered. To date, the use of elective nodal irradiation (ENI) is still controversial in the field of radiotherapy. Some investigators use involved-field radiotherapy (IFRT) in order to reduce treatment-related toxicities. It is thought that micrometastases can be controlled, to some extent, by chemotherapy and the abscopal effects of radiation. It is the presence of overtly involved lymph nodes rather than the micrometastatic nodes negatively affects survival in patients with EC. In another hand, lymph nodes stationed near primary tumors also receive considerable incidental irradiation doses that may contribute to the elimination of subclinical lesions. These data indicate that an irradiation volume covering only the gross tumor is appropriate. When using ENI or IFRT, very few patients experience solitary regional node failure and out-of-field lymph node failure is not common. Primary tumor recurrence and distant metastases, rather than regional lymph node failure, affect the overall survival in patients with EC. The available evidence indicates that the use of ENI seems to prevent or delay regional nodal relapse rather than improve survival. In a word, these data suggest that IFRT is feasible in EC patients. PMID:26846932

  16. RNA interference for epidermal growth factor receptor enhances the radiosensitivity of esophageal squamous cell carcinoma cell line Eca109

    PubMed Central

    ZHANG, HEPING; LI, JIANCHENG; CHENG, WENFANG; LIU, DI; CHEN, CHENG; WANG, XIAOYING; LU, XUJING; ZHOU, XIFA

    2015-01-01

    The present study investigated the effects of small interfering RNAs (siRNAs) specific to the epidermal growth factor receptor (EGFR) gene, on the radiosensitivity of esophageal squamous cell carcinoma cells. EGFR gene siRNAs (EGFR-siRNA) were introduced into esophageal cancer Eca109 cells using Lipofectamine® 2000. The EGFR messenger (m)RNA expression levels, EGFR protein expression and cell growth were assessed using reverse transcription-polymerase chain reaction analysis, western blot analysis and a Cell Counting Kit-8 (CCK-8), respectively. In addition, colony assays were used to determine the inhibitory effects of X-ray radiation on EGFR-silenced cells. EGFR mRNA and protein levels were reduced in the Eca109 cells transfected with EGFR-siRNA. The relative EGFR mRNA expression levels were reduced to 26.74, 9.52 and 4.61% in Eca109 cells transfected with EGFR-siRNA1, 2 and 3, respectively. These mRNA levels were significantly reduced compared with the those of the control group (42.44%; P<0.0001). Transfection with siRNA3 resulted in the greatest reduction in EGFR mRNA expression, with an inhibition rate of 85%. The relative EGFR protein expression levels were reduced to 24.05, 34.91 and 34.14% in Eca109 cells transfected with EGFR-siRNA1, 2 and 3, respectively. These protein levels were significantly reduced compared with those of the control group (78.57%; P<0.0001). Transfection with siRNA1 resulted in the greatest reduction in EGFR protein expression, with an inhibition rate of 72.84%. This reduction in EGFR expression inhibited the proliferation of Eca109 cells, which was identified using the CCK-8 assay. The proliferation inhibition ratio was 28.2%. The cells treated with irradiation in addition to EGFR-siRNA, demonstrated reduced radiobiological parameters (D0, Dq and SF2) compared with those of cells treated with irradiation only, with a sensitization enhancing ratio of 1.5. In conclusion, suppression of EGFR expression may enhance the radiosensitivity

  17. Retrospective Analysis of Outcome Differences in Preoperative Concurrent Chemoradiation With or Without Elective Nodal Irradiation for Esophageal Squamous Cell Carcinoma

    SciTech Connect

    Hsu, Feng-Ming; Lee, Jang-Ming; Huang, Pei-Ming; Lin, Chia-Chi; Hsu, Chih-Hung; Tsai, Yu-Chieh; Lee, Yung-Chie; Chia-Hsien Cheng, Jason

    2011-11-15

    Purpose: To evaluate the efficacy and patterns of failure of elective nodal irradiation (ENI) in patients with esophageal squamous cell carcinoma (SCC) undergoing preoperative concurrent chemoradiation (CCRT) followed by radical surgery. Methods and Materials: We retrospectively studied 118 patients with AJCC Stage II to III esophageal SCC undergoing preoperative CCRT (median, 36 Gy), followed by radical esophagectomy. Of them, 73 patients (62%) had ENI and 45 patients (38%) had no ENI. Patients with ENI received radiotherapy to either supraclavicular (n = 54) or celiac (n = 19) lymphatics. Fifty-six patients (57%) received chemotherapy with paclitaxel plus cisplatin. The 3-year progression-free survival, overall survival, and patterns of failure were analyzed. Distant nodal recurrence was classified into M1a and M1b regions. A separate analysis using matched cases was conducted. Results: The median follow-up was 38 months. There were no differences in pathological complete response rate (p = 0.12), perioperative mortality rate (p = 0.48), or delayed Grade 3 or greater cardiopulmonary toxicities (p = 0.44), between the groups. More patients in the non-ENI group had M1a failure than in the ENI group, with 3-year rates of 11% and 3%, respectively (p = 0.05). However, the 3-year isolated distant nodal (M1a + M1b) failure rates were not different (ENI, 10%; non-ENI, 14%; p = 0.29). In multivariate analysis, pathological nodal status was the only independent prognostic factor associated with overall survival (hazard ratio = 1.78, p = 0.045). The 3-year overall survival and progression-free survival were 45% and 45%, respectively, in the ENI group, and 52% and 43%, respectively, in the non-ENI group (p = 0.31 and 0.89, respectively). Matched cases analysis did not show a statistical difference in outcomes between the groups. Conclusions: ENI reduced the M1a failure rate but was not associated with improved outcomes in patients undergoing preoperative CCRT for esophageal

  18. Squamous cell carcinoma

    Cancer.gov

    The hallmarks of squamous cell carcinoma are the differentiation features of the squamous epithelium: keratinization and intercellular bridges. Large central masses of keratin, individual cell keratinization, and/or keratin pearls may form. Necrosis of tumor cell nests and accumulation of acute inflammatory cells are frequent features of poorly differentiated squamous cell carcinoma.

  19. High sex determining region Y-box 2 (SOX2) expression correlates with absence of nodal metastasis in esophageal squamous cell carcinoma

    PubMed Central

    Chuang, Wen-Yu; Chang, Yu-Sun; Chao, Yin-Kai; Yeh, Chi-Ju; Liu, Yun-Hen; Tseng, Chen-Kan; Chang, Hsien-Kun; Wan, Yung-Liang; Hsueh, Chuen

    2015-01-01

    Sex determining region Y-box 2 (SOX2) is a transcription factor involved in self-renewal and pluripotency. Dysregulation of SOX2 expression has been found in squamous cell carcinoma (SCC), including esophageal SCC. Recently, high SOX2 expression was found to be a negative predictor of occult lymph node metastasis in early oral SCC, but the clinical significance of SOX2 expression in esophageal SCC remains controversial. Here we investigated SOX2 expression by immunohistochemistry in 75 cases of surgically resected esophageal SCC. Similar to oral SCC, we found for the first time that high SOX2 expression correlates with absence of clinical nodal metastasis (P = 0.011). Podoplanin is a glycoprotein which is variably expressed by esophageal SCC. Since we previously found that podoplanin expression correlates with nodal metastasis in esophageal SCC, we also assessed podoplanin expression in these cases. Interestingly, SOX2 expression correlates negatively with podoplanin expression (P = 0.018). It is in contrast with a recent finding that SOX2 can up-regulate podoplanin expression in SCC of the skin. Our result suggests that SOX2 might suppress nodal metastasis through down-regulation of podoplanin in esophageal SCC. Further studies are needed to clarify the exact mechanism of regulation. PMID:26464673

  20. Tissue microarray analysis reveals a tight correlation between protein expression pattern and progression of esophageal squamous cell carcinoma

    PubMed Central

    Xue, Li-yan; Hu, Nan; Song, Yong-mei; Zou, Shuang-mei; Shou, Jian-zhong; Qian, Lu-xia; Ren, Li-qun; Lin, Dong-mei; Tong, Tong; He, Zu-gen; Zhan, Qi-min; Taylor, Philip R; Lu, Ning

    2006-01-01

    Background The development of esophageal squamous cell carcinoma (ESCC) progresses a multistage process, collectively known as precursor lesions, also called dysplasia (DYS) and carcinoma in situ (CIS), subsequent invasive lesions and final metastasis. In this study, we are interested in investigating the expression of a variety of functional classes of proteins in ESCC and its precursor lesions and characterizing the correlation of these proteins with ESCC malignant progression. Methods Fas, FADD, caspase 8, CDC25B, fascin, CK14, CK4, annexin I, laminin-5γ2 and SPARC were analyzed using immunohistochemistry on tissue microarray containing 205 ESCC and 173 adjacent precursor lesions as well as corresponding normal mucosa. To confirm the immunohistochemical results, three proteins, fascin, CK14 and laminin-5γ2, which were overexpressed in ESCC on tissue microarray, were detected in 12 ESCC cell lines by Western blot assay. Results In ESCC and its precursor lesions, FADD, CDC25B, fascin, CK14, laminin-5γ2 and SPARC were overexpressed, while Fas, caspase 8, CK4 and annexin I were underexpressed. The abnormalities of these proteins could be classified into different groups in relation to the stages of ESCC development. They were "early" corresponding to mild and moderate DYS with overexpression of fascin, FADD and CDC25B and underexpression of Fas, caspase 8, CK4 and annexin I, "intermediate" to severe DYS and CIS with overexpression of FADD and CK14, and "late" to invasive lesions (ESCC) and to advanced pTNM stage ESCC lesions with overexpression of CK14, laminin-5γ2 and SPARC. Conclusion Analyzing the protein expression patterns of Fas, FADD, caspase 8, CDC25B, fascin, CK14, CK4, annexin I, laminin-5γ2 and SPARC would be valuable to develop rational strategies for early detection of lesions at risk in advance as well as for prevention and treatment of ESCC. PMID:17187659

  1. Increased risk of esophageal squamous cell carcinoma in patients with gastric atrophy: independent of the severity of atrophic changes.

    PubMed

    de Vries, Annemarie C; Capelle, Lisette G; Looman, Caspar W N; van Blankenstein, Mark; van Grieken, Nicole C T; Casparie, Mariël K; Meijer, Gerrit A; Kuipers, Ernst J

    2009-05-01

    An association between gastric atrophy and esophageal squamous cell carcinomas (ESCC) has been described. However, the mechanism of this association is unknown. In this study, we aimed to examine this relationship in a cohort of patients with varying grades of gastric atrophy to increase the understanding about the causality of the association. Patients diagnosed with gastric atrophy between 1991 and 2005 were identified in the Dutch nationwide histopathology registry (PALGA). The incidence of ESCC and, presumably unrelated, small cell lung carcinomas (SCLC) observed in these patients was compared with that in the general Dutch population. Relative risks (RRs) and 95% confidence intervals were calculated by a Poisson model. At baseline histological examination, 97,728 patients were diagnosed with gastric atrophy, of whom 23,278 with atrophic gastritis, 65,934 with intestinal metaplasia and 8,516 with dysplasia. During follow-up, 126 patients were diagnosed with ESCC and 263 with SCLC (overall rates 0.19, respectively 0.39/1,000 person-years at risk). Compared with the general Dutch population, patients with gastric atrophy ran a RR of developing ESCC of 2.2 [95% CI 1.8-2.6] and of SCLC of 1.8 [95% CI 1.6-2.1]. The risk of ESCC did not increase with increasing severity of gastric atrophy (p = 0.90). In conclusion, this study found an association between gastric atrophy and both ESCC and SCLC, but the risk of ESCC did not increase with the severity of gastric atrophy. Therefore, a causal relationship seems unlikely. Confounding factors, such as smoking, may explain both associations. PMID:19107937

  2. Upregulation of the long noncoding RNA PCAT-1 correlates with advanced clinical stage and poor prognosis in esophageal squamous carcinoma.

    PubMed

    Shi, Wei-hong; Wu, Qing-quan; Li, Su-qing; Yang, Tong-xin; Liu, Zi-hao; Tong, Yu-suo; Tuo, Lei; Wang, Shan; Cao, Xiu-Feng

    2015-04-01

    Recent studies reveal that long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. Prostate cancer-associated ncRNA transcript 1 (PCAT-1) is one of the lncRNAs involved in cell apoptosis and proliferation of prostate cancer. This study aimed to assess the potential role of PCAT-1 specifically in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of PCAT-1 in matched cancerous tissues and adjacent noncancerous tissues from 130 patients with ESCC, 34 patients with non-small cell lung cancer (NSCLC), and 30 patients with gastric carcinoma (GC). The correlation of PCAT-1 with clinicopathological features and prognosis were also analyzed. The expression of PCAT-1 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (70.8%, p < 0.01), and the high level of PCAT-1 expression was significantly correlated with invasion of the tumor (p = 0.024), advanced clinical stage (p = 0.003), lymph node metastasis (p = 0.032), and poor prognosis. However, PCAT-1 mRNA expression had no significant difference between paired primary cancerous tissues and the adjacent noncancerous tissues in 34 cases of NSCLC (p = 0.293) and 30 cases of GC (p = 0.125). High expression of PCAT-1 was specifically correlated with invasion of cancer tissues, metastasis of lymph node, and advanced tumor stage of ESCC. High expression of PCAT-1 might reflect poor prognosis of ESCC and indicate a potential diagnostic target in ESCC patients. Adjuvant therapy targeting PCAT-1 molecule might be effective in treatment of ESCC. PMID:25731728

  3. LncRNAs and Esophageal Squamous Cell Carcinoma - Implications for Pathogenesis and Drug Development

    PubMed Central

    Shen, Wen-Jun; Zhang, Fan; Zhao, Xing; Xu, Jianzhen

    2016-01-01

    LncRNAs are a group of ncRNA species longer than 200 nt, which have fundamental regulatory roles in diverse cellular processes and diseases progression. Esophageal cancer is a serious malignancy with respect to prognosis and mortality rate. It is among the five leading cancer types for the cancer deaths in males of middle age in the United States. In China, esophageal cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death. The molecular mechanisms of esophageal cancer development are not fully understood, but emerging studies point out that lncRNAs may actively associate with the pathogenesis. In this review, we first provided an introduction of lncRNAs classifications. Then we focused on the recent findings on lncRNA expression and function in esophageal cancer development. Implications for pathogenesis and potential drug developments will also be discussed. PMID:27390601

  4. Inhibition of human esophageal squamous cell carcinomas by targeted silencing of tumor enhancer genes: an overview

    PubMed Central

    Islamian, Jalil Pirayesh; Mohammadi, Mohsen; Baradaran, Behzad

    2014-01-01

    Esophageal cancer has been reported as the ninth most common malignancy and ranks as the sixth most frequent cause of death worldwide. Esophageal cancer treatment involves surgery, chemotherapy, radiation therapy, or combination therapy. Novel strategies are needed to boost the oncologic outcome. Recent advances in the molecular biology of esophageal cancer have documented the role of genetic alterations in tumorigenesis. Oncogenes serve a pivotal function in tumorigenesis. Targeted therapies are directed at the unique molecular signature of cancer cells for enhanced efficacy with low toxicity. RNA interference (RNAi) technology is a powerful tool for silencing endogenous or exogenous genes in mammalian cells. Related results have shown that targeting oncogenes with siRNAs, specifically the mRNA, effectively reduces tumor cell proliferation and induces apoptotic cell death. This article will briefly review studies on silencing tumor enhancer genes related to the induction of esophageal cancer. PMID:25009749

  5. Evaluating the effect of four extracts of avocado fruit on esophageal squamous carcinoma and colon adenocarcinoma cell lines in comparison with peripheral blood mononuclear cells.

    PubMed

    Vahedi Larijani, Laleh; Ghasemi, Maryam; AbedianKenari, Saeid; Naghshvar, Farshad

    2014-01-01

    Most patients with gastrointestinal cancers refer to the health centers at advanced stages of the disease and conventional treatments are not significantly effective for these patients. Therefore, using modern therapeutic approaches with lower toxicity bring higher chance for successful treatment and reduced adverse effects in such patients. The aim of this study is to evaluate the effect of avocado fruit extracts on inhibition of the growth of cancer cells in comparison with normal cells. In an experimental study, ethanol, chloroform, ethyl acetate, and petroleum extracts of avocado (Persea americana) fruit were prepared. Then, the effects if the extracts on the growth of esophageal squamous cell carcinoma and colon adenocarcinoma cell lines were evaluated in comparison with the control group using the MTT test in the cell culture medium. Effects of the four extracts of avocado fruit on three cells lines of peripheral blood mononuclear cells, esophageal squamous cell carcinoma, and colon adenocarcinoma were tested. The results showed that avocado fruit extract is effective in inhibition of cancer cell growth in comparison with normal cells (P<0.05). Avocado fruit is rich in phytochemicals, which play an important role in inhibition of growth of cancer cells. The current study for the first time demonstrates the anti-cancer effect of avocado fruit extracts on two cancers common in Iran. Therefore, it is suggested that the fruit extracts can be considered as appropriate complementary treatments in treatment of esophageal and colon cancers. PMID:24901722

  6. Cellular Retinoic Acid Binding Protein 2 Is Strikingly Downregulated in Human Esophageal Squamous Cell Carcinoma and Functions as a Tumor Suppressor

    PubMed Central

    Xiao, Weifan; Sun, Fenyong; Yuan, Hong; Pan, Qiuhui

    2016-01-01

    Esophageal squamous cell carcinoma (ESCC) is the predominant pathotype of esophageal carcinoma (EC) in China, especially in Henan province, with poor prognosis and limited 5-year survival rate. Cellular retinoic acid binding protein 2 (CRABP2) is a member of the retinoic acid (RA) and lipocalin/cytosolic fatty-acid binding protein family and plays a completely contrary role in tumorigenesis through the retinoid signaling pathway, depending on the nuclear RA receptors (RAR) and PPARbeta/delta receptors. Presently, the biological role of CRABP2 in the development of ESCC has never been reported. Here, we firstly evaluated the expression of CRABP2 at both mRNA and protein levels and showed that it was remarkably downregulated in clinical ESCC tissues and closely correlated with the occurrence position, pathology, TNM stage, size, infiltration depth and cell differentiation of the tumor. Additionally, the biological function assays demonstrated that CRABP2 acted as a tumor suppressor in esophageal squamous carcinogenesis by significantly inhibiting cell growth, inducing cell apoptosis and blocking cell metastasis both in vitro and in vivo. All in all, our finding simplicate that CRABP2 is possibly an efficient molecular marker for diagnosing and predicting the development of ESCC. PMID:26839961

  7. The role of PD-L1 in the radiation response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell immunosuppression.

    PubMed

    Chen, Miao-Fen; Chen, Ping-Tsung; Chen, Wen-Cheng; Lu, Ming-Shian; Lin, Paul-Yang; Lee, Kuan Der

    2016-02-16

    The aim of this study was to assess the significance of programmed cell death 1 ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) and its association with IL-6 and radiation response. Weretrospectively enrolled 162 patients with ESCC, and examined the correlation between PD-L1 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T and TE2 were selected for cellular experiments to investigate the role of PD-L1 in T cell functions and radiation response. Here we demonstrated that PD-L1 expression was significantly higher in esophageal cancer specimens than in non-malignant epithelium. In clinical outcome analysis, this staining of PD-L1 was positively linked to the clinical T4 stage (p=0.004), development of LN metastasis (p=0.012) and higher loco-regional failure rate (p=0.0001). In addition, the frequency of PD-L1 immunoreactivity was significantly higher in IL-6-positive esophageal cancer specimens. When IL-6 signaling was inhibited in vitro, the level of PD-L1 is significantly down-regulated. PD-L1 is a significant predictor for poor treatment response and shorter survival.As demonstrated through in vitro experiments, Irradiation increased PD-L1 expression in human esophageal cancer cells. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells might be the mechanisms responsible to the role of PD-L1 in radiation response. In conclusion, PD-L1 is important in determining the radiation response and could predict the prognosis of patients with esophageal SCC. Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC. PMID:26761210

  8. The role of PD-L1 in the radiation response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell immunosuppression

    PubMed Central

    Chen, Miao-Fen; Chen, Ping-Tsung; Chen, Wen-Cheng; Lu, Ming-Shian; Lin, Paul-Yang; Lee, Kuan-Der

    2016-01-01

    The aim of this study was to assess the significance of programmed cell death 1 ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) and its association with IL-6 and radiation response. Weretrospectively enrolled 162 patients with ESCC, and examined the correlation between PD-L1 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T and TE2 were selected for cellular experiments to investigate the role of PD-L1 in T cell functions and radiation response. Here we demonstrated that PD-L1 expression was significantly higher in esophageal cancer specimens than in non-malignant epithelium. In clinical outcome analysis, this staining of PD-L1 was positively linked to the clinical T4 stage (p=0.004), development of LN metastasis (p=0.012) and higher loco-regional failure rate (p=0.0001). In addition, the frequency of PD-L1 immunoreactivity was significantly higher in IL-6-positive esophageal cancer specimens. When IL-6 signaling was inhibited in vitro, the level of PD-L1 is significantly down-regulated. PD-L1 is a significant predictor for poor treatment response and shorter survival. As demonstrated through in vitro experiments, Irradiation increased PD-L1 expression in human esophageal cancer cells. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells might be the mechanisms responsible to the role of PD-L1 in radiation response. In conclusion, PD-L1 is important in determining the radiation response and could predict the prognosis of patients with esophageal SCC. Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC. PMID:26761210

  9. Epb41l3 suppresses esophageal squamous cell carcinoma invasion and inhibits MMP2 and MMP9 expression.

    PubMed

    Zeng, Rong; Huang, Jun-Peng; Li, Xu Feng; Xiong, Wei-Bin; Wu, Gang; Jiang, Zhao-Jing; Song, Shu-Jie; Li, Ji-Qiang; Zheng, Yan-Fang; Zhang, Ji-Ren

    2016-04-01

    EPB41L3 may play a role as a metastasis suppressor by supporting regular arrangements of actin stress fibres and alleviating the increase in cell motility associated with enhanced metastatic potential. Downregulation of epb41l3 has been observed in many cancers, but the role of this gene in esophageal squamous cell carcinoma (ESCC) remains unclear. Our study aimed to determine the effect of epb41l3 on ESCC cell migration and invasion. We investigated epb41l3 protein expression in tumour and non-tumour tissues by immunohistochemical staining. Expression in the non-neoplastic human esophageal cell line Het-1a and four ESCC cell lines - Kyse150, Kyse510, Kyse450 and Caes17 - was assessed by quantitative Polymerase Chain Reaction (qPCR) and Western blotting. Furthermore, an EPB41L3 overexpression plasmid and EPB41L3-specific small interfering RNA were used to upregulate EPB41L3 expression in Kyse150 cells and to downregulate EPB41L3 expression in Kyse450 cells, respectively. Cell migration and invasion were evaluated by wound healing and transwell assays, respectively. The expression levels of p-AKT, matrix metalloproteinase (MMP)2 and MMP9 were evaluated. Expression of epb41l3 was significantly lower in tumour tissues than in non-tumour tissues and in ESCC cell lines compared with the Het-1a cell line. Kyse450 and Caes17 cells exhibited higher expression of epb41l3 than Kyse150 and Kyse510 cells. Overexpressing epb41l3 decreased Kyse150 cell migration and invasion, whereas EPB41L3-specific small interfering RNA silencing increased these functions in Kyse450 cells. Furthermore, overexpressing epb41l3 led to downregulation of MMP2 and MMP9 in Kyse150 and Kyse510 cells. Our findings reveal that EPB41L3 suppresses tumour cell invasion and inhibits MMP2 and MMP9 expression in ESCC cells. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26916087

  10. Identity-by-descent approaches identify regions of importance for genetic susceptibility to hereditary esophageal squamous cell carcinoma.

    PubMed

    Ko, Josephine My; Zhang, Peng; Law, Simon; Fan, Yanhui; Song, You-Qiang; Zhao, Xue Ke; Wong, Elibe H W; Tang, Sa; Song, Xin; Lung, Maria Li; Wang, Li Dong

    2014-08-01

    Worldwide, the highest prevalence of esophageal cancer (EC) occurs in Northern China. High-density SNP arrays allow identification of identity-by-descent (IBD) segments in genomic DNAs representative of shared common ancestral regions. We utilized IBD approaches to map susceptibility loci associated with low-penetrance SNPs in high-risk Henan hereditary esophageal squamous cell carcinoma (ESCC) patients. Affymetrix GeneChip Human mapping SNP array IBD analysis was performed in 32 Henan family history-positive (FH+) ESCC patients, 18 Henan healthy unrelated individuals, and 45 Chinese individuals from a CHB HapMap dataset using PLink (scoring IBD segments individually) and Beagle (scoring of shared IBD segments among case/case vs. control/control pairs) software. Both analyses identified longer IBD segment lengths associated with FH+ ESCC compared to controls. However, there was no strong evidence for a genetic founder effect. Pairing IBD analysis with BEAGLE identified 8 critical IBD segments residing at 2q32.1-q32.2, 3p22.3-p22.2, 4q21.1-q21.21, 7p22.2, 8q23.2-q23.3, 10q23.33-q24.1, 14q24.3 and 16q11.2-q12.1, which were more significantly shared among case/case compared to control/control. The shared IBD segments in FH+ ESCC samples with no overlap with control/CHB Hapmap may encompass potential cancer susceptibility loci. Selected targeted genes, PLCE1, GPT2, SIAH1 and CYP2C-18, residing within the IBD segments at 10q23.33-q24.1 and 16q11.2-q12.1, had statistically significant differential expression in primary ESCC tissues and are likely involved in ESCC carcinogenesis. The importance of these IBD segments to the etiology and development of ESCC in high-risk areas requires further study with expanded sample sizes. This is the first report employing the pairing IBD approach for elucidation of the genetic basis of hereditary ESCC in Henan by applying high throughput SNP array analysis. PMID:24890309

  11. 14-3-3σ confers cisplatin resistance in esophageal squamous cell carcinoma cells via regulating DNA repair molecules.

    PubMed

    Lai, Kenneth K Y; Chan, Kin Tak; Choi, Mei Yuk; Wang, Hector K; Fung, Eva Y M; Lam, Ho Yu; Tan, Winnie; Tung, Lai Nar; Tong, Daniel K H; Sun, Raymond W Y; Lee, Nikki P; Law, Simon

    2016-02-01

    Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used in chemoradiation for unresectable ESCC patients. However, the treatment efficacy is diminished in patients with established cisplatin resistance. To understand the mechanism leading to the development of cisplatin resistance in ESCC, we compared the proteomes from a cisplatin-resistant HKESC-2R cell line with its parental-sensitive counterpart HKESC-2 to identify key molecule involved in this process. Mass spectrometry analysis detected 14-3-3σ as the most abundant molecule expressed exclusively in HKESC-2R cells, while western blot result further validated it to be highly expressed in HKESC-2R cells when compared to HKESC-2 cells. Ectopic expression of 14-3-3σ increased cisplatin resistance in HKESC-2 cells, while its suppression sensitized SLMT-1 cells to cisplatin. Among the molecules involved in drug detoxification, drug transportation, and DNA repair, the examined DNA repair molecules HMGB1 and XPA were found to be highly expressed in HKESC-2R cells with high 14-3-3σ expression. Subsequent manipulation of 14-3-3σ by both overexpression and knockdown approaches concurrently altered the expression of HMGB1 and XPA. 14-3-3σ, HMGB1, and XPA were preferentially expressed in cisplatin-resistant SLMT-1 cells when compared to those more sensitive to cisplatin. In ESCC patients with poor response to cisplatin-based chemoradiation, their pre-treatment tumors expressed higher expression of HMGB1 than those with response to such treatment. In summary, our results demonstrate that 14-3-3σ induces cisplatin resistance in ESCC cells and that 14-3-3σ-mediated cisplatin resistance involves DNA repair molecules HMGB1 and XPA. Results from this study provide evidences for further work in researching the potential use of 14-3-3σ and DNA repair molecules HMGB1 and XPA as biomarkers and therapeutic targets for ESCC. PMID:26346170

  12. Expression and clinical role of NF45 as a novel cell cycle protein in esophageal squamous cell carcinoma (ESCC).

    PubMed

    Ni, Sujie; Zhu, Junya; Zhang, Jianguo; Zhang, Shu; Li, Mei; Ni, Runzhou; Liu, Jinxia; Qiu, Huiyuan; Chen, Wenjuan; Wang, Huijie; Guo, Weijian

    2015-02-01

    NF45 (also known as ILF2), as one subunit of NF-AT (nuclear factor of activated T cells), repairs DNA breaks, inhibits viral replication, and also functions as a negative regulator in the microRNA processing pathway in combination with NF90. Recently, it was found that implicated in the mitotic control of HeLa cells and deletion of endogenous NF45 decreases growth of HeLa cells. While the role of NF45 in cancer biology remains under debate. In this study, we analyzed the expression and clinical significance of NF45 in esophageal squamous cell carcinoma ESCC. The expression of NF45 was evaluated by Western blot in 8 paired fresh ESCC tissues and immunohistochemistry on 105 paraffin-embedded slices. NF45 was highly expressed in ESCC and significantly associated with ESCC cells tumor stage and Ki-67. Besides, high NF45 expression was an independent prognostic factor for ESCC patients' poor survival. To determine whether NF45 could regulate the proliferation of ESCC cells, we increased endogenous NF45 and analyzed the proliferation of TE1 ESCC cells using Western blot, CCK8, flow cytometry assays and colony formation analyses, which together indicated that overexpression of NF45 favors cell cycle progress of TE1 ESCC cells. While knockdown of NF45 resulted in cell cycle arrest at G0/G1-phase and thus abolished the cell growth. These findings suggested that NF45 might play an important role in promoting the tumorigenesis of ESCC, and thus be a promising therapeutic target to prevent ESCC progression. PMID:25286760

  13. Reduction of TIP30 in esophageal squamous cell carcinoma cells involves promoter methylation and microRNA-10b

    SciTech Connect

    Dong, Wenjie; Shen, Ruizhe; Cheng, Shidan

    2014-10-31

    Highlights: • TIP30 expression is frequently suppressed in ESCC. • TIP30 was hypermethylated in ESCC. • Reduction of TIP30 was significantly correlated with LN metastasis. • miR-10b is a direct regulator of TIP30. - Abstract: TIP30 is a putative tumor suppressor that can promote apoptosis and inhibit angiogenesis. However, the role of TIP30 in esophageal squamous cell carcinoma (ESCC) biology has not been investigated. Immunohistochemistry was used to investigate the expression of TIP30 in 70 ESCC. Hypermethylation of TIP30 was evaluated by the methylation specific PCR (MSP) method in ESCC (tumor and paired adjacent non-tumor tissues). Lost expression of TIP30 was observed in 50 of 70 (71.4%) ESCC. 61.4% (43 of 70) of primary tumors analyzed displayed TIP30 hypermethylation, indicating that this aberrant characteristic is common in ESCC. Moreover, a statistically significant inverse association was found between TIP30 methylation status and expression of the TIP30 protein in tumor tissues (p = 0.001). We also found that microRNA-10b (miR-10b) targets a homologous DNA region in the 3′untranslated region of the TIP30 gene and represses its expression at the transcriptional level. Reporter assay with 3′UTR of TIP30 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-10b, providing strong evidence that miR-10b is a direct regulator of TIP30. These results suggest that TIP30 expression is regulated by promoter methylation and miR-10b in ESCC.

  14. SEMA3B improves the survival of patients with esophageal squamous cell carcinoma by upregulating p53 and p21.

    PubMed

    Tang, Hong; Wu, Yufeng; Liu, Ming; Qin, Yanru; Wang, Haiying; Wang, Lili; Li, Shaomei; Zhu, Hui; He, Zheng; Luo, Junpeng; Wang, Hongyan; Wang, Qiming; Luo, Suxia

    2016-08-01

    As one of the most common malignancies, esophageal squamous cell carcinoma (ESCC) is ranked as the sixth leading cause of cancer-related death worldwide. In our previous study, by employing cDNA microarray analysis, semaphorin 3B (SEMA3B) was found to be significantly downregulated in ESCC. In the present study, SEMA3B downregulation at the mRNA level was found in 34 of 60 primary ESCCs (56.7%) and in 6 of 9 ESCC cell lines (66.7%) by transcription-polymerase chain reaction (RT-PCR). Moreover, immunohistochemical (IHC) staining of SEMA3B in a tissue microarray further indicated that downregulated expression of SEMA3B protein was found in 125 of 222 (56.3%) ESCC cases and downregulation of SEMA3B protein was significantly correlated with lymph node metastasis (P=0.000), advanced clinicopathological stage (P=0.001) and poor disease-specific survival (P=0.017) of ESCC patients. In addition, functional studies demonstrated that the SEMA3B gene could suppress the tumorigenic ability of ESCC cells and cell motility. Furthermore, it was found that by upregulating p53 and p21 expression and inhibiting Akt (Ser473) phosphorylation, SEMA3B could induce cell cycle arrest at G1/S phase. Taken together, our results suggest that SEMA3B may be an important tumor-suppressor gene in the malignant progression of ESCC, as well as a valuable prognostic marker for ESCC patients. PMID:27349960

  15. Novel circulating peptide biomarkers for esophageal squamous cell carcinoma revealed by a magnetic bead-based MALDI-TOFMS assay.

    PubMed

    Jia, Kun; Li, Wei; Wang, Feng; Qu, Haixia; Qiao, Yuanyuan; Zhou, Lanping; Sun, Yulin; Ma, Qingwei; Zhao, Xiaohang

    2016-04-26

    Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant neoplasms worldwide. Patients are often diagnosed at advanced stages with poor prognosis due to the absence of obvious early symptoms. Here, we applied a high-throughput serum peptidome analysis to identify circulating peptide markers of ESCC. Weak cationic exchange magnetic beads coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used for two-stage proteotypic peptide profiling in complex serum samples collected from 477 cancer patients and healthy controls. We established a genetic algorithm model containing three significantly differentially expressed peptides at 1,925.5, 2,950.6 and 5,900.0 Da with a sensitivity and specificity of 97.00% and 95.92% in the training set and 97.03% and 100.00% in the validation set, respectively. The model's diagnostic capability was significantly better than SCC-Ag and Cyfra 21-1, especially for early stage ESCC, with an achieved sensitivity of 96.94%. Subsequently, these peptides were identified as fragments of AHSG, TSP1 and FGA by linear ion trap-orbitrap hybrid tandem mass spectrometry. Notably, increased tissue and serum levels of TSP1 in ESCC were verified and correlated with disease progression. In addition, tissue TSP1 was an independent poor prognostic factor in ESCC. In conclusion, the newly established circulating peptide panel and identified proteins could serve as potential biomarkers for the early detection and diagnosis of ESCC. Nevertheless, a larger cohort will be required for further unequivocal validation of their clinical application. PMID:26993605

  16. The prognostic significance of Smad3, Smad4, Smad3 phosphoisoform expression in esophageal squamous cell carcinoma.

    PubMed

    Cho, Soo Youn; Ha, Sang Yun; Huang, Song-Mei; Kim, Jeong Hoon; Kang, Myung Soo; Yoo, Hae-Yong; Kim, Hyeon-ho; Park, Cheol-Keun; Um, Sung-Hee; Kim, Kyung-Hee; Kim, Seok-Hyung

    2014-11-01

    Smad3 functions as an integrator of diverse signaling, including transforming growth factor β signaling and the function of Smad3 is complexly regulated by differential phosphorylation at various sites of Smad3. Despite the importance of Smad3 and its various phosphoisoforms, their prognostic significance has rarely been studied. In this study, we demonstrated the prognostic significance of Smad3, its phosphoisoforms, and Smad4 expression by immunohistochemistry in 126 esophageal squamous cell carcinomas. The phosphoisoforms of Smad3 studied in this article included phosphorylation at C-terminal (pSmad3C)(Ser(423/425)) and phosphorylation at the linker region (pSmad3L)(Ser(213)). High expression of Smad3 was associated with shorter overall survival. Co-existence of high expression of pSmad3L(S213) and low expression of pSmad3C(S423/425) were associated with advanced N stage and an independent prognostic factor for overall [hazard ratio (HR) 2.03, 95 % confidence interval (CI) (1.10-3.75), p = 0.023] and disease-free survival [HR 2.41, 95 % CI (1.32-4.39), p = 0.004]. In conclusion, co-existence of high pSmad3L(Ser(213)) expression and low pSmad3C(Ser(423/425)) expression can be considered as immunohistochemical biomarkers for predicting prognosis as well as future therapeutic targets. In addition, our results of combinatory effect of differential phosphorylation of Smad3 on prognosis suggest the mode of action of Smad3 might be logically determined by its phosphorylation pattern. PMID:25267569

  17. A Functional TNFAIP2 3'-UTR rs8126 Genetic Polymorphism Contributes to Risk of Esophageal Squamous Cell Carcinoma

    PubMed Central

    Zhang, Jian; Yu, Hongchen; Zhang, Yi; Zhang, Xiaoshi; Zheng, Guixin; Gao, Yang; Wang, Chuanxin; Zhou, Liqing

    2014-01-01

    Background Accumulated evidences demonstrated that single nucleotide polymorphisms (SNPs) in mRNA 3'-untranslated region (3'-UTR) may impact microRNAs (miRNAs)-mediated expression regulation of oncogenes and tumor suppressors. There is a TNFAIP2 3'-UTR rs8126 T>C genetic variant which has been proved to be associated with head and neck cancer susceptibility. This SNP could disturb binding of miR-184 with TNFAIP2 mRNA and influence TNFAIP2 regulation. However, it is still unclear how this polymorphism is involved in development of esophageal squamous cell carcinoma (ESCC). Therefore, we hypothesized that the functional TNFAIP2 rs8126 SNP may affect TNFAIP2 expression and, thus, ESCC risk. Methods We investigated the association between the TNFAIP2 rs8126 variant and ESCC risk as well as the functional relevance on TNFAIP2 expression in vivo. Genotypes were determined in a case-control set consisted of 588 ESCC patients and 600 controls. The allele-specific regulation on TNFAIP2 expression by the rs8126 SNP was examined in normal and cancerous tissue specimens of esophagus. Results We found that individuals carrying the rs8126 CC or CT genotype had an OR of 1.89 (95%CI  = 1.23–2.85, P = 0.003) or 1.38 (95%CI  = 1.05–1.73, P = 0.017) for developing ESCC in Chinese compared with individual carrying the TT genotype. Carriers of the rs8126 CC and CT genotypes had significantly lower TNFAIP2 mRNA levels than those with the TT genotypes in normal esophagus tissues (P<0.05). Conclusions Our data demonstrate that functional TNFAIP2 rs8126 genetic variant is a ESCC susceptibility SNP. These results support the hypothesis that genetic variants interrupting miRNA-mediated gene regulation might be important genetic modifiers of cancer risk. PMID:25383966

  18. Association between a microRNA-214 binding site polymorphism in the methylenetetrahydrofolate reductase gene and esophageal squamous cell carcinoma.

    PubMed

    Shen, G R; Li, W Z; Liu, Y C; Li, X P; Yuan, H Y

    2016-01-01

    MicroRNAs (miRNAs) are key regulators of gene expression and play an important role in the development and progression of various diseases including esophageal squamous cell carcinoma (ESCC). In this study, we determined whether a polymorphism at the miR-214 binding site in the 3'-untranslated region (3'-UTR) of the methylenetetrahydrofolate reductase gene (MTHFR) is associated with susceptibility to ESCC. A total of 448 ESCC cases and 460 gender- and age-matched subjects were recruited for the study. The genotypes of the rs114673809 single nucleotide polymorphism (SNP) were determined by polymerase chain reaction sequencing. Associations between genotypes of MTHFR rs114673809 and ESCC risk were determined using logistic regression analyses. In the recessive model, when the MTHFR rs114673809 GG homozygote genotype was used as the reference group, the GA genotype was not associated with the risk of ESCC (GA vs GG: OR = 1.261, 95%CI = 0.960-1.657, P = 0.110), but the AA genotype was associated with increased risk of ECSS (AA vs GG: OR = 1.752, 95%CI = 1.076-2.853, P = 0.027). Additionally, the rs114673809 A allele carriers also showed a 1.286-fold increased ESCC risk compared with those carrying the rs114673809 G allele genotype. Furthermore, we observed a significant increase in plasma homocysteine levels in ESCC cases carrying the AA genotype relative to ESCC cases carrying the GG genotype. Our data demonstrate that a polymorphism at the miR-214 binding site in the 3'-UTR of MTHFR is an ESCC susceptibility SNP in the Chinese population. PMID:27323028

  19. Circulating Tumor Cell Analyses in Patients With Esophageal Squamous Cell Carcinoma Using Epithelial Marker-Dependent and -Independent Approaches

    PubMed Central

    Li, Hao; Song, Pingping; Zou, Benkui; Liu, Min; Cui, Kai; Zhou, Pengfei; Li, Sheng; Zhang, Baijiang

    2015-01-01

    Abstract In several epithelial malignancies, detection of circulating tumor cells (CTCs) in the peripheral blood has diagnostic, prognostic, and therapeutic implications. However, the clinical relevance of CTCs in esophageal squamous cell carcinoma (ESCC) has not yet been ascertained. The study was conducted with the aim of determining the clinical significance of CTCs in patients with ESCC by using 2 CTC detection systems, one epithelial marker-dependent and the other epithelial marker-independent. Paired peripheral blood samples were prospectively obtained from 61 ESCC patients before treatment and were analyzed for CTCs isolated by the CellSearchTM system (CS) and the method of isolation by size of epithelial tumor (ISET). Blood samples from 22 healthy volunteers were used as controls. Out of 61 study subjects, CTCs were detected in 20 patients (32.8%) by the ISET method and in only 1 patient (1.6%) by the CS method. Circulating tumor microemboli (CTM) were observed in 3 of 61 (4.9%) patients using ISET, but were undetectable in any of the patient by CS method. No CTCs/CTM were detected by either method in control groups. By ISET method, the presence of CTCs appeared to correlate with the stage of ESCC and with the baseline median platelet levels. No correlation with any other relevant clinicopathological variables was observed. Our results clearly indicate the ability of both CS and ISET methods to detect CTCs in peripheral blood samples from ESCC patients. However, the CellSearchTM system appears to have a poorer sensitivity as compared with the ISET method. Further studies are essential for assessing the role of such technologies in ESCC. PMID:26402816

  20. Prevalence of metastasis in T1b esophageal squamous cell carcinoma: a retrospective analysis of 258 Chinese patients

    PubMed Central

    Qi, Xiaotong; Li, Mingna; Zhao, Sheng; Luo, Jinhua; Shao, Yongfeng

    2016-01-01

    Background There is controversy regarding the impact of different depths of submucosal invasion on lymph node metastasis (LNM) and overall survival (OS). We evaluated the impact of depth of submucosal invasion on the presence of metastatic lymphadenopathy and survival in a Chinese population with esophageal squamous cell carcinoma (ESCC). Methods A total of 258 patients who underwent esophagectomy from November 2009 to March 2014 were studied. Demographics of patients, tumor characteristics, and surgical information were retrospectively collected through medical records. Submucosal invasion was equally categorized into inner one-third (sm1), middle one-third (sm2), and deep one-third (sm3) invasion by pathologists. The patients were observed at the outpatient department in accordance with appointed time and recurrence, and deaths were recorded. The median follow-up duration was 26 months and the deadline was April 2015. Cancer characteristics and its association with LNM and OS were analyzed. Results The study included 75 (29.1%) sm1, 73 (28.3%) sm2, and 110 (42.6%) sm3 patients, and the rates of LNM were 12% (9/75), 11% (8/73), and 20.9% (23/110), respectively. sm3 might be associated with regional LNM (univariate analysis, P=0.041). Tumor volume >1.856 cm3 (P=0.022) and lymphovascular invasion (LVI) (P=0.004) predicted LNM using multivariate analysis. No significant differences in distant metastases were observed according to the depth of invasion. Only metastatic lymph nodes predicted OS (P<0.001) rather than the depth of invasion. Conclusions Submucosal ESCC showed a substantial rate of LNM. In T1b ESCC, after adjusting for possible covariates, depth of invasion does not predict LNM or OS. PMID:27162673

  1. Oral Microbiota and Risk for Esophageal Squamous Cell Carcinoma in a High-Risk Area of China

    PubMed Central

    Chen, Xingdong; Winckler, Björn; Lu, Ming; Cheng, Hongwei; Yuan, Ziyu; Yang, Yajun; Jin, Li; Ye, Weimin

    2015-01-01

    Poor oral health has been linked with an increased risk of esophageal squamous cell carcinoma (ESCC). We investigated whether alteration of oral microbiota is associated with ESCC risk. Fasting saliva samples were collected from 87 incident and histopathologicallly diagnosed ESCC cases, 63 subjects with dysplasia and 85 healthy controls. All subjects were also interviewed with a questionnaire. V3–V4 region of 16S rRNA was amplified and sequenced by 454-pyrosequencing platform. Carriage of each genus was compared by means of multivariate-adjusted odds ratios derived from logistic regression model. Relative abundance was compared using Metastats method. Beta diversity was estimated using Unifrac and weighted Unifrac distances. Principal coordinate analysis (PCoA) was applied to ordinate dissimilarity matrices. Multinomial logistic regression was used to compare the coordinates between different groups. ESCC subjects had an overall decreased microbial diversity compared to control and dysplasia subjects (P<0.001). Decreased carriage of genera Lautropia, Bulleidia, Catonella, Corynebacterium, Moryella, Peptococcus and Cardiobacterium were found in ESCC subjects compared to non-ESCC subjects. Multinomial logistic regression analyses on PCoA coordinates also revealed that ESCC subjects had significantly different levels for several coordinates compared to non-ESCC subjects. In conclusion, we observed a correlation between altered salivary bacterial microbiota and ESCC risk. The results of our study on the saliva microbiome are of particular interest as it reflects the shift in microbial communities. Further studies are warranted to verify this finding, and if being verified, to explore the underlying mechanisms. PMID:26641451

  2. Oral Microbiota and Risk for Esophageal Squamous Cell Carcinoma in a High-Risk Area of China.

    PubMed

    Chen, Xingdong; Winckler, Björn; Lu, Ming; Cheng, Hongwei; Yuan, Ziyu; Yang, Yajun; Jin, Li; Ye, Weimin

    2015-01-01

    Poor oral health has been linked with an increased risk of esophageal squamous cell carcinoma (ESCC). We investigated whether alteration of oral microbiota is associated with ESCC risk. Fasting saliva samples were collected from 87 incident and histopathologicallly diagnosed ESCC cases, 63 subjects with dysplasia and 85 healthy controls. All subjects were also interviewed with a questionnaire. V3-V4 region of 16S rRNA was amplified and sequenced by 454-pyrosequencing platform. Carriage of each genus was compared by means of multivariate-adjusted odds ratios derived from logistic regression model. Relative abundance was compared using Metastats method. Beta diversity was estimated using Unifrac and weighted Unifrac distances. Principal coordinate analysis (PCoA) was applied to ordinate dissimilarity matrices. Multinomial logistic regression was used to compare the coordinates between different groups. ESCC subjects had an overall decreased microbial diversity compared to control and dysplasia subjects (P<0.001). Decreased carriage of genera Lautropia, Bulleidia, Catonella, Corynebacterium, Moryella, Peptococcus and Cardiobacterium were found in ESCC subjects compared to non-ESCC subjects. Multinomial logistic regression analyses on PCoA coordinates also revealed that ESCC subjects had significantly different levels for several coordinates compared to non-ESCC subjects. In conclusion, we observed a correlation between altered salivary bacterial microbiota and ESCC risk. The results of our study on the saliva microbiome are of particular interest as it reflects the shift in microbial communities. Further studies are warranted to verify this finding, and if being verified, to explore the underlying mechanisms. PMID:26641451

  3. Phase II clinical and exploratory biomarker study of dacomitinib in recurrent and/or metastatic esophageal squamous cell carcinoma

    PubMed Central

    Kim, Hyo Song; Kim, Sung-Moo; Kim, Hyunki; Pyo, Kyoung-Ho; Sun, Jong-Mu; Ahn, Myung-Ju; Park, Keunchil; Keam, Bhumsuk; Kwon, Nak-Jung; Yun, Hwan Jung; Kim, Hoon-Gu; Chung, Ik-Joo; Lee, Jong Seok; Lee, Kyung Hee; Kim, Dae Joon; Lee, Chang-Geol; Hur, Jin; Chung, Hyunsoo; Park, Jun Chul; Shin, Sung Kwan; Lee, Sang Kil; Kim, Hye Ryun; Moon, Yong Wha; Lee, Yong Chan; Kim, Joo Hang; Paik, Soonmyung; Cho, Byoung Chul

    2015-01-01

    The purpose of this study was to investigate the clinical activity, safety and predictive biomarkers of dacomitinib, an irreversible pan-HER inhibitor, in patients with recurrent or metastatic esophageal squamous cell carcinoma (R/M-ESCC). Patients, whose diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, were treated with dacomitinib 45mg/day. The primary endpoint was objective response rate by RECISTv 1.1. Predictive biomarker analyses included the characterization of somatic mutations and gene expression using the Ion Torrent AmpliSeq Cancer Hotspot Panel and Nanostring nCounter, and investigation of their relationship with clinical outcomes. Of the 48 evaluable patients, 6 (12.5%) achieved partial responses and 29 (60.4%) had stable disease. The median response duration was 7.1 months. The median progression free survival (PFS) and overall survival (OS) was 3.3 months (95% CI, 2.4-4.3 months) and 6.4 months (95% CI, 4.4-8.4 months). Adverse events were mostly grade 1-2. Gene set enrichment analysis revealed that ERBB signaling pathway is significantly enriched in patients with PFS ≥4 months (n = 12) than PFS < 4 months (n = 21) (p < 0.001). Upregulation of ERBB signaling pathway was significantly associated with longer PFS (5.0 vs. 2.9 months, P = 0.016) and OS (10.0 vs. 4.8 months, P = 0.022). The most frequent mutations were TP53 (61%) followed by CDKN2A (8%), MLH1 (8%), FLT3 (8%) and EGFR (8%). Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-ESCC. Screening of ERBB pathway-related gene expression profiles may help identify patients who are most likely benefit from dacomitinib. PMID:26462025

  4. Aurora-A modulates MMP-2 expression via AKT/NF-κB pathway in esophageal squamous cell carcinoma cells.

    PubMed

    Wang, Xiaoxia; Li, Xiaozhong; Li, Chaohui; He, Chun; Ren, Benhong; Deng, Qing; Gao, Wei; Wang, Binquan

    2016-06-01

    Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies. It is necessary to identify new markers for predicting tumor progression and therapeutic molecular targets. It has been reported that overexpressions of Aurora-A and matrix metalloproteinases 2 (MMP-2) may promote the malignant development of tumor. However, the relationship between Aurora-A and MMP-2 expression in tumor patients has not been investigated. In addition, the underlying mechanisms that Aurora-A regulates MMP-2 expression are still not fully elucidated. In this study, we demonstrated that Aurora-A and MMP-2 were overexpressed in ESCC tissues compared with paired normal adjacent tissues (P < 0.0001). Overexpression of Aurora-A was associated with the lymph node metastasis of ESCC (P = 0.01). Significantly, Aurora-A protein expression was positively correlated with MMP-2 protein expression in ESCC tissues (r = 0.66, P < 0.0001) as well as in ESCC cell lines. The level of Aurora-A expression was also positively correlated with the invasion capability of ESCC cells. Furthermore, Aurora-A overexpression significantly increased ESCC cell invasion by the upregulation of MMP-2 expression. In addition, Aurora-A overexpression promoted nuclear factor-kappaB (NF-κB) activation, and Aurora-A-mediated MMP-2 upregulation was abrogated by NF-κB inhibitor. Further analysis showed that activation of NF-κB was severely attenuated by AKT inhibitor in cells overexpressing Aurora-A. Taken together, these data indicate that Aurora-A overexpression upregulates MMP-2 expression through activating AKT/NF-κB signaling pathway in ESCC cells. These findings reveal that Aurora-A may be used as an important indicator for the judgment of malignant behavior of ESCC, and may be an attractive target for cancer therapy. PMID:27125974

  5. Circulating miR-21 as an independent predictive biomarker for chemoresistance in esophageal squamous cell carcinoma

    PubMed Central

    Komatsu, Shuhei; Ichikawa, Daisuke; Kawaguchi, Tsutomu; Miyamae, Mahito; Okajima, Wataru; Ohashi, Takuma; Imamura, Taisuke; Kiuchi, Jun; Konishi, Hirotaka; Shiozaki, Atsushi; Fujiwara, Hitoshi; Okamoto, Kazuma; Otsuji, Eigo

    2016-01-01

    Only a few studies indentified the significance of circulating microRNAs in blood as a predictive biomarker for chemoresistance in esophageal squamous cell carcinoma (ESCC). In this study, we tested whether oncogenic miR-21 promoted chemoresistance in ESCC and served as a biomarker for predicting chemoresistance in plasma of patients with ESCC. All consecutive patients underwent the preoperative chemotherapy regimen (JCOG9907 trial) with cisplatin plus 5-fluorouracil. As a result, pretreatment plasma concentrations of miR-21 were significantly higher in ESCC patients with a low histopathological response than in those with a high histopathological response (P = 0.0416). Multivariate analysis revealed that a high pretreatment plasma concentration of miR-21 was an independent risk factor of chemoresistance (p = 0.0150; Odds Ratio 9.95 (range: 1.56-63.4)). The expression of miR-21 was also significantly higher in pretreatment ESCC tissues with a low histopathological response than in those with a high histopathological response (P = 0.0409). In vitro, although the growth of KYSE 170 ESCC cells transfected with the control mimics was markedly inhibited by the 5-fluorouracil or cisplatin treatment, the inhibitory effects of 5-FU (P < 0.05) or cisplatin (P < 0.05) were significantly reduced in KYSE170 cells that overexpressed miR-21. Taken together, the overexpression of miR-21 contributed to chemoresistance and circulating miR-21 in plasma of patients with ESCC could be a useful biomarker for predicting chemoresistance. PMID:27508093

  6. Protein-protein interaction network analyses for elucidating the roles of LOXL2-delta72 in esophageal squamous cell carcinoma.

    PubMed

    Wu, Bing-Li; Zou, Hai-Ying; Lv, Guo-Qing; Du, Ze-Peng; Wu, Jian-Yi; Zhang, Pi-Xian; Xu, Li-Yan; Li, En-Min

    2014-01-01

    Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase (LOX) family, is a copper-dependent enzyme that catalyzes oxidative deamination of lysine residues on protein substrates. LOXL2 was found to be overexpressed in esophageal squamous cell carcinoma (ESCC) in our previous research. We later identified a LOXL2 splicing variant LOXL2-delta72 and we overexpressed LOXL2-delta72 and its wild type counterpart in ESCC cells following microarray analyses. First, the differentially expressed genes (DEGs) of LOXL2 and LOXL2-delta72 compared to empty plasmid were applied to generate protein-protein interaction (PPI) sub-networks. Comparison of these two sub-networks showed hundreds of different proteins. To reveal the potential specific roles of LOXL2- delta72 compared to its wild type, the DEGs of LOXL2-delta72 vs LOXL2 were also applied to construct a PPI sub-network which was annotated by Gene Ontology. The functional annotation map indicated the third PPI sub-network involved hundreds of GO terms, such as "cell cycle arrest", "G1/S transition of mitotic cell cycle", "interphase", "cell-matrix adhesion" and "cell-substrate adhesion", as well as significant "immunity" related terms, such as "innate immune response", "regulation of defense response" and "Toll signaling pathway". These results provide important clues for experimental identification of the specific biological roles and molecular mechanisms of LOXL2-delta72. This study also provided a work flow to test the different roles of a splicing variant with high-throughput data. PMID:24716982

  7. BC200 LncRNA a potential predictive marker of poor prognosis in esophageal squamous cell carcinoma patients

    PubMed Central

    Zhao, Rui-Hua; Zhu, Cai-hua; Li, Xiang-Ke; Cao, Wei; Zong, Hong; Cao, Xin-Guang; Hu, Hai-Yan

    2016-01-01

    Objective To explore the expression and prognosis significance of BC200 in esophageal squamous cell carcinoma (ESCC) patients who received radical resection. Methods We used quantitative real-time polymerase chain reaction to detect the expression level of BC200 in cancer tissue and paired adjacent normal tissue samples from 70 ESCC patients who received radical surgical resection and analyzed the correlation of the relative expression level of BC200 with clinical-pathological features and prognosis. Results We found that the relative expression of BC200 was significantly higher in ESCC tissues compared with adjacent normal tissue samples (P=0.023). But the expression of BC200 were not related to clinical-pathological features, such as age, TNM stages, and histological grade (P>0.05). Kaplan–Meier analysis showed that high expression levels of BC200 were correlated with poor prognosis in ESCC patients. Patients with a high level of BC200 had a shorter disease-free survival and overall survival than those with low BC200 expression (P=0.034 and P=0.031, respectively). On multivariate analysis, the hazard ratio (HR) of BC200 expression was 2.17 (95% confidence interval [CI]=1.12–4.19, P=0.022) for disease-free survival and 2.24 (95% CI=1.12–4.49, P=0.023) for overall survival. Conclusion Our results indicate that high expression of BC200 reflects poor prognosis and could serve as a novel predictive marker for ESCC patients who received radical resection. PMID:27143917

  8. SMYD3 stimulates EZR and LOXL2 transcription to enhance proliferation, migration, and invasion in esophageal squamous cell carcinoma.

    PubMed

    Zhu, Ying; Zhu, Meng-Xiao; Zhang, Xiao-Dan; Xu, Xiu-E; Wu, Zhi-Yong; Liao, Lian-Di; Li, Li-Yan; Xie, Yang-Min; Wu, Jian-Yi; Zou, Hai-Ying; Xie, Jian-Jun; Li, En-Min; Xu, Li-Yan

    2016-06-01

    Epigenetic alterations, including DNA methylation and histone modifications, are involved in the regulation of cancer initiation and progression. SET and MYND domain-containing protein 3 (SMYD3), a methyltransferase, plays an important role in transcriptional regulation during human cancer progression. However, SMYD3 expression and its function in esophageal squamous cell carcinoma (ESCC) remain unknown. In this study, SMYD3 expression was studied by immunohistochemistry in a tumor tissue microarray from 131 cases of ESCC patients. Statistical analysis showed that overall survival of patients with high SMYD3 expressing in primary tumors was significantly lower than that of patients with low SMYD3-expressing tumors (P = .008, log-rank test). Increased expression of SMYD3 was found to be associated with lymph node metastasis in ESCC (P = .036) and was an independent prognostic factor for poor overall survival (P = .025). RNAi-mediated knockdown of SMYD3 suppressed ESCC cell proliferation, migration, and invasion in vitro and inhibited local tumor invasion in vivo. SMYD3 regulated transcription of EZR and LOXL2 by directly binding to the sequences of the promoter regions of these target genes, as demonstrated by a chromatin immunoprecipitation assay. Immunohistochemical staining of ESCC tissues also confirmed that protein levels of EZR and LOXL2 positively correlated with SMYD3 expression, and the Spearman correlation coefficients (rs) were 0.78 (n = 81; P < .01) and 0.637 (n = 103; P < .01), respectively. These results indicate that SMYD3 enhances tumorigenicity in ESCC through enhancing transcription of genes involved in proliferation, migration, and invasion. PMID:26980013

  9. Secondhand Smoking and the Risk of Esophageal Squamous Cell Carcinoma in a High Incidence Region, Kashmir, India

    PubMed Central

    Rafiq, Rumaisa; Shah, Idrees Ayoub; Bhat, Gulzar Ahmad; Lone, Mohd Maqbool; Islami, Farhad; Boffetta, Paolo; Dar, Nazir Ahmad

    2016-01-01

    Abstract Studies have associated secondhand smoking (SHS) with cancers of the lung, larynx, and pharynx. Only a few studies have examined the association between SHS and esophageal squamous cell carcinoma (ESCC) and the findings are inconclusive. We aimed to investigate the association between SHS and risk of ESCC in a case-control study in Kashmir, where the incidence of ESCC is high. We recruited 703 histopathologically confirmed ESCC cases and 1664 hospital-based controls individually matched to the cases for age, sex, and district of residence. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using conditional logistic regression models. Among never-tobacco users, the ORs for the association between SHS and ESCC risk were above unity with ever exposure to SHS (OR = 1.32; 95% CI, 0.43–4.02) and exposure to SHS for >14 h/wk (median value) (OR = 2.69; 95% CI, 0.75–20.65). In the analysis of data from all participants, the OR (95% CI) for the association between SHS and ESCC was (OR = 1.02; 95% CI, 0.53–1.93) for SHS ≤14 h/wk and (OR = 1.91; 95% CI, 0.75–4.89) for SHS >14 h/wk in the models adjusted for tobacco use and several other potential confounding factors. We found an indication of increased risk of ESCC associated with exposure to SHS. Studies with larger numbers of SHS-exposed never tobacco users are required to further examine this association. PMID:26735535

  10. Discovery of a Good Responder Subtype of Esophageal Squamous Cell Carcinoma with Cytotoxic T-Lymphocyte Signatures Activated by Chemoradiotherapy

    PubMed Central

    Komatsuzaki, Rie; Komatsu, Masayuki; Chiwaki, Fumiko; Tamaoki, Masashi; Nishimura, Takao; Takahashi, Naoki; Oda, Ichiro; Tachimori, Yuji; Arao, Tokuzo; Nishio, Kazuto; Kitano, Shigehisa; Narumi, Kenta; Aoki, Kazunori; Fujii, Satoshi; Ochiai, Atsushi; Yoshida, Teruhiko; Muto, Manabu; Yamada, Yasuhide; Sasaki, Hiroki

    2015-01-01

    Definitive chemoradiotherapy (CRT) is a less invasive therapy for esophageal squamous cell carcinoma (ESCC). Five-year survival rate of locally advanced ESCC patients by definitive CRT were 37%. We previously reported that tumor-specific cytotoxic T-lymphocyte (CTL) activation signatures were preferentially found in long-term survivors. However, it is unknown whether the CTL activation is actually driven by CRT. We compared gene expression profiles among pre- and post-treatment biopsy specimens of 30 ESCC patients and 121 pre-treatment ESCC biopsy specimens. In the complete response (CR) cases, 999 overexpressed genes including at least 234 tumor-specific CTL-activation associated genes such as IFNG, PRF1, and GZMB, were found in post-treatment biopsy specimens. Clustering analysis using expression profiles of these 234 genes allowed us to distinguish the immune-activated cases, designating them as I-type, from other cases. However, despite the better CR rate in the I-type, overall survival was not significantly better in both these 30 cases and another 121 cases. Further comparative study identified a series of epithelial to mesenchymal transition-related genes overexpressed in the early relapse cases. Importantly, the clinical outcome of CDH2-negative cases in the I-type was significantly better than that of the CDH2-positive cases in the I-type. Furthermore, NK cells, which were activated by neutrophils-producing S100A8/S100A9, and CTLs were suggested to cooperatively enhance the effect of CRT in the CDH2-negative I-type. These results suggested that CTL gene activation may provide a prognostic advantage in ESCCs with epithelial characteristics. PMID:26625258

  11. Krüppel-like factor 9 was down-regulated in esophageal squamous cell carcinoma and negatively regulated beta-catenin/TCF signaling.

    PubMed

    Qiao, Fan; Yao, Feng; Chen, Ling; Lu, Chengjun; Ni, Yiqian; Fang, Wentao; Jin, Hai

    2016-03-01

    Krüppel-like factor 9 (KLF9) has been found to play suppressive roles in several types of tumor. However, the expression pattern and biological functions of KLF9 in esophageal squamous cell carcinoma (ESCC) are still unknown. In this study, it was found that the expression of KLF9 was significantly down-regulated in ESCC compared to their adjacent normal esophageal tissues. Meanwhile, the expression of KLF9 was inversely correlated with the clinical features of ESCC patients. Moreover, in the biological function study, KLF9 was further validated to inhibit the growth, migration, and metastasis of ESCC cells in vitro and in vivo. Mechanistically, KLF9 bind with TCF4 and suppressed the beta-catenin/TCF signaling as well as the expression of its target gene Cyr61. Collectively, our study clarified the function of KLF9 in both ESCC progression and the regulation of beta-catenin/TCF signaling. PMID:25641762

  12. Quantitative evaluation of SPRR3 expression in esophageal squamous cell carcinoma by qPCR and its potential use as a biomarker.

    PubMed

    de A Simão, Tatiana; Souza-Santos, Paulo T; de Oliveira, Diego S L; Bernardo, Vagner; Lima, Sheila C S; Rapozo, Davy C M; Kruel, Cleber D P; Faria, Paulo A; Ribeiro Pinto, Luis F; Albano, Rodolpho M

    2011-10-01

    Esophageal squamous cell carcinoma (ESCC) is highly fatal due to late diagnosis and inefficient treatment. Early disease detection could improve diagnosis and patient survival. Esophageal squamous epithelial cells express SPRR3, a member of the small proline-rich protein family, which is downregulated in ESCC. Therefore, SPRR3 expression may be used as a biomarker to follow the transition from healthy mucosa to ESCC. Both SPRR3 mRNA splice variants, v1 and v2, were evaluated by real time PCR in tumor and histologically normal adjacent tissue biopsies from 84 ESCC patients and 18 healthy controls. SPRR3-v1 was most highly expressed in the esophageal mucosa of healthy subjects, with an increasingly lower expression in the adjacent mucosa of ESCC patients and in tumors, respectively. SPRR3-v2 expression was low in normal mucosa and in tumors but it was higher in the adjacent mucosa of ESCC patients. In addition, we found a significant correlation between a lower SPRR3-v1 and SPRR3-v2 expression and age and alcohol consumption, respectively. SPRR3 protein expression presented a good correlation with SPRR3 mRNA expression. Cut-off points to discriminate between healthy mucosa, tumor and adjacent mucosa were determined with receiver operating characteristic (ROC) curves. This analysis showed that SPRR3-v1 expression discriminates the esophageal mucosa of healthy subjects from the adjacent mucosa and the tumor of ESCC patients with high sensitivity and specificity. Our data shows that the quantitative analysis of SPRR3 mRNA is a robust and reliable method to monitor the malignant transformation of the healthy esophageal mucosa into ESCC. PMID:21777580

  13. Overexpression of FXYD-3 Is Involved in the Tumorigenesis and Development of Esophageal Squamous Cell Carcinoma

    PubMed Central

    Zhu, Zhen-Long; Yan, Bao-Yong; Yang, Yan-Hong; Wang, Ming-Wei; Zentgraf, Hanswalter; Zhang, Xiang-Hong; Sun, Xiao-Feng

    2013-01-01

    Objective. To investigate the association of FXYD-3 expression with clinicopathological variables and PINCH in patients with ESCC. Patients and Methods. Expression of FXYD-3 protein was immunohistochemically examined in normal esophageal mucous (n = 20) and ESCC (n = 64). Results. Expression of FXYD-3 in the cytoplasm markedly increased from normal esophageal epithelial cells to primary ESCC (P = 0.001). The expression of FXYD-3 was correlated with TNM stages and depth of tumor invasion. Furthermore, the cases with lymph node metastasis tended to show a higher frequency of positive expression than those without metastasis (P = 0.086), and FXYD-3 expression tended to be positively related to the expression of PINCH (P = 0.063). Moreover, the cases positive for both proteins had the highest frequency of lymph node metastasis (P = 0.001). However, FXYD-3 expression was not correlated with patient's gender (P = 0.847), age (P = 0.876), tumor location (P = 0.279), size (P = 0.771), grade of differentiation (P = 0.279), and survival (P = 0.113). Conclusion. Overexpression of FXYD-3 in the cytoplasm may play an important role in the tumorigenesis and development in the human ESCC, particularly in combination with PINCH expression. PMID:24167366

  14. Oncogenic but non-essential role of N-myc downstream regulated gene 1 in the progression of esophageal squamous cell carcinoma

    PubMed Central

    Wei, Wei; Bracher-Manecke, Jacqueline C.; Zhao, Xiaohang; Davies, Neil H.; Zhou, Lanping; Ai, Runna; Oliver, Lisa; Vallette, Francois; Hendricks, Denver T.

    2013-01-01

    N-myc downstream regulated gene 1 (NDRG1/Cap43/Drg-1) has previously been shown to be dysregulated in esophageal squamous cell carcinoma (ESCC). In this study, we investigated the role of NDRG1 in the neoplastic progression of ESCC using ectopic gain-of-function and loss-of-function approaches. Stable transfectants of the KYSE30 ESCC cell line with altered NDRG1 levels were generated by lentiviral transduction. Although no measurable effects on in vitro cell proliferation were observed with altered NDRG1 expression, the ectopic overexpression of NDRG1 was positively linked to recognized markers of metastasis, angiogenesis and apoptotic evasion. Accordingly, in the nude mouse xenograft model system, NDRG1 overexpression promoted the in vivo growth of KYSE30 derived xenografts, which could be attributed to the reduced apoptotic and enhanced angiogenic activities associated with this gene. These processes were mediated in part by increased NFκB activity in NDRG1 overexpressing cells. Nevertheless, no significant phenotypic changes were observed in response to NDRG1 knock-down, suggesting that this gene might not be essential for the neoplastic progression of ESCC. Taken together, our results suggest that NDRG1 may play positive but dispensable roles in the progression of esophageal squamous cell carcinoma. PMID:23192272

  15. Simultaneous fingerprint and high-wavenumber fiber-optic Raman spectroscopy improves in vivo diagnosis of esophageal squamous cell carcinoma at endoscopy

    PubMed Central

    Wang, Jianfeng; Lin, Kan; Zheng, Wei; Yu Ho, Khek; Teh, Ming; Guan Yeoh, Khay; Huang, Zhiwei

    2015-01-01

    This work aims to evaluate clinical value of a fiber-optic Raman spectroscopy technique developed for in vivo diagnosis of esophageal squamous cell carcinoma (ESCC) during clinical endoscopy. We have developed a rapid fiber-optic Raman endoscopic system capable of simultaneously acquiring both fingerprint (FP)(800–1800 cm−1) and high-wavenumber (HW)(2800–3600 cm−1) Raman spectra from esophageal tissue in vivo. A total of 1172 in vivo FP/HW Raman spectra were acquired from 48 esophageal patients undergoing endoscopic examination. The total Raman dataset was split into two parts: 80% for training; while 20% for testing. Partial least squares-discriminant analysis (PLS-DA) and leave-one patient-out, cross validation (LOPCV) were implemented on training dataset to develop diagnostic algorithms for tissue classification. PLS-DA-LOPCV shows that simultaneous FP/HW Raman spectroscopy on training dataset provides a diagnostic sensitivity of 97.0% and specificity of 97.4% for ESCC classification. Further, the diagnostic algorithm applied to the independent testing dataset based on simultaneous FP/HW Raman technique gives a predictive diagnostic sensitivity of 92.7% and specificity of 93.6% for ESCC identification, which is superior to either FP or HW Raman technique alone. This work demonstrates that the simultaneous FP/HW fiber-optic Raman spectroscopy technique improves real-time in vivo diagnosis of esophageal neoplasia at endoscopy. PMID:26243571

  16. Xerophilusin B induces cell cycle arrest and apoptosis in esophageal squamous cell carcinoma cells and does not cause toxicity in nude mice.

    PubMed

    Yao, Ran; Chen, Zhaoli; Zhou, Chengcheng; Luo, Mei; Shi, Xuejiao; Li, Jiagen; Gao, Yibo; Zhou, Fang; Pu, Jianxin; Sun, Handong; He, Jie

    2015-01-23

    Esophageal cancer is the eighth most common cancer in the world and ranks as the sixth leading cause of cancer-related mortality. Esophageal cancer has a poor prognosis partially due to its low sensitivity to chemotherapy agents, and the development of new therapeutic agents is urgently needed. Here, the antitumor activity of a natural ent-kaurane diterpenoid, xerophilusin B (1), which was isolated from Isodon xerophilus, a perennial herb frequently used in Chinese folk medicine for tumor treatment, was investigated. Compound 1 exhibited antiproliferative effects against esophageal squamous cell carcinoma (ESCC) cell lines in a time- and dose-dependent manner with lower toxicity against normal human and murine cell lines. In vivo studies demonstrated that 1 inhibited tumor growth of a human esophageal tumor xenograft in BALB/c nude mice without significant secondary adverse effects, indicating its safety in treating ESCC. Furthermore, 1 induced G2/M cell cycle arrest and promoted apoptosis through mitochondrial cytochrome c-dependent activation of the caspase-9 and caspase-3 cascade pathway in ESCC cell lines. In conclusion, the observations herein reported showed that 1 is a potential chemotherapeutic agent for ESCC and merits further preclinical and clinical investigation for cancer drug development. PMID:25555195

  17. Simultaneous fingerprint and high-wavenumber fiber-optic Raman spectroscopy improves in vivo diagnosis of esophageal squamous cell carcinoma at endoscopy

    NASA Astrophysics Data System (ADS)

    Wang, Jianfeng; Lin, Kan; Zheng, Wei; Yu Ho, Khek; Teh, Ming; Guan Yeoh, Khay; Huang, Zhiwei

    2015-08-01

    This work aims to evaluate clinical value of a fiber-optic Raman spectroscopy technique developed for in vivo diagnosis of esophageal squamous cell carcinoma (ESCC) during clinical endoscopy. We have developed a rapid fiber-optic Raman endoscopic system capable of simultaneously acquiring both fingerprint (FP)(800-1800 cm-1) and high-wavenumber (HW)(2800-3600 cm-1) Raman spectra from esophageal tissue in vivo. A total of 1172 in vivo FP/HW Raman spectra were acquired from 48 esophageal patients undergoing endoscopic examination. The total Raman dataset was split into two parts: 80% for training; while 20% for testing. Partial least squares-discriminant analysis (PLS-DA) and leave-one patient-out, cross validation (LOPCV) were implemented on training dataset to develop diagnostic algorithms for tissue classification. PLS-DA-LOPCV shows that simultaneous FP/HW Raman spectroscopy on training dataset provides a diagnostic sensitivity of 97.0% and specificity of 97.4% for ESCC classification. Further, the diagnostic algorithm applied to the independent testing dataset based on simultaneous FP/HW Raman technique gives a predictive diagnostic sensitivity of 92.7% and specificity of 93.6% for ESCC identification, which is superior to either FP or HW Raman technique alone. This work demonstrates that the simultaneous FP/HW fiber-optic Raman spectroscopy technique improves real-time in vivo diagnosis of esophageal neoplasia at endoscopy.

  18. Knockdown of long non-coding RNA TP73-AS1 inhibits cell proliferation and induces apoptosis in esophageal squamous cell carcinoma

    PubMed Central

    Zang, Wenqiao; Wang, Tao; Wang, Yuanyuan; Chen, Xiaonan; Du, Yuwen; Sun, Qianqian; Li, Min; Dong, Ziming; Zhao, Guoqiang

    2016-01-01

    Recent studies have shown that long non-coding RNAs (lncRNAs) are involved in a variety of biological processes and diseases in humans, including cancer. Our study serves as the first comprehensive analysis of lncRNA TP73-AS1 in esophageal cancer. We utilized a lncRNA microarray to analyze the expression profile of lncRNAs in esophageal squamous cell carcinoma. Our results show that lncRNA TP73-AS1 and BDH2 levels are generally upregulated in esophageal cancer tissues and are strongly correlated with tumor location or TNM stage in clinical samples. LncRNA TP73-AS1 knockdown inhibited BDH2 expression in EC9706 and KYSE30 cells, whereas BDH2 knockdown repressed esophageal cancer cell proliferation and induced apoptosis via the caspase-3 dependent apoptotic pathway. Overexpression of BDH2 in lncRNA TP73-AS1 knockdown cells partially rescued cell proliferation rates and suppressed apoptosis. In mouse xenografts, tumor size was reduced in lncRNA TP73-ASI siRNA-transfected tumors, suggesting that downregulation of lncRNA TP73-AS1 attenuated EC proliferation in vitro and in vivo. In addition, BDH2 or lncRNA TP73-AS1 knockdown enhanced the chemosensitivity of esophageal cancer cells to 5-FU and cisplatin. Our results suggest that lncRNA TP73-AS1 may be a novel prognostic biomarker that could serve as a potential therapeutic target for the treatment of esophageal cancer. PMID:26799587

  19. miR141 expression is downregulated and negatively correlated with STAT5 expression in esophageal squamous cell carcinoma

    PubMed Central

    TAN, HONGWU; ZHU, YUNFENG; ZHANG, JILING; PENG, LIJUN; JI, TAO

    2016-01-01

    The aim of the present study was to investigate the association between microRNA-141 (miR141) and signal transducer and activator of transcription 5 (STAT5) expression levels in human esophageal squamous cell carcinoma (ESCC) and to investigate the effects of miR141 on ESCC cells. A total of 45 consecutive patients with ESCC were enrolled in the study. The expression of miR141 in ESCC tissue samples was detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR). The expression of STAT5 in the ESCC tissues was detected using immunohistochemical staining and western blotting. In addition, Eca109 cells were transfected with miR141 mimic, and the levels of STAT5 were detected using western blotting. The effects of miR141 on the proliferation, invasion and migration of the cells were also detected using MTT, scratch and Transwell invasion assays, respectively. The miR141 expression level in the ESCC tissue samples was significantly decreased compared with that in the adjacent normal tissues (P<0.05). The expression of miR141 in the tissues from patients with lymph node metastasis was significantly decreased compared with that in the tissues of patients without such metastasis (P<0.05). The expression levels of STAT were significantly increased in the ESCC tissues compared with those in the adjacent normal tissues (P<0.05). Furthermore, the levels of STAT5 were significantly increased in the tissues from patients with lymph node metastasis compared with those without such metastasis (P<0.05); however, no statistically significant differences in miR141 expression were observed according to gender, age, tumor size, lesion location, differentiation and invasion (P>0.05). The results suggest that the miR141 mimic significantly inhibited the proliferation, migration and invasion of Eca109 cells in vitro. miR141 and STAT5 expression levels exhibited a negative association in the ESCC tissues, and were both closely associated with the progression of

  20. Authentication of newly established human esophageal squamous cell carcinoma cell line (YM-1) using short tandem repeat (STR) profiling method.

    PubMed

    Ayyoob, Khosravi; Masoud, Khoshnia; Vahideh, Kazeminejad; Jahanbakhsh, Asadi

    2016-03-01

    Cross-contamination during or early after establishment of a new cell line could result in the worldwide spread of a misidentified cell line. Therefore, newly established cell lines need to be authenticated by a reference standard method. This study was conducted to investigate the authenticity of a newly established epithelial cell line of human esophageal squamous cell carcinoma (ESCC) called YM-1 using short tandem repeat (STR) DNA profiling method. Primary human ESCC epithelial cells were cultured from the fresh tumor tissue of an adult female patient. Growth characteristics and epithelial originality of YM-1 cells were studied. Genomic DNA was isolated from YM-1 cells harvested at passage 22 and ESCC donor tumor sample on two different days to prevent probable DNA contamination. STR profiling was performed using AmpFℓSTR® Identifiler® Plus PCR Amplification Kit. To address whether YM-1 cells undergo genetic alteration as the passage number increases, STR profiling was performed again on harvested cells at passage 51. YM-1 cells grew as a monolayer with a population doubling time of 40.66 h. Epithelial originality of YM-1 cells was confirmed using ICC/IF staining of cytokeratins AE1/AE3. The STR profile of the ESCC donor tumor sample was the same with YM-1 cells at passage 22. However, STR profile of the donor tumor sample showed an off-ladder (OL) allele in their D7S820 locus. Also, re-profiling of YM-1 cells at passage 51 showed a loss of heterozygosity (LOH) at D18S51 locus. This suggests that long-term culture of cell lines may alter their DNA profile. Comparison of the DNA fingerprinting results in DSMZ, and ATCC STR profiling databases confirmed unique identity of YM-1 cell line. This study provides an easy, fast, and reliable procedure for authentication of newly established cell lines, which helps in preventing the spread of misidentified cells and improving the reproducibility and validity of experiments, consequently. PMID:26432330

  1. miR-486-5p expression pattern in esophageal squamous cell carcinoma, gastric cancer and its prognostic value

    PubMed Central

    Han, Chongxu; Fu, Deyuan; Zhou, Lin; Jin, Guangfu; Wang, Fuan; Wang, Daxin; Chen, Yong; Ma, Li; Zheng, Xucai; Han, Dongsheng

    2016-01-01

    Micro RNA (miR)-486-5p is often aberrantly expressed in human cancers. The aim of this study was to identify the prognostic value of miR-486-5p expression in digestive system cancers. Tissue microarrays were constructed with 680 samples including 185 esophageal squamous cell carcinomas (ESCCs), 90 gastric adenocarcinomas (GCs), and 60 digestive system cancer tissues from 10 ESCC, 10 GC, 10 colon, 10 rectum, 10 liver, 10 pancreatic cancer, and corresponding normal tissues. Twenty normal digestive system mucosa tissues from healthy volunteers were included as normal controls. In GC, miR-486-5p expression was decreased in 62.8% of cases (59/94), increased in 33.0% (31/94), and unchanged in 4.2% (4/94); in ESCC its expression was decreased in 66.2% (129/195), increased in 32.3% (63/195), and unchanged in 1.5% (3/195). Expression of miR-486-5p was decreased in 12, and increased in 8, of 20 cases of colon or rectum cancer; decreased in 6, and increased in 4, of 10 cases of liver cancer; and decreased in 8, and increased in 2, of 10 cases of pancreatic cancer. Multivariate and univariate regression analysis demonstrated that low/unchanged miR-486-5p predicted poor prognosis in ESCC (hazard ratio [HR], 4.32; 95% confidence interval [CI], 2.62–7.14; P < 0.001; HR, 3.88; 95% CI, 2.43–6.22; P < 0.001, respectively) and GC (HR, 2.46; 95% CI, 1.35–4.50; P = 0.003; HR, 2.55; 95% CI, 1.39–4.69; P = 0.002, respectively). MiR-486-5p might therefore be an independent tumor marker for evaluating prognosis in patients with ESCC or GC. PMID:26895105

  2. Three-dimensional telomere architecture of esophageal squamous cell carcinoma: comparison of tumor and normal epithelial cells.

    PubMed

    Sunpaweravong, S; Sunpaweravong, P; Sathitruangsak, C; Mai, S

    2016-05-01

    Telomeres are repetitive nucleotide sequences (TTAGGG)n located at the ends of chromosomes that function to preserve chromosomal integrity and prevent terminal end-to-end fusions. Telomere loss or dysfunction results in breakage-bridge-fusion cycles, aneuploidy, gene amplification and chromosomal rearrangements, which can lead to genomic instability and promote carcinogenesis. Evaluating the hypothesis that changes in telomeres contribute to the development of esophageal squamous cell carcinoma (ESCC) and to determine whether there are differences between young and old patients, we compared the three-dimensional (3D) nuclear telomere architecture in ESCC tumor cells with that of normal epithelial cells obtained from the same patient. Patients were equally divided by age into two groups, one comprising those less than 45 years of age and the other consisting of those over 80 years of age. Tumor and normal epithelial cells located at least 10 cm from the border of the tumor were biopsied in ESCC patients. Hematoxylin and eosin staining was performed for each sample to confirm and identify the cancer and normal epithelial cells. This study was based on quantitative 3D fluorescence in situ hybridization (Q-FISH), 3D imaging and 3D analysis of paraffin-embedded slides. The 3D telomere architecture data were computer analyzed using 100 nuclei per slide. The following were the main parameters compared: the number of signals (number of telomeres), signal intensity (telomere length), number of telomere aggregates, and nuclear volume. Tumor and normal epithelial samples from 16 patients were compared. The normal epithelial cells had more telomere signals and higher intensities than the tumor cells, with P-values of P < 0.0001 and P = 0.0078, respectively. There were no statistically significant differences in the numbers of telomere aggregates or the nuclear volumes between the tumor and normal epithelial cells. Secondary analyses examined the effects of age on 3D telomere

  3. A retrospective study: the prognostic value of anemia, smoking and drinking in esophageal squamous cell carcinoma with primary radiotherapy

    PubMed Central

    2013-01-01

    Background Few studies have investigated the relationship between anemia, smoking, drinking and survival in esophageal squamous cell carcinoma (ESCC) with primary radiotherapy. This study had the aim of evaluating the prognostic value of anemia, smoking and drinking in patients receiving primary radiotherapy for ESCC. Methods A total of 79 patients who underwent radiotherapy during initial treatment for ESCC were included in this study. The 2-year overall survival (OS) and disease-free survival (DFS) were analyzed between the anemic and non-anemic groups, non-smokers and smokers, and non-drinkers and drinkers using the Kaplan-Meier method and the Cox proportional hazards model. Results There were 79 patients (10 male) of median age 63 (range 38 to 84) years. The 2-year OS and DFS were 36% and 25%, respectively, in the non-anemic group, and 17% and 13%, respectively, in the anemic group (P = 0.019 for OS; P = 0.029 for DFS) using the Kaplan-Meier method. Survival analysis using the Kaplan-Meier method showed that the 2-year OS and DFS had no statistical difference between smoking, drinking and survival. In a univariate analysis, anemia was identified as a significant prognostic factor for 2-year OS (hazard ratio (HR) = 1.897; P = 0.024) and 2-year DFS (HR = 1.776; P = 0.036), independent of tumor, lymph node, metastasis (TNM) stage. In a multivariate analysis, anemia was identified as a highly significant prognostic factor for 2-year OS (HR = 2.125; P = 0.011) and 2-year DFS (HR = 1.898; P = 0.025), independent of TNM stage and initial treatment. We found no statistical difference in the 2-year OS and DFS associated with smoking (P > 0.2) and drinking (P > 0.6) using univariate and multivariate analysis. Conclusions Smoking and drinking were not prognostic for 2-year OS or DFS. Anemia before radiotherapy was associated with poor prognosis and an increased risk of relapse, which may serve as a new prognostic characteristic in ESCC treated with primary radiotherapy

  4. Aggressive surgical resection does not improve survival in operable esophageal squamous cell carcinoma with N2-3 status

    PubMed Central

    Zheng, Yu-Zhen; Zhao, Wei; Hu, Yi; Ding-Lin, Xiao-Xiao; Wen, Jing; Yang, Hong; Liu, Qian-Wen; Luo, Kong-Jia; Huang, Qing-Yuan; Chen, Jun-Ying; Fu, Jian-Hua

    2015-01-01

    AIM: To investigate the influence of nodal status on response and clarify the optimal treatment for operable esophageal squamous cell carcinoma (OSCC). METHODS: We retrospectively analyzed 1490 OSCC patients who underwent transthoracic esophagectomy and lymphadenectomy between December 1996 and December 2009 at the Sun Yat-sen University Cancer Center. The surgical approach and the number of resected lymph nodes (LNs) were considered in the assessment of surgery. Patients were classified according to their nodal statuses (N0 vs N1 vs N2-3). Overall survival was defined as the time from the date of death or final follow-up. Survival analysis was performed using the Kaplan-Meier method and differences between curves were assessed by the log-rank test. Univariate and multivariate Cox regression analyses were used to identify factors associated with prognosis. Statistical significance was assumed at a P < 0.05. RESULTS: With a median time from surgery to the last censoring date for the entire cohort of 72.2 mo, a total of 631 patients were still alive at the last follow-up and the median survival time was 35.5 mo. The surgical approach (left transthoracic vs Ivor-Lewis/tri-incisional) was verified as independent prognostic significance in patients with N0 or N1 status, but not in those with N2-3 status. Similar results were also observed with the number of resected LNs (≤ 14 vs ≥ 15). Compared with surgery alone, combined therapy achieved better outcomes in patients with N1 or N2-3 status, but not in those with N0 status. For those with N2-3 status, neither the surgical approach nor the number of resected LNs reached significance by univariate analysis, with unadjusted HRs of 0.826 (95%CI: 0.644-1.058) and 0.849 (95%CI: 0.668-1.078), respectively, and aggressiveness of surgery did not influence the outcome; the longest survival was observed in those patients who received the combined therapy. CONCLUSION: Combined therapy has a positive role in OSCC with LN

  5. An Old Story Retold: Loss of G1 Control Defines A Distinct Genomic Subtype of Esophageal Squamous Cell Carcinoma

    PubMed Central

    Wang, Qiyan; Bai, Jian; Abliz, Amir; Liu, Ying; Gong, Kenan; Li, Jingjing; Shi, Wenjie; Pan, Yaqi; Liu, Fangfang; Lai, Shujuan; Yang, Haijun; Lu, Changdong; Zhang, Lixin; Chen, Wei; Xu, Ruiping; Cai, Hong; Ke, Yang; Zeng, Changqing

    2015-01-01

    Esophageal squamous cell carcinoma (ESCC) has a high mortality rate. To determine the molecular basis of ESCC development, this study sought to identify characteristic genome-wide alterations in ESCC, including exonic mutations and structural alterations. The clinical implications of these genetic alterations were also analyzed. Exome sequencing and verification were performed for nine pairs of ESCC and the matched blood samples, followed by validation with additional samples using Sanger sequencing. Whole-genome SNP arrays were employed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) in 55 cases, including the nine ESCC samples subjected to exome sequencing. A total of 108 non-synonymous somatic mutations (NSSMs) in 102 genes were verified in nine patients. The chromatin modification process was found to be enriched in our gene ontology (GO) analysis. Tumor genomes with TP53 mutations were significantly more unstable than those without TP53 mutations. In terms of the landscape of genomic alterations, deletion of 9p21.3 covering CDKN2A/2B (30.9%), amplification of 11q13.3 covering CCND1 (30.9%), and TP53 point mutation (50.9%) occurred in two-thirds of the cases. These results suggest that the deregulation of the G1 phase during the cell cycle is a key event in ESCC. Furthermore, six minimal common regions were found to be significantly altered in ESCC samples and three of them, 9p21.3, 7p11.2, and 3p12.1, were associated with lymph node metastasis. With the high correlation of TP53 mutation and genomic instability in ESCC, the amplification of CCND1, the deletion of CDKN2A/2B, and the somatic mutation of TP53 appear to play pivotal roles via G1 deregulation and therefore helps to classify this cancer into different genomic subtypes. These findings provide clinical significance that could be useful in future molecular diagnoses and therapeutic targeting. PMID:26386145

  6. Comparison of long non-coding RNAs, microRNAs and messenger RNAs involved in initiation and progression of esophageal squamous cell carcinoma

    PubMed Central

    LI, SU-QING; LI, FENG; XIAO, YUN; WANG, CHUN-MEI; TUO, LEI; HU, JING; YANG, XIAO-BIN; WANG, JIN-SONG; SHI, WEI-HONG; LI, XIA; CAO, XIU-FENG

    2014-01-01

    Traditionally, cancer research has focused on protein-coding genes, which are considered the principal effectors and regulators of tumorigenesis. Non-coding RNAs, in particular microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been widely reported to be important in the regulation of tumorigenesis and cancer development. However, to the best of our knowledge, investigation of the expression profiles of lncRNAs and a comparison of the involvement of lncRNAs, miRNAs and messenger RNAs (mRNAs) in esophageal tumorigenesis and development have not previously been performed. In the current study, intrinsic associations among the expression profiles of lncRNAs, miRNAs and mRNAs from normal esophageal tissues and those from cancer tissues were investigated. Oligonucleotide microarrays were used to detect the expression profiles of the three types of RNA in the canceration processes of human esophageal squamous cell carcinoma (ESCC) tissues. It was demonstrated that the different RNAs exhibit associated patterns of expression among normal esophageal epithelium, low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and carcinoma tissues, particularly in the critical period of canceration (HGIN to ESCC). Furthermore, the results indicated a high level of similarity in the potential function of lncRNAs, miRNAs and mRNAs in the processes of ESCC development. In the current study, a first generation atlas of lncRNA profiling and its association with miRNAs and mRNAs in the canceration processes of ESCC were presented. PMID:24888564

  7. Genetic Variants in Epidermal Growth Factor Receptor Pathway Genes and Risk of Esophageal Squamous Cell Carcinoma and Gastric Cancer in a Chinese Population

    PubMed Central

    Li, Wen-Qing; Hu, Nan; Wang, Zhaoming; Yu, Kai; Su, Hua; Wang, Lemin; Wang, Chaoyu; Chanock, Stephen J.; Burdett, Laurie; Ding, Ti; Qiao, You-Lin; Fan, Jin-Hu; Wang, Yuan; Xu, Yi; Giffen, Carol; Xiong, Xiaoqin; Murphy, Gwen; Tucker, Margaret A.; Dawsey, Sanford M.; Freedman, Neal D.; Abnet, Christian C.; Goldstein, Alisa M.; Taylor, Philip R.

    2013-01-01

    The epidermal growth factor receptor (EGFR) signaling pathway regulates cell proliferation, differentiation, and survival, and is frequently dysregulated in esophageal and gastric cancers. Few studies have comprehensively examined the association between germline genetic variants in the EGFR pathway and risk of esophageal and gastric cancers. Based on a genome-wide association study in a Han Chinese population, we examined 3443 SNPs in 127 genes in the EGFR pathway for 1942 esophageal squamous cell carcinomas (ESCCs), 1758 gastric cancers (GCs), and 2111 controls. SNP-level analyses were conducted using logistic regression models. We applied the resampling-based adaptive rank truncated product approach to determine the gene- and pathway-level associations. The EGFR pathway was significantly associated with GC risk (P = 2.16×10−3). Gene-level analyses found 10 genes to be associated with GC, including FYN, MAPK8, MAP2K4, GNAI3, MAP2K1, TLN1, PRLR, PLCG2, RPS6KB2, and PIK3R3 (P<0.05). For ESCC, we did not observe a significant pathway-level association (P = 0.72), but gene-level analyses suggested associations between GNAI3, CHRNE, PAK4, WASL, and ITCH, and ESCC (P<0.05). Our data suggest an association between specific genes in the EGFR signaling pathway and risk of GC and ESCC. Further studies are warranted to validate these associations and to investigate underlying mechanisms. PMID:23874846

  8. Activin A enhances MMP-7 activity via the transcription factor AP-1 in an esophageal squamous cell carcinoma cell line.

    PubMed

    Yoshinaga, Keiji; Mimori, Koshi; Inoue, Hiroshi; Kamohara, Yukio; Yamashita, Keishi; Tanaka, Fumiaki; Mori, Masaki

    2008-09-01

    Activin A, a member of the transforming growth factor beta (TGF-beta) superfamily, is often overexpressed in solid carcinomas. We have previously reported that the expression of activin A is associated with lymph node metastasis in esophageal cancer. In the current study, our goal was to clarify the molecular mechanisms underlying the aggressive behavior of tumors expressing high levels of activin A. Using cDNA microarrays, the gene expression profile of a human esophageal carcinoma cell line (KYSE170) stably transfected with activin betaA (Act-betaA, a subunit of activin A) was compared with those of control human esophageal carcinoma cell lines. We found that expression of MMP-7 was higher in the Act-betaA transfectants than in the control cells. To reveal the mechanism of expression of MMP-7 mediated by activin A, we evaluated mRNA expression of MMP-7 and Act-betaA with or without activin A neutralizing antibody, using real-time PCR and Northern blot analysis. We also performed promoter analysis of the MMP-7 promoter and assessed c-Jun and Smad2/3 expression. MMP-7 expression in the transfectants was correlated with the level of Act-betaA expression and was reduced by activin A neutralizing antibody. The Act-betaA transfectants had higher MMP-7 promoter activity than control cells. MMP-7 promoter activity was not affected by mutation in the Smad binding site, while mutation of the AP-1 binding site did reduce activity. Moreover, the expression of c-Jun was increased in Act-betaA transfectants. These results indicate that activin A may modulate the expression of MMP-7 via AP-1 and not through Smad2/3. PMID:18695873

  9. Relationships between Micro-Vascular and Iodine-Staining Patterns in the Vicinity of the Tumor Front of Superficial Esophageal Squamous Carcinoma

    PubMed Central

    Ohta, Shunsuke; Kawada, Kenro; Swangsri, Jirawat; Fujiwara, Naoto; Saito, Katsumasa; Fujiwara, Hisashi; Ryotokuji, Tairo; Okada, Takuya; Miyawaki, Yutaka; Tohkairin, Yutaka; Nakajima, Yasuaki; Kumagai, Youichi; Nagai, Kagami; Ito, Takashi; Eishi, Yoshinobu; Kawano, Tatsuyuki

    2015-01-01

    Objective The aim of the present study was to clarify differences between micro-vascular and iodine-staining patterns in the vicinity of the tumor fronts of superficial esophageal squamous cell carcinomas (ESCCs). Methods Ten consecutive patients with ESCCs who were treated by endoscopic submucosal dissection (ESD) were enrolled. At the edge of the iodine-unstained area, we observed 183 sites in total using image-enhanced magnifying endoscopy. We classified the micro-vascular and iodine-staining patterns into three types: Type A, in which the line of vascular change matched the border of the iodine-unstained area; Type B, in which the border of the iodine-unstained area extended beyond the line of vascular change; Type C, in which the line of vascular change extended beyond the border of the iodine-unstained area. Then, by examining histopathological sections, we compared the diameter of intra-papillary capillary loops (IPCLs) in cancerous areas and normal squamous epithelium. Results We investigated 160 sites that the adequate quality of pictures were obtained. There was no case in which the line of vascular change completely matched the whole circumference of the border of an iodine-unstained area. Among the 160 sites, type A was recognized at 76 sites (47.5%), type B at 79 sites (49.4%), and type C at 5 sites (3.1%). Histological examination showed that the mean diameter of the IPCLs in normal squamous epithelium was 16.2±3.7μm, whereas that of IPCLs in cancerous lesions was 21.0±4.4μm. Conclusions The development of iodine-unstained areas tends to precede any changes in the vascularity of the esophageal surface epithelium. PMID:26301414

  10. Flowers of Camellia nitidissima cause growth inhibition, cell-cycle dysregulation and apoptosis in a human esophageal squamous cell carcinoma cell line.

    PubMed

    Dai, Lu; Li, Ji-Lin; Liang, Xin-Qiang; Li, Lin; Feng, Yan; Liu, Hai-Zhou; Wei, Wen-Er; Ning, Shu-Fang; Zhang, Li-Tu

    2016-08-01

    The present study aimed to investigate the chemopreventive effect of Camellia nitidissima flowers water extract (CNFE) on the Eca109 human esophageal squamous cell carcinoma (ESCC) cell line. The antiproliferative effect on Eca109 cells was determined using the trypan blue exclusion assay. The effects of CNFE on apoptosis and cell cycle arrest were investigated by flow cytometry. CNFE inhibited cell growth in both a dose‑ and time‑dependent manner in Eca109 cells. CNFE also caused dose‑ and time‑dependent apoptosis of these cells. Treatment of cells with CNFE resulted in dose‑dependent G0/G1 phase arrest of the cell cycle. The data demonstrated that CNFE serves antiproliferative effects against human ESCC Eca109 cells by inducing apoptosis and interrupting the cell cycle. These results suggested that CNFE has the potential to be a chemoprotective agent for ESCC. PMID:27314447