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Sample records for r01 par-08-052 r21

  1. Citation Impact of NHLBI R01 Grants Funded Through the American Recovery and Reinvestment Act as Compared to R01 Grants Funded Through a Standard Payline

    PubMed Central

    Danthi, Narasimhan S.; Wu, Colin O.; DiMichele, Donna; Hoots, W. Keith; Lauer, Michael S.

    2015-01-01

    Rationale The American Recovery and Reinvestment Act (ARRA) allowed NHLBI to fund R01 grants that fared less well on peer review than those funded by meeting a payline threshold. It is not clear whether the sudden availability of additional funding enabled research of similar or lesser citation impact than already funded work. Objective To compare the citation impact of ARRA-funded de novo NHLBI R01 grants with concurrent de novo NHLBI R01 grants funded by standard-payline mechanisms. Methods and Results We identified de novo (“Type 1”) R01 grants funded by NHLBI in fiscal year (FY) 2009: these included 458 funded by meeting Institute’s published payline and 165 funded only because of ARRA funding. Compared to payline grants, ARRA grants received fewer total funds (median values $1.03 million versus $1.87 million, P<0.001) for a shorter duration (median values including no-cost extensions 3.0 versus 4.9 years, P<0.001). Through May 2014, the payline R01 grants generated 3895 publications, while the ARRA R01 grants generated 996. Using the InCites database from Thomson-Reuters, we calculated a “normalized citation impact” for each grant by weighting each paper for the number of citations it received normalizing for subject, article type, and year of publication. The ARRA R01 grants had a similar normalized citation impact per $1 million spent as the payline grants (median values[IQR] 2.15[0.73–4.78] versus 2.03[0.75–4.10], P=0.61). The similar impact of the ARRA grants persisted even after accounting for potential confounders. Conclusions Despite shorter durations and lower budgets, ARRA R01 grants had comparable citation outcomes per $million spent to that of contemporaneously funded payline R01 grants. PMID:25722441

  2. Targeting miR-21 to treat psoriasis.

    PubMed

    Guinea-Viniegra, Juan; Jiménez, María; Schonthaler, Helia B; Navarro, Raquel; Delgado, Yolanda; Concha-Garzón, María José; Tschachler, Erwin; Obad, Susanna; Daudén, Esteban; Wagner, Erwin F

    2014-02-26

    Psoriasis is a common inflammatory skin disease with limited treatment options that is characterized by a complex interplay between keratinocytes, immune cells, and inflammatory mediators. MicroRNAs (miRNAs) are regulators of gene expression and play critical roles in many human diseases. A number of miRNAs have been described to be up-regulated in psoriasis, but their causal contribution to disease development has not been demonstrated. We confirm that miR-21 expression is increased in epidermal lesions of patients with psoriasis and that this leads to reduced epidermal TIMP-3 (tissue inhibitor of matrix metalloproteinase 3) expression and activation of TACE (tumor necrosis factor-α-converting enzyme)/ADAM17 (a disintegrin and metalloproteinase 17). Using patient-derived skin samples and mouse models of psoriasis, we demonstrate that increased miR-21 may be a consequence of impaired transcriptional activity of Jun/activating protein 1 (AP-1), leading to activation of the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (Stat3) pathway. Inhibition of miR-21 by locked nucleic acid (LNA)-modified anti-miR-21 compounds ameliorated disease pathology in patient-derived psoriatic skin xenotransplants in mice and in a psoriasis-like mouse model. Targeting miR-21 may represent a potential therapeutic option for the treatment of psoriasis. PMID:24574341

  3. miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma.

    PubMed

    Jiang, Lie-Hao; Ge, Ming-Hua; Hou, Xiu-Xiu; Cao, Jun; Hu, Si-Si; Lu, Xiao-Xiao; Han, Jing; Wu, Yi-Chen; Liu, Xiang; Zhu, Xin; Hong, Lian-Lian; Li, Pei; Ling, Zhi-Qiang

    2015-12-01

    miR-21, which is a putative tumor onco-miR and frequently overexpressed microRNA in various tumors, has been linked to tumor progression through targeting of tumor-suppressor genes. In this study, we sought to determine whether miR-21 has any role on tumor progression of salivary adenoid cystic carcinoma (SACC) and the possible mechanisms. We found that the level of miR-21 expression was significantly higher in SACC than that in normal salivary tissues, and it is also higher in tumors with metastasis than that without metastasis. Using an anti-miR-21 inhibitor in an in vitro model, downregulation of miR-21 significantly decreased the capacity of invasion and migration of SACC cells, whereas a pre-miR-21 increased the capacity of invasion and migration of SACC cells. To explore the potential mechanisms by which miR-21 regulate invasion and migration, we identified one direct miR-21 target gene, programmed cell death 4 (PDCD4), which has been implicated in invasion and metastasis. The suppression of miR-21 in metastatic SACC-LM cells significantly increased the report activity of PDCD4 promoter and the expression of PDCD4 protein. This subsequently resulted in downregulation of the p-STAT3 protein. The level of miR-21 expression positively related to the expression of PDCD4 protein and negatively related to the expression of p-STAT3 protein in SACC specimens, respectively, indicating the potential role of the STAT3-miR-21-PDCD4 pathway in these tumors. Dysregulation of miR-21 has an important role in tumor growth and invasion by targeting PDCD4. Therefore, suppression of miR-21 may provide a potential approach for the treatment of advanced SACC patients. PMID:26367487

  4. miR-21 Is Linked to Glioma Angiogenesis: A Co-Localization Study.

    PubMed

    Hermansen, Simon Kjær; Nielsen, Boye Schnack; Aaberg-Jessen, Charlotte; Kristensen, Bjarne Winther

    2016-02-01

    MicroRNA-21 (miR-21) is the most consistently over-expressed microRNA (miRNA) in malignant gliomas. We have previously reported that miR-21 is upregulated in glioma vessels and subsets of glioma cells. To better understand the role of miR-21 in glioma angiogenesis and to characterize miR-21-positive tumor cells, we systematically stained consecutive serial sections from ten astrocytomas for miR-21, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), phosphatase and tensin homolog (PTEN), octamer-binding transcription factor 4 (Oct4), sex-determining region Y box 2 (Sox2) and CD133. We developed an image analysis-based co-localization approach allowing global alignment and quantitation of the individual markers, and measured the miR-21 in situ hybridization signal against the immunohistochemical staining of the six different markers. miR-21 significantly co-localized with the hypoxia- and angiogenesis-associated markers HIF-1α (p=0.0020) and VEGF (p=0.0096), whereas the putative miR-21 target, PTEN, was expressed independently of miR-21. Expression of stem cell markers Oct4, Sox2 and CD133 was not associated with miR-21. In six glioblastoma cultures, miR-21 did not correlate with the six markers. These findings suggest that miR-21 is linked to glioma angiogenesis, that miR-21 is unlikely to regulate PTEN, and that miR-21-positive tumor cells do not possess stem cell characteristics. PMID:26701969

  5. Folate status, folate-related genes and serum miR-21 expression: Implications for miR-21 as a biomarker

    PubMed Central

    Beckett, Emma Louise; Martin, Charlotte; Choi, Jeong Hwa; King, Katrina; Niblett, Suzanne; Boyd, Lyndell; Duesing, Konsta; Yates, Zoe; Veysey, Martin; Lucock, Mark

    2015-01-01

    Background Free circulating microRNA (miRNA) in serum may be valuable biomarkers for disease diagnosis and prognosis. miR-21, the archetypal oncogenic miRNA, has been proposed as a biomarker for colorectal cancer and its benign precursor, adenomatous polyps. However, it is now becoming clear that circulating miRNA profiles may be sensitive to lifestyle and environmental influences. Dietary components involved in one-carbon metabolism are particularly well placed to modulate miRNA expression through an influence on DNA methylation pathways. Methods We investigated the role of methyl group donors (folate, B12, cysteine, homocysteine), polymorphisms of the enzymes of one-carbon metabolism, and serum miR-21 expression in a primary case–control cohort (colonoscopy confirmed adenomatous colon polyps vs controls; n = 253) and a secondary cross-sectional cohort (over 65s; n = 649). The relationships between these parameters and serum miR-21 levels were assessed, stratified by gender. Conclusions Serum miR-21 expression was related to occurrence of adenomatous polyps in females, but not males. Folate levels and MTHFR-C677T genotype was associated with miR-21 expression in both genders. Additionally, DHFR-19 del and MSR-A66G were associated with miR-21 expression in females and males, respectively. Stimulation with excess folate increased expression of miR-21 in colon cancer cell lines. General significance This study demonstrates that serum miR-21 expression correlates with folate status and related genetic status. This may have consequences for the proposed use of miR-21 as a colorectal cancer biomarker. PMID:26674922

  6. Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia.

    PubMed

    Zhou, Minran; Zeng, Jiping; Wang, Xiaoming; Wang, Xiangyu; Huang, Tao; Fu, Yue; Sun, Ting; Jia, Jihui; Chen, Chunyan

    2015-01-20

    Chronic myeloid leukemia in the blastic phase (CML-BP) responds poorly to clinical treatments and is usually fatal. In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP. The RBP2 histone demethylase stimulates leukemia cell differentiation and inhibits cell proliferation. We identified miR-21 was directly downregulated by RBP2 and found that miR-21 downregulated PDCD4 expression in leukemia cells. By binding to miR-21 promoter and by demethylating of trimethylated H3K4 at the miR-21 locus, RBP2 downregulated miR-21 expression. This in turn activated PDCD4. In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML. PMID:25575817

  7. MiR-21 Enhances Melanoma Invasiveness via Inhibition of Tissue Inhibitor of Metalloproteinases 3 Expression: In Vivo Effects of MiR-21 Inhibitor

    PubMed Central

    Martin del Campo, Sara E.; Latchana, Nicholas; Levine, Kala M.; Grignol, Valerie P.; Fairchild, Ene T.; Jaime-Ramirez, Alena Cristina; Dao, Thao-Vi; Karpa, Volodymyr I.; Carson, Mary; Ganju, Akaansha; Chan, Anthony N.; Carson III, William E.

    2015-01-01

    Metastatic melanoma is the most aggressive form of this cancer. It is important to understand factors that increase or decrease metastatic activity in order to more effectively research and implement treatments for melanoma. Increased cell invasion through the extracellular matrix is required for metastasis and is enhanced by matrix metalloproteinases (MMPs). Tissue inhibitor of metalloproteinases 3 (TIMP3) inhibits MMP activity. It was previously shown by our group that miR-21, a potential regulator of TIMP3, is over-expressed in cutaneous melanoma. It was therefore hypothesized that increased levels of miR-21 expression would lead to decreased expression of TIMP3 and thereby enhance the invasiveness of melanoma cells. miR-21 over-expression in the melanoma cell lines WM1552c, WM793b, A375 and MEL 39 was accomplished via transfection with pre-miR-21. Immunoblot analysis of miR-21-overexpressing cell lines revealed reduced expression of TIMP3 as compared to controls. This in turn led to a significant increase in the invasiveness of the radial growth phase cell line WM1552c and the vertical growth phase cell line WM793b (p < 0.05), but not in the metastatic cell lines A375 or MEL 39. The proliferation and migration of miR-21 over-expressing cell lines was not affected. Reduced expression of TIMP3 was achieved by siRNA knockdown and significantly enhanced invasion of melanoma cell lines, mimicking the effects of miR-21 over-expression. Treatment of tumor cells with a linked nucleic acid antagomir to miR-21 inhibited tumor growth and increased tumor expression of TIMP3 in vivo in 01B74 Athymic NCr-nu/nu mice. Intra-tumoral injections of anti-miR-21 produced similar effects. This data shows that increased expression of miR-21 enhanced the invasive potential of melanoma cell lines through TIMP3 inhibition. Therefore, inhibition of miR-21 in melanoma may reduce melanoma invasiveness. PMID:25587717

  8. Role of miR-21 in the pathogenesis of atrial fibrosis.

    PubMed

    Adam, Oliver; Löhfelm, Björn; Thum, Thomas; Gupta, Shashi K; Puhl, Sarah-Lena; Schäfers, Hans-Joachim; Böhm, Michael; Laufs, Ulrich

    2012-09-01

    Atrial fibrosis is important for the pathogenesis of atrial fibrillation (AF) but the underlying signal transduction is incompletely understood. We therefore studied the role of microRNA-21 (miR-21) and its downstream target Sprouty 1 (Spry1) during atrial fibrillation. Left atria (LA) from patients with AF showed a 2.5-fold increased expression of miR-21 compared to matched LA of patients in sinus rhythm. Increased miR-21 expression correlated positively with atrial collagen content and was associated with a reduced protein expression of Spry1 and increased expression of connective tissue growth factor (CTGF), lysyl oxidase and Rac1-GTPase. Neonatal cardiac fibroblasts treated with angiotensin II (AngII) or CTGF showed an increased miR-21 and decreased Spry1 expression. Pretreatment with an inhibitor of Rac1 GTPase, NSC23766, reduced the AngII-induced upregulation of miR-21. A small molecule inhibitor of lysyl oxidase, BAPN, prevented the AngII as well as the CTGF-induced miR-21 expression. Transgenic mice with cardiac overexpression of Rac1, which develop spontaneous AF and atrial fibrosis with increasing age, showed upregulation of miR-21 expression associated with reduced Spry1 expression. miR-21 expression and signalling in vivo were prevented by long-term treatment of the mice with statins. Direct inhibition of miR-21 by antagomir-21 prevented fibrosis of the atrial myocardium post-myocardial infarction. Left atria of patients with atrial fibrillation are characterized by upregulation of miR-21 und reduced expression of Spry1. Activation of Rac1 by angiotensin II leads to a CTGF- and lysyl oxidase-mediated increase of miR-21 expression contributing to structural remodelling of the atrial myocardium. PMID:22760500

  9. Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth

    PubMed Central

    Leone, Emanuela; Morelli, Eugenio; Di Martino, Maria T.; Amodio, Nicola; Foresta, Umberto; Gullà, Annamaria; Rossi, Marco; Neri, Antonino; Giordano, Antonio; Munshi, Nikhil C.; Anderson, Kenneth C.; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2014-01-01

    Purpose Deregulated expression of microRNAs (miRNAs) plays a role in the pathogenesis and progression of multiple myeloma (MM). Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of MM. Experimental design Here, we investigated the in vitro and in vivo anti-MM activity of miR-21 inhibitors. Results Either transient enforced expression or lentivirus-based constitutive expression of miR-21 inhibitors triggered significant growth inhibition of primary patient MM cells or IL-6-dependent/independent MM cell lines and overcame the protective activity of human bone marrow stromal cells. Conversely, transfection of miR-21 mimics significantly increased proliferation of MM cells, demonstrating its tumor promoting potential in MM. Importantly, upregulation of miR-21 canonical validated targets (PTEN, Rho-B and BTG2), together with functional impairment of both AKT and ERK signaling, were achieved by transfection of miR-21 inhibitors into MM cells. In vivo delivery of miR-21 inhibitors in SCID mice bearing human MM xenografts expressing miR-21 induced significant anti-tumor activity. Upregulation of PTEN and downregulation of p-AKT were observed in retrieved xenografts following treatment with miR-21 inhibitors. Conclusions Our findings show the first evidence that in vivo antagonism of miR-21 exerts anti-MM activity, providing the rationale for clinical development of miR-21 inhibitors in this still incurable disease. PMID:23446999

  10. MiR-21 Targets 15-PGDH and Promotes Cholangiocarcinoma Growth

    PubMed Central

    Lu, Lu; Byrnes, Kathleen; Han, Chang; Wang, Ying; Wu, Tong

    2014-01-01

    MicroRNAs (miRs) are a group of small, non-coding RNAs that modulate the translation of genes by binding to specific target sites in the target mRNA. This study investigated the biological function and molecular mechanism of microRNA-21 (miR-21) in human cholangiocarcinoma. In situ hybridization analysis of human cholangiocarcinoma specimens showed increased miR-21 in cholangiocarcinoma tissue compared to the non-cancerous biliary epithelium. Lentiviral transduction of miR-21 enhanced human cholangiocarcinoma cell growth and clonogenic efficiency in vitro, whereas inhibition of miR-21 decreased these parameters. Over-expression of miR-21 also promoted cholangiocarcinoma growth using an in vivo xenograft model system. The NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH/HPGD), a key enzyme that converts the protumorigenic prostaglandin E2 (PGE2) to its biologically inactive metabolite, was identified as a direct target of miR-21 in cholangiocarcinoma cells. In parallel, cyclooxygenase-2 (COX2) over-expression and PGE2 treatment increased miR-21 levels and enhanced miR-21 promoter activity in human cholangiocarcinoma cells. PMID:24699315

  11. miR-21 promotes human nucleus pulposus cell proliferation through PTEN/AKT signaling.

    PubMed

    Liu, Hongzhe; Huang, Xiangwang; Liu, Xiangyang; Xiao, Sheng; Zhang, Yi; Xiang, Tiecheng; Shen, Xiongjie; Wang, Guoping; Sheng, Bin

    2014-01-01

    The precise role of nucleus pulposus cell proliferation in the pathogenesis of intervertebral disc degeneration remains to be elucidated. Recent findings have revealed that microRNAs, a class of small noncoding RNAs, may regulate cell proliferation in many pathological conditions. Here, we showed that miR-21 was significantly upregulated in degenerative nucleus pulposus tissues when compared with nucleus pulposus tissues that were isolated from patients with idiopathic scoliosis and that miR-10b levels were associated with disc degeneration grade. Moreover, bioinformatics target prediction identified PTEN as a putative target of miR-21. miR-21 inhibited PTEN expression by directly targeting the 3'UTR, and this inhibition was abolished through miR-21 binding site mutations. miR-21 overexpression stimulated cell proliferation and AKT signaling pathway activation, which led to cyclin D1 translation. Additionally, the increase in proliferation and cyclin D1 expression induced by miR-21 overexpression was almost completely blocked by Ly294002, an AKT inhibitor. Taken together, aberrant miR-21 upregulation in intervertebral disc degeneration could target PTEN, which would contribute to abnormal nucleus pulposus cell proliferation through derepressing the Akt pathway. Our study also underscores the potential of miR-21 and the PTEN/Akt pathway as novel therapeutic targets in intervertebral disc degeneration. PMID:24603539

  12. miR-21 Promotes Human Nucleus Pulposus Cell Proliferation through PTEN/AKT Signaling

    PubMed Central

    Liu, Hongzhe; Huang, Xiangwang; Liu, Xiangyang; Xiao, Sheng; Zhang, Yi; Xiang, Tiecheng; Shen, Xiongjie; Wang, Guoping; Sheng, Bin

    2014-01-01

    The precise role of nucleus pulposus cell proliferation in the pathogenesis of intervertebral disc degeneration remains to be elucidated. Recent findings have revealed that microRNAs, a class of small noncoding RNAs, may regulate cell proliferation in many pathological conditions. Here, we showed that miR-21 was significantly upregulated in degenerative nucleus pulposus tissues when compared with nucleus pulposus tissues that were isolated from patients with idiopathic scoliosis and that miR-10b levels were associated with disc degeneration grade. Moreover, bioinformatics target prediction identified PTEN as a putative target of miR-21. miR-21 inhibited PTEN expression by directly targeting the 3′UTR, and this inhibition was abolished through miR-21 binding site mutations. miR-21 overexpression stimulated cell proliferation and AKT signaling pathway activation, which led to cyclin D1 translation. Additionally, the increase in proliferation and cyclin D1 expression induced by miR-21 overexpression was almost completely blocked by Ly294002, an AKT inhibitor. Taken together, aberrant miR-21 upregulation in intervertebral disc degeneration could target PTEN, which would contribute to abnormal nucleus pulposus cell proliferation through derepressing the Akt pathway. Our study also underscores the potential of miR-21 and the PTEN/Akt pathway as novel therapeutic targets in intervertebral disc degeneration. PMID:24603539

  13. A Quantitative Linguistic Analysis of National Institutes of Health R01 Application Critiques from Investigators at One Institution

    PubMed Central

    Kaatz, Anna; Magua, Wairimu; Zimmerman, David R.; Carnes, Molly

    2014-01-01

    Purpose Career advancement in academic medicine often hinges on the ability to garner research funds, and the National Institutes of Health’s (NIH’s) R01 award is the “gold standard” of an independent research program. Studies show inconsistencies in R01 reviewers’ scoring and in award outcomes for certain applicant groups. Consistent with the NIH recommendation to examine potential bias in R01 peer review, the authors performed a text analysis of R01 reviewers’ critiques. Method The authors collected 454 critiques (262 from 91 unfunded and 192 from 67 funded applications) from 67 of 76 (88%) R01 investigators at the University of Wisconsin-Madison with initially unfunded applications subsequently funded between December 2007 and May 2009. To analyze critiques the authors developed positive and negative grant application evaluation word categories and selected 5 existing categories relevant to grant review. The authors analyzed results with linear mixed effects models for differences due to applicant and application characteristics. Results Critiques of funded applications contained more positive descriptors and superlatives and fewer negative evaluation words than critiques of unfunded applications. Experienced investigators’ critiques contained more references to competence. Critiques showed differences due to applicant sex despite similar application scores or funding outcomes: more praise for applications from female investigators; greater reference to competence/ability for funded applications from female experienced investigators; and more negative evaluation words for applications from male investigators (Ps < .05). Conclusions Results suggest that text analysis is a promising tool for assessing consistency in R01 reviewers’ judgments and gender stereotypes may operate in R01 review. PMID:25140529

  14. 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

  15. Role of miR-21 in alkalinity stress tolerance in tilapia.

    PubMed

    Zhao, Yan; Wu, Jun-Wei; Wang, Yan; Zhao, Jin-Liang

    2016-02-26

    MicroRNAs (miRNAs) are a class of short, evolutionary conserved non-coding RNA molecules, which are shown as the key regulators of many biological functions. External stress can alter miRNA expression levels, thereby changing the expression of mRNA target genes. Here, we show that miR-21 is involved in the regulation of alkalinity tolerance in Nile tilapia. Alkalinity stress results in a marked reduction in miR-21 levels. miR-21 loss of function could affect ion balance regulation, ROS production, and antioxidant enzyme activity in vivo. Moreover, miR-21 knockdown protects cell against alkalinity stress-induced injury in vitro. miR-21 directly regulates VEGFB and VEGFC expression by targeting the 3'-untranslated regions (UTRs) of their mRNAs, and inhibition of miR-21 significantly increases the levels of VEGFB and VEGFC expression in vivo. Taken together, our study reveals that miR-21 knockdown plays a protective role in alkalinity tolerance in tilapia. PMID:26855132

  16. MiR-21 Protected Cardiomyocytes against Doxorubicin-Induced Apoptosis by Targeting BTG2

    PubMed Central

    Tong, Zhongyi; Jiang, Bimei; Wu, Yanyang; Liu, Yanjuan; Li, Yuanbin; Gao, Min; Jiang, Yu; Lv, Qinglan; Xiao, Xianzhong

    2015-01-01

    Doxorubicin (DOX) is an anthracycline drug with a wide spectrum of antineoplastic activities. However, it causes cardiac cytotoxicity, and this limits its clinical applications. MicroRNA-21 (miR-21) plays a vital role in regulating cell proliferation and apoptosis. While miR-21 is preferentially expressed in adult cardiomyocytes and involved in cardiac development and heart disease, little is known regarding its biological functions in responding to DOX-induced cardiac cytotoxicity. In this study, the effects of DOX on mouse cardiac function and the expression of miR-21 were examined in both mouse heart tissues and rat H9C2 cardiomyocytes. The results showed that the cardiac functions were more aggravated in chronic DOX injury mice compared with acute DOX-injury mice; DOX treatment significantly increased miR-21 expression in both mouse heart tissue and H9C2 cells. Over-expression of miR-21 attenuated DOX-induced apoptosis in cardiamyocytes whereas knocking down its expression increased DOX-induced apoptosis. These gain- and loss- of function experiments showed that B cell translocation gene 2 (BTG2) was a target of miR-21. The expression of BTG2 was significantly decreased both in myocardium and H9C2 cells treated with DOX. The present study has revealed that miR-21 protects mouse myocardium and H9C2 cells against DOX-induced cardiotoxicity probably by targeting BTG2. PMID:26132560

  17. Traumatic brain injury increases levels of miR-21 in extracellular vesicles: implications for neuroinflammation.

    PubMed

    Harrison, Emily B; Hochfelder, Colleen G; Lamberty, Benjamin G; Meays, Brittney M; Morsey, Brenda M; Kelso, Matthew L; Fox, Howard S; Yelamanchili, Sowmya V

    2016-08-01

    Traumatic brain injury (TBI) is an important health concern and effective treatment strategies remain elusive. Understanding the complex multicellular response to TBI may provide new avenues for intervention. In the context of TBI, cell-cell communication is critical. One relatively unexplored form of cell-cell communication in TBI is extracellular vesicles (EVs). These membrane-bound vesicles can carry many different types of cargo between cells. Recently, miRNA in EVs have been shown to mediate neuroinflammation and neuronal injury. To explore the role of EV-associated miRNA in TBI, we isolated EVs from the brain of injured mice and controls, purified RNA from brain EVs, and performed miRNA sequencing. We found that the expression of miR-212 decreased, while miR-21, miR-146, miR-7a, and miR-7b were significantly increased with injury, with miR-21 showing the largest change between conditions. The expression of miR-21 in the brain was primarily localized to neurons near the lesion site. Interestingly, adjacent to these miR-21-expressing neurons were activated microglia. The concurrent increase in miR-21 in EVs with the elevation of miR-21 in neurons, suggests that miR-21 is secreted from neurons as potential EV cargo. Thus, this study reveals a new potential mechanism of cell-cell communication not previously described in TBI. PMID:27516962

  18. The Oncogenic MicroRNA miR-21 Promotes Regulated Necrosis in Mice

    PubMed Central

    Ma, Xiaodong; Conklin, Daniel J.; Li, Fenge; Dai, Zhongping; Hua, Xiang; Li, Yan; Xu-Monette, Zijun Y.; Young, Ken H.; Xiong, Wei; Wysoczynski, Marcin; Sithu, Srinivas D.; Srivastava, Sanjay; Bhatnagar, Aruni; Li, Yong

    2015-01-01

    MicroRNAs (miRNAs) regulate apoptosis, yet their role in regulated necrosis remains unknown. miR-21 is overexpressed in nearly all human cancer types and its role as an oncogene is suggested to largely depend on its anti-apoptotic action. Here we show that miR-21 is overexpressed in a murine model of acute pancreatitis, a pathologic condition involving RIP3-dependent regulated necrosis (necroptosis). Therefore, we investigate the role of miR-21 in acute pancreatitis injury and necroptosis. miR-21 deficiency protects against caerulein- or L-arginine-induced acute pancreatitis in mice. miR-21 inhibition using locked-nucleic-acid-modified oligonucleotide effectively reduces pancreatitis severity. miR-21 deletion is also protective in tumor necrosis factor-induced systemic inflammatory response syndrome. These data suggest that miRNAs are critical participants in necroptosis, and miR-21 enhances cellular necrosis by negatively regulating tumor suppressor genes associated with the death-receptor-mediated intrinsic apoptosis pathway and could be a therapeutic target for preventing pathologic necrosis. PMID:25990308

  19. Neurotrophin-3 mRNA a putative target of miR21 following status epilepticus

    PubMed Central

    Risbud, Rashmi M.; Lee, Carolyn; Porter, Brenda E.

    2014-01-01

    Status epilepticus induces a cascade of protein expression changes contributing to the subsequent development of epilepsy. By identifying the cascade of molecular changes that contribute to the development of epilepsy we hope to be able to design therapeutics for preventing epilepsy. MicroRNAs influence gene expression by altering mRNA stability and/or translation and have been implicated in the pathology of multiple diseases. MiR21 and its co-transcript miR21*, microRNAs produced from either the 5″ or 3′ ends of the same precursor RNA strand, are increased in the hippocampus following status epilepticus. We have identified a miR21 binding site, in the 3′ UTR of neurotrophin-3 that inhibits translation. Neurotrophin-3 mRNA levels decrease in the hippocampus following SE concurrent with the increase in miR21. MiR21 levels in cultured hippocampal neurons inversely correlate with neurotrophin-3 mRNA levels. Treatment of hippocampal neuronal cultures with excess K+Cl−, a depolarizing agent mimicking the episode of status epilepticus, also results in an increase in miR21 and a decrease in neurotrophin-3 mRNA. MiR21 is a candidate for regulating neurotrophin-3 signaling in the hippocampus following status epilepticus. PMID:22019057

  20. Inhibition of miR-21 in glioma cells using catalytic nucleic acids

    PubMed Central

    Belter, Agnieszka; Rolle, Katarzyna; Piwecka, Monika; Fedoruk-Wyszomirska, Agnieszka; Naskręt-Barciszewska, Mirosława Z.; Barciszewski, Jan

    2016-01-01

    Despite tremendous efforts worldwide, glioblastoma multiforme (GBM) remains a deadly disease for which no cure is available and prognosis is very bad. Recently, miR-21 has emerged as a key omnipotent player in carcinogenesis, including brain tumors. It is recognized as an indicator of glioma prognosis and a prosperous target for anti-tumor therapy. Here we show that rationally designed hammerhead ribozymes and DNAzymes can target miR-21 and/or its precursors. They decrease miR-21 level, and thus silence this oncomiR functions. We demonstrated that anti-miRNA catalytic nucleic acids show a novel terrific arsenal for specific and effective combat against diseases with elevated cellular miR-21 content, such as brain tumors. PMID:27079911

  1. MiR-21/Smad 7 signaling determines TGF-β1-induced CAF formation

    PubMed Central

    Li, Qiong; Zhang, Daoxiang; Wang, Yongbin; Sun, Pan; Hou, Xiaodan; Larner, James; Xiong, Wujun; Mi, Jun

    2013-01-01

    How TGF-β1-mediated signaling pathways are finely tuned to orchestrate the generation of carcinoma-associated fibroblasts (CAFs) is poorly understood. Here, we demonstrate that miR-21 and the signaling of its target Smad 7 determine TGF-β1-induced CAF formation. In primary cultured fibroblasts, mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3′ UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. Collectively, these findings clearly demonstrate that miR-21 and Smad7 are critical regulators of TGF-β1 signaling during the induction of CAF formation. PMID:23784029

  2. Induction of MiR-21 by Stereotactic Body Radiotherapy Contributes to the Pulmonary Fibrotic Response.

    PubMed

    Kwon, Ok-Seon; Kim, Keun-Tae; Lee, Eunioo; Kim, Myoungjae; Choi, Seo-Hyun; Li, Henghong; Fornace, Albert J; Cho, Jae-Ho; Lee, Yun-Sil; Lee, Ji-Seon; Lee, Yoon-Jin; Cha, Hyuk-Jin

    2016-01-01

    Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-β signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis. PMID:27171163

  3. Induction of MiR-21 by Stereotactic Body Radiotherapy Contributes to the Pulmonary Fibrotic Response

    PubMed Central

    Kwon, Ok-Seon; Kim, Keun-Tae; Lee, Eunioo; Kim, Myoungjae; Choi, Seo-Hyun; Li, Henghong; Fornace, Albert J.; Cho, Jae-Ho; Lee, Yun-Sil; Lee, Ji-Seon; Lee, Yoon-Jin; Cha, Hyuk-Jin

    2016-01-01

    Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-β signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis. PMID:27171163

  4. Increased Circulating miR-21 Levels Are Associated with Kidney Fibrosis

    PubMed Central

    Gnemmi, Viviane; Buob, David; Van der Hauwaert, Cynthia; Lo-Guidice, Jean-Marc; Bouyé, Sébastien; Hazzan, Marc; Pottier, Nicolas; Perrais, Michaël

    2013-01-01

    MicroRNAs (miRNAs) are a class of noncoding RNA acting at a post-transcriptional level to control the expression of large sets of target mRNAs. While there is evidence that miRNAs deregulation plays a causative role in various complex disorders, their role in fibrotic kidney diseases is largely unexplored. Here, we found a strong up-regulation of miR-21 in the kidneys of mice with unilateral ureteral obstruction and also in the kidneys of patients with severe kidney fibrosis. In addition, mouse primary fibroblasts derived from fibrotic kidneys exhibited higher miR-21 expression level compared to those derived from normal kidneys. Expression of miR-21 in normal primary kidney fibroblasts was induced upon TGFβ exposure, a key growth factor involved in fibrogenesis. Finally, ectopic expression of miR-21 in primary kidney fibroblasts was sufficient to promote myofibroblast differentiation. As circulating miRNAs have been suggested as promising non-invasive biomarkers, we further assess whether circulating miR-21 levels are associated with renal fibrosis using sera from 42 renal transplant recipients, categorized according to their renal fibrosis severity, evaluated on allograft biopsies (Interstitial Fibrosis/Tubular Atrophy (IF/TA). Circulating miR-21 levels are significantly increased in patients with severe IF/TA grade (IF/TA grade 3: 3.0±1.0 vs lower grade of fibrosis: 1.5±1.2; p = 0.001). By contrast, circulating miR-21 levels were not correlated with other renal histological lesions. In a multivariate linear regression model including IF/TA grade and estimated GFR, independent associations were found between circulating miR-21 levels and IF/TA score (ß = 0.307, p = 0.03), and between miR-21 levels and aMDRD (ß = −0.398, p = 0.006). Altogether, these data suggest miR-21 has a key pathogenic role in kidney fibrosis and may represent a novel, predictive and reliable blood marker of kidney fibrosis. PMID:23469132

  5. Sirt2 suppresses glioma cell growth through targeting NF-κB–miR-21 axis

    SciTech Connect

    Li, Ya’nan; Dai, Dongwei; Lu, Qiong; Fei, Mingyu; Li, Mengmeng; Wu, Xi

    2013-11-22

    Highlights: •Sirt2 expression is down-regulated in human glioma tissues and cell lines. •Sirt2 regresses glioma cell growth and colony formation via inducing apoptosis. •miR-21 is essential for the functions of Sirt2 in glioma cells. •Sirt2 deacetylates p65 to decrease miR-21 expression. -- Abstract: Sirtuins are NAD{sup +}-dependent deacetylases that regulate numerous cellular processes including aging, DNA repair, cell cycle, metabolism, and survival under stress conditions. The roles of sirtuin family members are widely studied in carcinogenesis. However, their roles in glioma remain unclear. Here we report that Sir2 was under expressed in human glioma tissues and cell lines. We found that Sirt2 overexpression decreased cell proliferation and colony formation capacity. In addition, Sirt2 overexpression induced cellular apoptosis via up-regulating cleaved caspase 3 and Bax, and down-regulating anti-apoptotic protein Bcl-2. Sirt2 knockdown obtained opposing results. We showed that Sirt2 overexpression inhibited miR-21 expression, and Sirt2 was not sufficient to reduce cell proliferation and colony formation as well as to induce apoptosis when miR-21 was knocked down in glioma cells. Mechanically, we demonstrated that Sirt2 deacetylated p65 at K310 and blocked p65 binding to the promoter region of miR-21, thus regressing the transcription of miR-21. In summary, Sirt2 is critical in human glioma via NF-κB–miR-21 pathway and Sirt2 activator may serve as candidate drug for glioma therapy.

  6. MiR-21 is involved in radiation-induced bystander effects

    PubMed Central

    Xu, Shuai; Ding, Nan; Pei, Hailong; Hu, Wentao; Wei, Wenjun; Zhang, Xurui; Zhou, Guangming; Wang, Jufang

    2014-01-01

    Radiation-induced bystander effects are well-established phenomena, in which DNA damage responses are induced not only in the directly irradiated cells but also in the non-irradiated bystander cells through intercellular signal transmission. Recent studies hint that bystander effects are possibly mediated via small non-coding RNAs, especially microRNAs. Thus, more details about the roles of microRNA in bystander effects are urgently needed to be elucidated. Here we demonstrated that bystander effects were induced in human fetal lung MRC-5 fibroblasts through medium-mediated way by different types of radiation. We identified a set of differentially expressed microRNAs in the cell culture medium after irradiation, among which the up-regulation of miR-21 was further verified with qRT-PCR. In addition, we found significant upregulation of miR-21 in both directly irradiated cells and bystander cells, which was confirmed by the expression of miR-21 precursor and its target genes. Transfection of miR-21 mimics into non-irradiated MRC-5 cells caused bystander-like effects. Taken together, our data reveals that miR-21 is involved in radiation-induced bystander effects. Elucidation of such a miRNA-mediated bystander effect is of utmost importance in understanding the biological processes related to ionizing radiation and cell-to-cell communication. PMID:25483031

  7. Percentile Ranking and Citation Impact of a Large Cohort of NHLBI-funded Cardiovascular R01 Grants

    PubMed Central

    Danthi, Narasimhan; Wu, Colin O.; Shi, Peibei; Lauer, Michael

    2014-01-01

    Rationale Funding decisions for cardiovascular R01 grant applications at NHLBI largely hinge on percentile rankings. It is not known whether this approach enables the highest impact science. Objective To conduct an observational analysis of percentile rankings and bibliometric outcomes for a contemporary set of funded NHLBI cardiovascular R01 grants. Methods and results We identified 1492 investigator-initiated de novo R01 grant applications that were funded between 2001 and 2008, and followed their progress for linked publications and citations to those publications. Our co-primary endpoints were citations received per million dollars of funding, citations obtained within 2-years of publication, and 2-year citations for each grant’s maximally cited paper. In 7654 grant-years of funding that generated $3004 million of total NIH awards, the portfolio yielded 16,793 publications that appeared between 2001 and 2012 (median per grant 8, 25th and 75th percentiles 4 and 14, range 0 – 123), which received 2,224,255 citations (median per grant 1048, 25th and 75th percentiles 492 and 1,932, range 0 – 16,295). We found no association between percentile ranking and citation metrics; the absence of association persisted even after accounting for calendar time, grant duration, number of grants acknowledged per paper, number of authors per paper, early investigator status, human versus non-human focus, and institutional funding. An exploratory machine-learning analysis suggested that grants with the very best percentile rankings did yield more maximally cited papers. Conclusions In a large cohort of NHLBI-funded cardiovascular R01 grants, we were unable to find a monotonic association between better percentile ranking and higher scientific impact as assessed by citation metrics. PMID:24406983

  8. MiR-21 promoted proliferation and migration in hepatocellular carcinoma through negative regulation of Navigator-3

    SciTech Connect

    Wang, Zhipeng; Yang, Huan; Ren, Lei

    2015-09-04

    MicroRNA-21 (miR-21) has been well-established and found to be over-expressed in various human cancers and has been associated with hepatocellular carcinoma (HCC) progression. However, the underlying mechanism of miR-21 involvement in the development and progression of HCC remains to be understood. In the present study, we firstly identified that the Navigator-3 (NAV-3) gene as a novel direct target of miR-21. Knock-down of NAV-3 using shRNA can rescue the effects of anti-miR-21 inhibitor in HCC cell lines, whereas re-expression of miR-21 using transfection with miR-21 mimics phenocopied the NAV-3 knock-down model. Additionally, miR-21 levels inversely correlated with NAV-3 both in HCC cells and tissues. Knock-down of NAV-3 promoted both the proliferation and migration in HCC cells. Together, our findings suggest an important role for miR-21 in the progression of HCC, which negatively regulated Navigator-3 in the migration of HCC. - Highlights: • Navigator-3 (NAV-3) suppresses proliferation, migration and tumorigenesis of HCC cells. • NAV-3 was a novel target of miR-21. • MiR-21 negatively regulates NAV-3 in HCC.

  9. miR-21 modulates resistance of HR-HPV positive cervical cancer cells to radiation through targeting LATS1

    SciTech Connect

    Liu, Shikai; Song, Lili Zhang, Liang; Zeng, Saitian; Gao, Fangyuan

    2015-04-17

    Although multiple miRNAs are found involved in radioresistance development in HR-HPV positive (+) cervical cancer, only limited studies explored the regulative mechanism of the miRNAs. miR-21 is one of the miRNAs significantly upregulated in HR-HPV (+) cervical cancer is also significantly associated with radioresistance. However, the detailed regulative network of miR-21 in radioresistance is still not clear. In this study, we confirmed that miR-21 overexpression was associated with higher level of radioresistance in HR-HPV (+) cervical cancer patients and thus decided to further explore its role. Findings of this study found miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells and decrease radiation induced G2/M block and increase S phase accumulation. By using dual luciferase assay, we verified a binding site between miR-21 and 3′-UTR of large tumor suppressor kinase 1 (LATS1). Through direct binding, miR-21 can regulate LATS1 expression in cervical cancer cells. LATS1 overexpression can reverse miR-21 induced higher colony formation rate and also reduced miR-21 induced S phase accumulation and G2/M phase block reduction under radiation treatment. These results suggested that miR-21-LATS1 axis plays an important role in regulating radiosensitivity. - Highlights: • miR-21 is highly expressed in HR-HPV (+) radioresistant cervical cancer patients. • miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells. • miR-21 can decrease radiation induced G2/M block and increase S phase accumulation. • miR-21 modulates radiosensitivity cervical cancer cell by directly targeting LATS1.

  10. The Type I IFN-Induced miRNA, miR-21

    PubMed Central

    Yang, Chuan He; Li, Kui; Pfeffer, Susan R.; Pfeffer, Lawrence M.

    2015-01-01

    The interferon (IFN) family of cytokines not only has antiviral properties at various steps in the viral replication cycle, but also anticancer activity through multiple pathways that include inhibiting cell proliferation, regulating cellular responses to inducers of apoptosis and modulating angiogenesis and the immune system. IFNs are known to induce their biological activity through the induction of protein encoding IFN-stimulated genes. However, recent studies have established that IFNs also induce the expression of microRNAs (miRNAs), which are small endogenous non-coding RNAs that suppress gene expression at the post-transcriptional level. MiRNAs play critical roles in tumorigenesis and have been implicated to act as either oncogenes or tumor suppressors in various human cancers. Therefore, IFN-induced miRNAs play an important role, not only in the host response to innate immune response to cancer, but also in the tumorigenic process itself. Furthermore, IFN-induced miRNAs may participate in and/or orchestrate antiviral defense in certain viral infections. In this review, we describe our recent studies on the induction of miR-21 by type I IFN, the role of the STAT3 and NFκB signaling pathways in IFN-induced miR-21 expression, the role of miR-21 in different cancers and the role of miR-21 in regulating the antiviral response. PMID:26610525

  11. Cardamonin Regulates miR-21 Expression and Suppresses Angiogenesis Induced by Vascular Endothelial Growth Factor

    PubMed Central

    Jiang, Fu-Sheng; Tian, Sha-Sha; Lu, Jin-Jian; Ding, Xing-Hong; Qian, Chao-Dong; Ding, Bin; Ding, Zhi-Shan; Jin, Bo

    2015-01-01

    Cardamonin has promising potential in cancer prevention and therapy by interacting with proteins and modifying the expressions and activities, including factors of cell survival, proliferation, and angiogenesis. In our precious study, we have demonstrated that cardamonin suppressed vascular endothelial growth factor- (VEGF-) induced angiogenesis as evaluated in the mouse aortic ring assay. It is also known that microRNAs (miRNAs) play important roles in angiogenesis. Herein, we hypothesized whether antiangiogenesis effect of cardamonin in human umbilical vein endothelial cells (HUVECs) triggered by VEGF was associated with miRNAs. We found that cardamonin reduced the miR-21 expression induced by VEGF in HUVECs. Treatment with miR-21 mimics abolished the effects of cardamonin on VEGF-induced cell proliferation, migration, and angiogenesis in HUVECs. However, treatment with miR-21 inhibitors presented the opposite effects, indicating the vital role of miR-21 in this process. Our study provides a new insight of the preliminary mechanism of anti-VEGF-induced angiogenesis by cardamonin in HUVECs. PMID:26266258

  12. ERβ regulates miR-21 expression and inhibits invasion and metastasis in cancer cells

    NASA Astrophysics Data System (ADS)

    Tian, Junmei; Tu, Zhenzhen; Chen, Wei R.; Gu, Yueqing

    2012-03-01

    In human, estrogens play important roles in many physiological processes, and is also found to be connected with numerous cancers. In these diseases, estrogen mediates its effects through the estrogen receptor (ER), which serves as the basis for many current clinical diagnosis. Two forms of the estrogen receptor have been identified, ERα and ERβ, and show different and specific functions. The two estrogen receptors belong to a family of ligand-regulated transcription factors. Estrogen via ERα stimulates proliferation in the breast, uterus, and developing prostate, while estrogen via ERβ inhibits proliferation and promotes differentiation in the prostate, mammary gland, colon, lung, and bone marrow stem cells. MicroRNAs (miRs) are small non-coding RNA molecules that occur naturally and downregulate protein expression by translational blockade of the target mRNA or by promoting mRNA decay. MiR-21 is one of the most studied miRNAs in cancers. MiR-21 is overexpressed in the most solid tumors, promoting progression and metastasis. The miR-21 gene is located on the chromosome 17, in the 10th intron of a protein-coding gene, TMEM49. While, the function of TMEM49 is currently unknown. Our experiment is designed to identity the relationship between miR-21 and ERβ in cancer progression. The human cancer cells were transfected with ERβ. Real-time PCR analysis showed that the expression level of miR-21 was significantly inhibited down by ERβ treatment. As MTT assay showed the tumor cell survival rate was also inhibited significantly. Go/Gl phase cell cycle arrest was founded and tumor cell apoptosis was induced in ERβ group.

  13. The function of MiR-21 expression differences and pathogenesis on familial and triple negative breast Cancer serum.

    PubMed

    Song, Ningning; Liang, Bing; Wang, Dandan

    2016-03-01

    This paper is to detect the expression differences of serum miR-21 in breast cancer, in order to further clarify the function of miR-21 in familial and TNBC pathogenesis of breast cancer. The serum had been collected for healthy check-up females, women with high risk of breast cancer and different types of breast cancer patients. Nematodes were taken as the external reference, real-time fluorescent quantitative PCR detection were taken for expression level of miR-21 in 77 cases of serum. The miR-21 expression level of familial breast cancer group, TNBC group and breast cancer high risk group were significantly higher than that in normal control group and other breast cancer group, P<0.01. Serum miR-21 expression level was associated with lymph node metastasis and Ki67 high expression, P<0.01. Results had proved that serum miR-21 expression quantity increased in familial breast cancer and TNBC and was correlated with lymph node metastasis and Ki67 expression. Serum miR-21 was closed related with TNBC and familial breast cancer. The relative expression quantity of miR-21 in breast cancer serum had no obvious relation with unilateral or bilateral tumor and menstrual situation. Its increased expression might be correlated to the breast cancer hereditary, malignant degree and prognosis judgement and its mechanism required further research. PMID:27113307

  14. Considering Exosomal miR-21 as a Biomarker for Cancer.

    PubMed

    Shi, Jian

    2016-01-01

    Cancer is a fatal human disease. Early diagnosis of cancer is the most effective method to prevent cancer development and to achieve higher survival rates for patients. Many traditional diagnostic methods for cancer are still not sufficient for early, more convenient and accurate, and noninvasive diagnosis. Recently, the use of microRNAs (miRNAs), such as exosomal microRNA-21(miR-21), as potential biomarkers was widely reported. This initial systematic review analyzes the potential role of exosomal miR-21 as a general biomarker for cancers. A total of 10 studies involving 318 patients and 215 healthy controls have covered 10 types of cancers. The sensitivity and specificity of pooled studies were 75% (0.70-0.80) and 85% (0.81-0.91), with their 95% confidence intervals (CIs), while the area under the summary receiver operating characteristic curve (AUC) was 0.93. Additionally, we examined and evaluated almost all other issues about biomarkers, including cutoff points, internal controls and detection methods, from the literature. This initial meta-analysis indicates that exosomal miR-21 has a strong potential to be used as a universal biomarker to identify cancers, although as a general biomarker the case number for each cancer type is small. Based on the literature, a combination of miRNA panels and other cancer antigens, as well as a selection of appropriate internal controls, has the potential to serve as a more sensitive and accurate cancer diagnosis tool. Additional information on miR-21 would further support its use as a biomarker in cancer. PMID:27043643

  15. Considering Exosomal miR-21 as a Biomarker for Cancer

    PubMed Central

    Shi, Jian

    2016-01-01

    Cancer is a fatal human disease. Early diagnosis of cancer is the most effective method to prevent cancer development and to achieve higher survival rates for patients. Many traditional diagnostic methods for cancer are still not sufficient for early, more convenient and accurate, and noninvasive diagnosis. Recently, the use of microRNAs (miRNAs), such as exosomal microRNA-21(miR-21), as potential biomarkers was widely reported. This initial systematic review analyzes the potential role of exosomal miR-21 as a general biomarker for cancers. A total of 10 studies involving 318 patients and 215 healthy controls have covered 10 types of cancers. The sensitivity and specificity of pooled studies were 75% (0.70–0.80) and 85% (0.81–0.91), with their 95% confidence intervals (CIs), while the area under the summary receiver operating characteristic curve (AUC) was 0.93. Additionally, we examined and evaluated almost all other issues about biomarkers, including cutoff points, internal controls and detection methods, from the literature. This initial meta-analysis indicates that exosomal miR-21 has a strong potential to be used as a universal biomarker to identify cancers, although as a general biomarker the case number for each cancer type is small. Based on the literature, a combination of miRNA panels and other cancer antigens, as well as a selection of appropriate internal controls, has the potential to serve as a more sensitive and accurate cancer diagnosis tool. Additional information on miR-21 would further support its use as a biomarker in cancer. PMID:27043643

  16. TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation

    PubMed Central

    Sobczak, Mateusz; Jozkowicz, Alicja; Dulak, Jozef

    2016-01-01

    Renal fibrosis, irrespective of its etiology, is a final common stage of almost all chronic kidney diseases. Increased apoptosis, epithelial-to-mesenchymal transition, and inflammatory cell infiltration characterize the injured kidney. On the molecular level, transforming growth factor-β1 (TGF-β1)-Smad3 signaling pathway plays a central role in fibrotic kidney disease. Recent findings indicate the prominent role of microRNAs, small noncoding RNA molecules that inhibit gene expression through the posttranscriptional repression of their target mRNAs, in different pathologic conditions, including renal pathophysiology. miR-21 was also shown to play a dynamic role in inflammatory responses and in accelerating injury responses to promote organ failure and fibrosis. Understanding the cellular and molecular bases of miR-21 involvement in the pathogenesis of kidney diseases, including inflammatory reaction, could be crucial for their early diagnosis. Moreover, the possibility of influencing miR-21 level by specific antagomirs may be considered as an approach for treatment of renal diseases. PMID:27610006

  17. TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation.

    PubMed

    Loboda, Agnieszka; Sobczak, Mateusz; Jozkowicz, Alicja; Dulak, Jozef

    2016-01-01

    Renal fibrosis, irrespective of its etiology, is a final common stage of almost all chronic kidney diseases. Increased apoptosis, epithelial-to-mesenchymal transition, and inflammatory cell infiltration characterize the injured kidney. On the molecular level, transforming growth factor-β1 (TGF-β1)-Smad3 signaling pathway plays a central role in fibrotic kidney disease. Recent findings indicate the prominent role of microRNAs, small noncoding RNA molecules that inhibit gene expression through the posttranscriptional repression of their target mRNAs, in different pathologic conditions, including renal pathophysiology. miR-21 was also shown to play a dynamic role in inflammatory responses and in accelerating injury responses to promote organ failure and fibrosis. Understanding the cellular and molecular bases of miR-21 involvement in the pathogenesis of kidney diseases, including inflammatory reaction, could be crucial for their early diagnosis. Moreover, the possibility of influencing miR-21 level by specific antagomirs may be considered as an approach for treatment of renal diseases. PMID:27610006

  18. EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours

    PubMed Central

    Bornachea, Olga; Santos, Mirentxu; Martínez-Cruz, Ana Belén; García-Escudero, Ramón; Dueñas, Marta; Costa, Clotilde; Segrelles, Carmen; Lorz, Corina; Buitrago, Agueda; Saiz-Ladera, Cristina; Agirre, Xabier; Grande, Teresa; Paradela, Beatriz; Maraver, Antonio; Ariza, José M.; Prosper, Felipe; Serrano, Manuel; Sánchez-Céspedes, Montse; Paramio, Jesús M.

    2012-01-01

    Missense mutations in TP53 gene promote metastasis in human tumours. However, little is known about the complete loss of function of p53 in tumour metastasis. Here we show that squamous cell carcinomas generated by the specific ablation of Trp53 gene in mouse epidermis are highly metastatic. Biochemical and genome-wide mRNA and miRNA analyses demonstrated that metastases are associated with the early induction of epithelial-mesenchymal transition (EMT) and deregulated miRNA expression in primary tumours. Increased expression of miR-21 was observed in undifferentiated, prometastatic mouse tumours and in human tumours characterized by p53 mutations and distant metastasis. The augmented expression of miR-21, mediated by active mTOR and Stat3 signalling, conferred increased invasive properties to mouse keratinocytes in vitro and in vivo, whereas blockade of miR-21 in a metastatic spindle cell line inhibits metastasis development. Collectively these data identify novel molecular mechanisms leading to metastasis in vivo originated by p53 loss in epithelia. PMID:22666537

  19. Targeted inhibition of oncogenic miR-21 maturation with designed RNA-binding proteins.

    PubMed

    Chen, Yu; Yang, Fan; Zubovic, Lorena; Pavelitz, Tom; Yang, Wen; Godin, Katherine; Walker, Matthew; Zheng, Suxin; Macchi, Paolo; Varani, Gabriele

    2016-09-01

    The RNA recognition motif (RRM) is the largest family of eukaryotic RNA-binding proteins. Engineered RRMs with well-defined specificity would provide valuable tools and an exacting test of the current understanding of specificity. We have redesigned the specificity of an RRM using rational methods and demonstrated retargeting of its activity in cells. We engineered the conserved RRM of human Rbfox proteins to specifically bind to the terminal loop of a microRNA precursor (pre-miR-21) with high affinity and inhibit its processing by Drosha and Dicer. We further engineered Giardia Dicer by replacing its PAZ domain with the designed RRM. The reprogrammed enzyme degrades pre-miR-21 specifically in vitro and suppresses mature miR-21 levels in cells, which results in increased expression of the tumor suppressor PDCD4 and significantly decreased viability for cancer cells. The results demonstrate the feasibility of rationally engineering the sequence-specificity of RRMs and of using this ubiquitous platform for diverse biological applications. PMID:27428511

  20. MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease

    PubMed Central

    Yelamanchili, Sowmya V.; Lamberty, Benjamin G.; Rennard, Deborah A.; Morsey, Brenda M.; Hochfelder, Colleen G.; Meays, Brittney M.; Levy, Efrat; Fox, Howard S.

    2015-01-01

    Recent studies have found that extracellular vesicles (EVs) play an important role in normal and disease processes. In the present study, we isolated and characterized EVs from the brains of rhesus macaques, both with and without simian immunodeficiency virus (SIV) induced central nervous system (CNS) disease. Small RNA sequencing revealed increased miR-21 levels in EVs from SIV encephalitic (SIVE) brains. In situ hybridization revealed increased miR-21 expression in neurons and macrophage/microglial cells/nodules during SIV induced CNS disease. In vitro culture of macrophages revealed that miR-21 is released into EVs and is neurotoxic when compared to EVs derived from miR-21-/- knockout animals. A mutation of the sequence within miR-21, predicted to bind TLR7, eliminates this neurotoxicity. Indeed miR-21 in EV activates TLR7 in a reporter cell line, and the neurotoxicity is dependent upon TLR7, as neurons isolated from TLR7-/- knockout mice are protected from neurotoxicity. Further, we show that EVs isolated from the brains of monkeys with SIV induced CNS disease activates TLR7 and were neurotoxic when compared to EVs from control animals. Finally, we show that EV-miR-21 induced neurotoxicity was unaffected by apoptosis inhibition but could be prevented by a necroptosis inhibitor, necrostatin-1, highlighting the actions of this pathway in a growing number of CNS disorders. PMID:26154133

  1. High mobility group box-1 promotes hepatocellular carcinoma progression through miR-21-mediated matrix metalloproteinase activity

    PubMed Central

    Chen, Man; Liu, Yao; Varley, Patrick; Chang, Ying; He, Xing-xing; Huang, Hai; Tang, Daolin; Lotze, Michael T.; Lin, Jusheng; Tsung, Allan

    2015-01-01

    Liver inflammation plays a critical role in hepatocellular carcinoma (HCC) etiology. Damage associated molecular patterns (DAMPs), such as high mobility group box-1 (HMGB1), and dysregulated microRNAs (miRNAs) involved in inflammatory disease states, such as miR-21, may participate in the link between inflammation and cancer. We sought to determine the role of HMGB1 signaling in HCC tumor progression. We first document the concordant expression increase of HMGB1 and miR-21 in HCC cell lines and primary HCC tumor samples and subsequently show that HMGB1 stimulation results in over-expression of miR-21. These changes were found to be dependent on the IL-6/Stat3 signaling axis. Invasion and migration of HCC cells in vitro was inhibited by both Stat3 and miR-21 antagonists, suggesting a role for this pathway in HCC tumor progression. We verified that HMGB1-induced expression of miR-21 in HCC provides a post-transcriptional repression of the matrix metalloproteinase (MMP) inhibitors RECK and TIMP3, which are known to impact HCC progression and metastases. Finally, we found that inhibition of miR-21 in murine HMGB1-overexpressing HCC xenografts led to reduced tumor MMP activity through released repression of the miR-21 targets RECK and TIMP3, which ultimately impeded tumor progression. The prototypical DAMP, HMGB1, is released during liver inflammation and provides a favorable environment for HCC growth. HMGB1 signaling increases miR-21 expression to mediate the enhanced activity of MMPs through RECK and TIMP3. These findings provide a novel mechanism for HMGB1-mediated HCC progression through the IL-6/Stat3-miR-21 axis. PMID:25720799

  2. PSMB4 promotes multiple myeloma cell growth by activating NF-κB-miR-21 signaling

    SciTech Connect

    Zheng, Peihao; Guo, Honggang; Li, Guangchao; Han, Siqi; Luo, Fei; Liu, Yi

    2015-03-06

    Proteasomal subunit PSMB4, was recently identified as potential cancer driver genes in several tumors. However, the regulatory mechanism of PSMB4 on carcinogenesis process remains unclear. In this study, we investigated the expression and roles of PSMB4 in multiple myeloma (MM). We found a significant up-regulation of PSMB4 in MM plasma and cell lines. Ectopic overexpression of PSMB4 promoted cell growth and colony forming ability of MM cells, whereas inhibition of PSMB4 led to a decrease of such events. Furthermore, our results demonstrated the up-regulation of miR-21 and a positive correlation between the levels of miR-21 and PSMB4 in MM. Re-expression of miR-21 markedly rescued PSMB4 knockdown-mediated suppression of cell proliferation and clone-formation. Additionally, while enforced expression of PSMB4 profoundly increased NF-κB activity and the level of miR-21, PSMB4 knockdown or NF-κB inhibition suppressed miR-21 expression in MM cells. Taken together, our results demonstrated that PSMB4 regulated MM cell growth in part by activating NF-κB-miR-21 signaling, which may represent promising targets for novel specific therapies. - Highlights: • First reported upregulation of PSMB4 in MM plasma and cell lines. • PSMB4 promoted MM cell growth and colony forming ability. • Further found miR-21 was up-regulated by PSMB4 in MM plasma and cell lines. • PSMB4-induced miR-21 expression was modulated by NF-κB. • PSMB4-NF-κB-miR-21 axis may be potential therapeutic targets of MM.

  3. The role of miR-21 in proliferation and invasion capacity of human tongue squamous cell carcinoma in vitro

    PubMed Central

    Wang, Yin; Zhu, Yu; Lv, Pin; Li, Longjiang

    2015-01-01

    Tongue squamous cell carcinoma is one of the most common cancers, which has the highest incidence in oral maxillofacial malignant tumors. MiR-21 may promote tumorigeness by down-regulating tumor suppressing genes and/or controlling the genes for cell differentiation and apoptosis, and it has been identified as the most expressive and unusual in a number of profiling experiments. The study shows there are high expressions of miR-21 in tongue squamous cell carcinoma cell lines (Tca8113 and its high metastatic lines), especially in high metastatic lines. miR-21 silencing could suppress the capacity of proliferation, migration and invasion, arrest the cell cycle and induce apoptosis of tongue squamous cell carcinoma cell lines (Tca8113 and its high metastatic lines). All the results indicate that miR-21 will probably open a new path to the gene therapy for oral squamous cell carcinoma. PMID:26191145

  4. miR-21-mediated decreased neutrophil apoptosis is a determinant of impaired coronary collateral growth in metabolic syndrome.

    PubMed

    Hutcheson, Rebecca; Terry, Russell; Hutcheson, Brenda; Jadhav, Rashmi; Chaplin, Jennifer; Smith, Erika; Barrington, Robert; Proctor, Spencer D; Rocic, Petra

    2015-06-01

    Coronary collateral growth (CCG) is impaired in metabolic syndrome. microRNA-21 (miR-21) is a proproliferative and antiapoptotic miR, which we showed to be elevated in metabolic syndrome. Here we investigate whether impaired CCG in metabolic syndrome involved miR-21-mediated aberrant apoptosis. Normal Sprague-Dawley (SD) and metabolic syndrome [J. C. Russel (JCR)] rats underwent transient, repetitive coronary artery occlusion [repetitive ischemia (RI)]. Antiapoptotic Bcl-2, phospho-Bad, and Bcl-2/Bax dimers were increased on days 6 and 9 RI, and proapoptotic Bax and Bax/Bax dimers and cytochrome-c release concurrently decreased in JCR versus SD rats. Active caspases were decreased in JCR versus SD rats (~50%). Neutrophils increased transiently on day 3 RI in the collateral-dependent zone of SD rats but remained elevated in JCR rats, paralleling miR-21 expression. miR-21 downregulation by anti-miR-21 induced neutrophil apoptosis and decreased Bcl-2 and Bcl-2/Bax dimers (~75%) while increasing Bax/Bax dimers, cytochrome-c release, and caspase activation (~70, 400, and 400%). Anti-miR-21 also improved CCG in JCR rats (~60%). Preventing neutrophil infiltration with blocking antibodies resulted in equivalent CCG recovery, confirming a major role for deregulated neutrophil apoptosis in CCG impairment. Neutrophil and miR-21-dependent CCG inhibition was in significant part mediated by increased oxidative stress. We conclude that neutrophil apoptosis is integral to normal CCG and that inappropriate prolonged miR-21-mediated survival of neutrophils plays a major role in impaired CCG, in part via oxidative stress generation. PMID:25840830

  5. miR-21 modulates tumor outgrowth induced by human adipose tissue-derived mesenchymal stem cells in vivo

    SciTech Connect

    Shin, Keun Koo; Lee, Ae Lim; Kim, Jee Young; Lee, Sun Young; Bae, Yong Chan; Jung, Jin Sup

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer miR-21 modulates hADSC-induced increase of tumor growth. Black-Right-Pointing-Pointer The action is mostly mediated by the modulation of TGF-{beta} signaling. Black-Right-Pointing-Pointer Inhibition of miR-21 enhances the blood flow recovery in hindlimb ischemia. -- Abstract: Mesenchymal stem cells (MSCs) have generated a great deal of interest in clinical situations, due principally to their potential use in regenerative medicine and tissue engineering applications. However, the therapeutic application of MSCs remains limited, unless the favorable effects of MSCs on tumor growth in vivo, and the long-term safety of the clinical applications of MSCs, can be more thoroughly understood. In this study, we determined whether microRNAs can modulate MSC-induced tumor outgrowth in BALB/c nude mice. Overexpression of miR-21 in human adipose-derived stem cells (hADSCs) inhibited hADSC-induced tumor growth, and inhibition of miR-21 increased it. Downregulation of transforming growth factor beta receptor II (TGFBR2), but not of signal transducer and activator of transcription 3, in hADSCs showed effects similar to those of miR-21 overexpression. Downregulation of TGFBR2 and overexpression of miR21 decreased tumor vascularity. Inhibition of miR-21 and the addition of TGF-{beta} increased the levels of vascular endothelial growth factor and interleukin-6 in hADSCs. Transplantation of miR-21 inhibitor-transfected hADSCs increased blood flow recovery in a hind limb ischemia model of nude mice, compared with transplantation of control oligo-transfected cells. These findings indicate that MSCs might favor tumor growth in vivo. Thus, it is necessary to study the long-term safety of this technique before MSCs can be used as therapeutic tools in regenerative medicine and tissue engineering.

  6. NFkappaB activation is essential for miR-21 induction by TGFβ1 in high glucose conditions

    SciTech Connect

    Madhyastha, Radha Madhyastha, HarishKumar; Pengjam, Yutthana; Nakajima, Yuichi; Omura, Sayuri; Maruyama, Masugi

    2014-09-05

    Highlights: • Transforming growth factor beta 1 (TGFβ1) induces miR-21 in high glucose conditions. • NFkappaB activation and subsequent ROS generation are necessary for TGFβ1’s effect. • TGFβ1 facilitates binding of NFkB p65 to miR-21 promoter. • SMAD proteins bind to R-SBE sites on primary miR-21, in NFkB dependent manner. - Abstract: Transforming growth factor beta1 (TGFβ1) is a pleiotropic growth factor with a very broad spectrum of effects on wound healing. Chronic non-healing wounds such as diabetic foot ulcers express reduced levels of TGFβ1. On the other hand, our previous studies have shown that the microRNA miR-21 is differentially regulated in diabetic wounds and that it promotes migration of fibroblast cells. Although interplay between TGFβ1 and miR-21 are studied in relation to cancer, their interaction in the context of chronic wounds has not yet been investigated. In this study, we examined if TGFβ1 could stimulate miR-21 in fibroblasts that are subjected to high glucose environment. MiR-21 was, in fact, induced by TGFβ1 in high glucose conditions. The induction by TGFβ1 was dependent on NFκB activation and subsequent ROS generation. TGFβ1 was instrumental in degrading the NFκB inhibitor IκBα and facilitating the nuclear translocation of NFκB p65 subunit. EMSA studies showed enhanced DNA binding activity of NFκB in the presence of TGFβ1. ChIP assay revealed binding of p65 to miR-21 promoter. NFκB activation was also required for the nuclear translocation of Smad 4 protein and subsequent direct interaction of Smad proteins with primary miR-21 as revealed by RNA-IP studies. Our results show that manipulation of TGFβ1–NFκB–miR-21 pathway could serve as an innovative approach towards therapeutics to heal diabetic ulcers.

  7. Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4.

    PubMed

    Xiao, J; Pan, Y; Li, X H; Yang, X Y; Feng, Y L; Tan, H H; Jiang, L; Feng, J; Yu, X Y

    2016-01-01

    Cardiac progenitor cells derived from adult heart have emerged as one of the most promising stem cell types for cardiac protection and repair. Exosomes are known to mediate cell-cell communication by transporting cell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we investigated the cardiac progenitor cell (CPC)-derived exosomal miRNAs on protecting myocardium under oxidative stress. Sca1(+)CPCs-derived exosomes were purified from conditional medium, and identified by nanoparticle trafficking analysis (NTA), transmission electron microscopy and western blotting using CD63, CD9 and Alix as markers. Exosomes production was measured by NTA, the result showed that oxidative stress-induced CPCs secrete more exosomes compared with normal condition. Although six apoptosis-related miRNAs could be detected in two different treatment-derived exosomes, only miR-21 was significantly upregulated in oxidative stress-induced exosomes compared with normal exosomes. The same oxidative stress could cause low miR-21 and high cleaved caspase-3 expression in H9C2 cardiac cells. But the cleaved caspase-3 was significantly decreased when miR-21 was overexpressed by transfecting miR-21 mimic. Furthermore, miR-21 mimic or inhibitor transfection and luciferase activity assay confirmed that programmed cell death 4 (PDCD4) was a target gene of miR-21, and miR-21/PDCD4 axis has an important role in anti-apoptotic effect of H9C2 cell. Western blotting and Annexin V/PI results demonstrated that exosomes pre-treated H9C2 exhibited increased miR-21 whereas decreased PDCD4, and had more resistant potential to the apoptosis induced by the oxidative stress, compared with non-treated cells. These findings revealed that CPC-derived exosomal miR-21 had an inhibiting role in the apoptosis pathway through downregulating PDCD4. Restored miR-21/PDCD4 pathway using CPC-derived exosomes could protect myocardial cells against oxidative stress-related apoptosis. Therefore

  8. Targeting miR-21 enhances the sensitivity of human colon cancer HT-29 cells to chemoradiotherapy in vitro

    SciTech Connect

    Deng, Jun; Lei, Wan; Fu, Jian-Chun; Zhang, Ling; Li, Jun-He; Xiong, Jian-Ping

    2014-01-17

    Highlight: •MiR-21 plays a significant role in 5-FU resistance. •This role might be attributed to targeting of hMSH2 as well as TP and DPD via miR-21 targeted hMSH2. •Indirectly targeted TP and DPD to influence 5-FU chemotherapy sensitivity. -- Abstract: 5-Fluorouracil (5-FU) is a classic chemotherapeutic drug that has been widely used for colorectal cancer treatment, but colorectal cancer cells are often resistant to primary or acquired 5-FU therapy. Several studies have shown that miR-21 is significantly elevated in colorectal cancer. This suggests that this miRNA might play a role in this resistance. In this study, we investigated this possibility and the possible mechanism underlying this role. We showed that forced expression of miR-21 significantly inhibited apoptosis, enhanced cell proliferation, invasion, and colony formation ability, promoted G1/S cell cycle transition and increased the resistance of tumor cells to 5-FU and X radiation in HT-29 colon cancer cells. Furthermore, knockdown of miR-21 reversed these effects on HT-29 cells and increased the sensitivity of HT-29/5-FU to 5-FU chemotherapy. Finally, we showed that miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells.

  9. 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

  10. IL-6 Inhibits the Targeted Modulation of PDCD4 by miR-21 in Prostate Cancer.

    PubMed

    Dong, Biao; Shi, Zhihao; Wang, Jiaping; Wu, Jing; Yang, Zhaoqing; Fang, Kewei

    2015-01-01

    Prostate cancer is the most common cancer among men in the Unites States. The cytokine IL-6 activates several prostate cancer pathways, but its upstream trans-signaling pathway remains poorly understood. In this study, we evaluated the role of IL-6 in PDCD4 gene expression and how the microRNA miR-21 regulates this process in prostate cancer cell lines PC-3 and LNCaP. The expression pattern of PDCD4 from samples from human prostate cancer, precancerous lesions, and benign prostatic hyperplasia was investigated by immunohistochemistry. PDCD4 transcription and translation were detected by quantitative real-time PCR (qRT-PCR) and Western blot analysis, respectively. The targeted modulation of PDCD4 by miR-21 was analyzed in PC-3 and LNCaP cells, and the effect of IL-6 on the expression of PDCD4 was studied in vitro. PDCD4 expression in samples from the 3 tissue types progressively increased, and the expression levels of PDCD4 and prostate-specific antigen were negatively correlated. The levels of PDCD4 mRNA and protein in PC-3 and LNCaP cells transfected with anti-miR-21 constructs were lower than those in control cells. The expression of PDCD4 was inhibited by IL-6, but this effect was weakened in cell lines with low expression of miR-21. Our study demonstrates that the regulation of PDCD4 by miR-21 is targeted and IL-6 inhibits expression of the PDCD4 gene in PC-3 and LNCaP cells through the targeted function of miR-21 on PDCD4. These findings support the feasibility of future efforts for diagnosis and gene therapy for prostate cancer that are based on IL-6, miR-21, and PDCD4. PMID:26252635

  11. [Secondary metabolites from a deep-sea-derived actinomycete Micrococcus sp. R21].

    PubMed

    Peng, Kun; Su, Rui-qiang; Zhang, Gai-yun; Cheng, Xuan-xuan; Yang, Quan; Liu, Yong-hong; Yang, Xian-wen

    2015-06-01

    To investigate cytotoxic secondary metabolites of Micrococcus sp. R21, an actinomycete isolated from a deep-sea sediment (-6 310 m; 142 degrees 19. 9' E, 10 degrees 54. 6' N) of the Western Pacific Ocean, column chromatography was introduced over silica gel, ODS, and Sephadex LH-20. As a result, eight compounds were obtained. By mainly detailed analysis of the NMR data, their structures were elucidated as cyclo(4-hydroxy-L-Pro-L-leu) (1), cyclo(L-Pro-L-Gly) (2), cyclo( L-Pro-L-Ala) (3), cyclo( D-Pro-L-Leu) (4), N-β-acetyltryptamine (5), 2-hydroxybenzoic acid (6), and phenylacetic acid (7). Compound 1 exhibited weak cytotoxic activity against RAW264. 7 cells with IC50 value of 9.1 μmol x L(-1). PMID:26591527

  12. Boiling heat transfer of refrigerant R-21 in upward flow in plate-fin heat exchanger

    NASA Astrophysics Data System (ADS)

    Kuznetsov, V. V.; Shamirzaev, A. S.

    2015-11-01

    The article presents the results of experimental investigation of boiling heat transfer of refrigerant R-21 in upward flow in a vertical plate-fin heat exchanger with transverse size of the channels that is smaller than the capillary constant. The heat transfer coefficients obtained in ranges of small mass velocities and low heat fluxes, which are typical of the industry, have been poorly studied yet. The characteristic patterns of the upward liquid-vapor flow in the heat exchanger channels and the regions of their existence are detected. The obtained data show a weak dependence of heat transfer coefficient on equilibrium vapor quality, mass flow rate, and heat flux density and do not correspond to calculations by the known heat transfer models. A possible reason for this behavior is a decisive influence of evaporation of thin liquid films on the heat transfer at low heat flux.

  13. Inhibition of miR-21 restores RANKL/OPG ratio in multiple myeloma-derived bone marrow stromal cells and impairs the resorbing activity of mature osteoclasts.

    PubMed

    Pitari, Maria Rita; Rossi, Marco; Amodio, Nicola; Botta, Cirino; Morelli, Eugenio; Federico, Cinzia; Gullà, Annamaria; Caracciolo, Daniele; Di Martino, Maria Teresa; Arbitrio, Mariamena; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2015-09-29

    miR-21 is an oncogenic microRNA (miRNA) with an emerging role as therapeutic target in human malignancies, including multiple myeloma (MM). Here we investigated whether miR-21 is involved in MM-related bone disease (BD). We found that miR-21 expression is dramatically enhanced, while osteoprotegerin (OPG) is strongly reduced, in bone marrow stromal cells (BMSCs) adherent to MM cells. On this basis, we validated the 3'UTR of OPG mRNA as miR-21 target. Constitutive miR-21 inhibition in lentiviral-transduced BMSCs adherent to MM cells restored OPG expression and secretion. Interestingly, miR-21 inhibition reduced RANKL production by BMSCs. Overexpression of protein inhibitor of activated STAT3 (PIAS3), which is a direct and validated target of miR-21, antagonized STAT3-mediated RANKL gene activation. Finally, we demonstrate that constitutive expression of miR-21 inhibitors in BMSCs restores RANKL/OPG balance and dramatically impairs the resorbing activity of mature osteoclasts. Taken together, our data provide proof-of-concept that miR-21 overexpression within MM-microenviroment plays a crucial role in bone resorption/apposition balance, supporting the design of innovative miR-21 inhibition-based strategies for MM-related BD. PMID:26160841

  14. Inhibition of miR-21 restores RANKL/OPG ratio in multiple myeloma-derived bone marrow stromal cells and impairs the resorbing activity of mature osteoclasts

    PubMed Central

    Pitari, Maria Rita; Rossi, Marco; Amodio, Nicola; Botta, Cirino; Morelli, Eugenio; Federico, Cinzia; Gullà, Annamaria; Caracciolo, Daniele; Di Martino, Maria Teresa; Arbitrio, Mariamena; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2015-01-01

    miR-21 is an oncogenic microRNA (miRNA) with an emerging role as therapeutic target in human malignancies, including multiple myeloma (MM). Here we investigated whether miR-21 is involved in MM-related bone disease (BD). We found that miR-21 expression is dramatically enhanced, while osteoprotegerin (OPG) is strongly reduced, in bone marrow stromal cells (BMSCs) adherent to MM cells. On this basis, we validated the 3′UTR of OPG mRNA as miR-21 target. Constitutive miR-21 inhibition in lentiviral-transduced BMSCs adherent to MM cells restored OPG expression and secretion. Interestingly, miR-21 inhibition reduced RANKL production by BMSCs. Overexpression of protein inhibitor of activated STAT3 (PIAS3), which is a direct and validated target of miR-21, antagonized STAT3-mediated RANKL gene activation. Finally, we demonstrate that constitutive expression of miR-21 inhibitors in BMSCs restores RANKL/OPG balance and dramatically impairs the resorbing activity of mature osteoclasts. Taken together, our data provide proof-of-concept that miR-21 overexpression within MM-microenviroment plays a crucial role in bone resorption/apposition balance, supporting the design of innovative miR-21 inhibition-based strategies for MM-related BD. PMID:26160841

  15. Difluorinated-Curcumin (CDF) Restores PTEN Expression in Colon Cancer Cells by Down-Regulating miR-21

    PubMed Central

    Roy, Sanchita; Yu, Yingjie; Padhye, Subhash B.; Sarkar, Fazlul H.; Majumdar, Adhip P.N.

    2013-01-01

    Despite recent advancement in medicine, nearly 50% of patients with colorectal cancer show recurrence of the disease. Although the reasons for the high relapse are not fully understood, the presence of chemo- and radiotherapy-resistant cancer stem/stem-like cells, where many oncomirs like microRNA-21 (miR-21) are upregulated, could be one of the underlying causes. miR-21 regulates the processes of invasion and metastasis by downregulating multiple tumor/metastatic suppressor genes including PTEN (phosphatase and tensin homolog). Tumor suppressor protein PTEN controls self-renewal of stem cells. Indeed, our current data demonstrate a marked downregulation of PTEN in SCID mice xenografts of miR-21 over-expressing colon cancer HCT116 cells. Colonospheres that are highly enriched in cancer stem/stem like cells reveal increased miR-21 expression and decreased PTEN. Difluorinated curcumin (CDF), a novel analog of the dietary ingredient curcumin, which has been shown to inhibit the growth of 5-Flurouracil + Oxaliplatin resistant colon cancer cells, downregulated miR-21 in chemo-resistant colon cancer HCT116 and HT-29 cells and restored PTEN levels with subsequent reduction in Akt phosphorylation. Similar results were also observed in metastatic colon cancer SW620 cells. Since PTEN-Akt confers drug resistance to different malignancies including colorectal cancer, our observation of normalization of miR-21-PTEN-Akt pathway by CDF suggests that the compound could be a potential therapeutic agent for chemotherapy-resistant colorectal cancer. PMID:23894315

  16. Dysregulation of miR-31 and miR-21 induced by zinc deficiency promotes esophageal cancer

    PubMed Central

    Croce, Carlo M; Fong, Louise Y.Y

    2012-01-01

    Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma (ESCC). In a rat model, chronic ZD induces an inflammatory gene signature that fuels ESCC development. microRNAs regulate gene expression and are aberrantly expressed in cancers. Here we investigated whether chronic ZD (23 weeks) also induces a protumorigenic microRNA signature. Using the nanoString technology, we evaluated microRNA profiles in ZD esophagus and six additional tissues (skin, lung, pancreas, liver, prostate and peripheral blood mononuclear cells [PBMC]). ZD caused overexpression of inflammation genes and altered microRNA expression across all tissues analyzed, predictive of disease development. Importantly, the inflammatory ZD esophagus had a distinct microRNA signature resembling human ESCC or tongue SCC miRNAomes with miR-31 and miR-21 as the top-up-regulated species. Circulating miR-31 was also the top-up-regulated species in PBMCs. In ZD esophagus and tongue, oncogenic miR-31 and miR-21 overexpression was accompanied by down-regulation of their respective tumor-suppressor targets PPP2R2A and PDCD4. Importantly, esophageal miR-31 and miR-21 levels were directly associated with the appearance of ESCC in ZD rats, as compared with their cancer-free Zn-sufficient or Zn-replenished counterparts. In situ hybridization analysis in rat and human tongue SCCs localized miR-31 to tumor cells and miR-21 to stromal cells. In regressing tongue SCCs from Zn-supplemented rats, miR-31 and miR-21 expression was concomitantly reduced, establishing their responsiveness to Zn therapy. A search for putative microRNA targets revealed a bias toward genes in inflammatory pathways. Our finding that ZD causes miR-31 and miR-21 dysregulation associated with inflammation provides insight into mechanisms whereby ZD promotes ESCC. PMID:22689922

  17. Differential expression of miR-21 and miR-75 in esophageal carcinoma patients and its clinical implication

    PubMed Central

    Lv, Hongbo; He, Zhanao; Wang, Hongjiang; Du, Tongxin; Pang, Zuoliang

    2016-01-01

    In Xinjiang, China, esophageal carcinoma has a high incidence in Kazak and Uighur populations. MicroRNA (miR)-21 and miR-375 are related to esophageal carcinoma. This study thus investigated their potencials in early diagnosis and prognosis in Kazak and Uighur populations, to provide evidences for serum markers of esophageal cancer. A total of 126 Kazak or Uighur esophageal cancer patients were enrolled as the disease group, along with 86 local Han patients as disease control cohort, and 80 healthy Kazak or Uighur individuals. MiRNA expression was detected by in situ hybridization in tissues and by qRT-PCR in serum. ROC approach was used to evaluate the diagnostic value of miRNA on esophageal carcinoma. Cox analysis was performed to screen factors governing prognosis. MiR-21 level was significantly elevated in both tissue and serum samples of esophageal cancer patients, while miR-375 was down-regulated. Such difference was more potent in disease group compared to disease control group. MiR expression was correlated with infiltration depth, TNM stage, vascular invasion, and lymph node metastasis. Elevated expression of miR-21 reduced the sensitivity of radio-therapy, and increased recurrence frequency. The diagnostic value of single assay for miR-21 or miR-375 was lower than the combined assay (AUC=0.812 or 0.739 vs. 0.858). They also affected patient prognosis (OR=1.53 or 0.652). MiR-21 and miR-375 presented abnormal expression in Kazak or Uighur esophageal carcinoma patients and were independent factors affecting prognosis. The combined assay of miR-21 and miR-375 may help to make early diagnosis of esophageal cancer. PMID:27508050

  18. MiR-21 is induced in endothelial cells by shear stress and modulates apoptosis and eNOS activity

    SciTech Connect

    Weber, Martina; Baker, Meredith B.; Moore, Jeffrey P.; Searles, Charles D.

    2010-03-19

    Mechanical forces associated with blood flow play an important role in regulating vascular signaling and gene expression in endothelial cells (ECs). MicroRNAs (miRNAs) are a class of noncoding RNAs that posttranscriptionally regulate the expression of genes involved in diverse cell functions, including differentiation, growth, proliferation, and apoptosis. miRNAs are known to have an important role in modulating EC biology, but their expression and functions in cells subjected to shear stress conditions are unknown. We sought to determine the miRNA expression profile in human ECs subjected to unidirectional shear stress and define the role of miR-21 in shear stress-induced changes in EC function. TLDA array and qRT-PCR analysis performed on HUVECs exposed to prolonged unidirectional shear stress (USS, 24 h, 15 dynes/cm{sup 2}) identified 13 miRNAs whose expression was significantly upregulated (p < 0.05). The miRNA with the greatest change was miR-21; it was increased 5.2-fold (p = 0.002) in USS-treated versus control cells. Western analysis demonstrated that PTEN, a known target of miR-21, was downregulated in HUVECs exposed to USS or transfected with pre-miR-21. Importantly, HUVECs overexpressing miR-21 had decreased apoptosis and increased eNOS phosphorylation and nitric oxide (NO{sup {center_dot}}) production. These data demonstrate that shear stress forces regulate the expression of miRNAs in ECs, and that miR-21 influences endothelial biology by decreasing apoptosis and activating the NO{sup {center_dot}} pathway. These studies advance our understanding of the mechanisms by which shear stress forces modulate vascular homeostasis.

  19. Comprehensive RNA dataset of AGO2 associated RNAs in Jurkat cells following miR-21 over-expression.

    PubMed

    Carissimi, Claudia; Colombo, Teresa; Azzalin, Gianluca; Cipolletta, Emanuela; Laudadio, Ilaria; Macino, Giuseppe; Fulci, Valerio

    2016-06-01

    We set out to identify miR-21 targets in Jurkat cells using a high-throughput biochemical approach (10.1016/j.biochi.2014.09.021[1]). Using a specific monoclonal antibody raised against AGO2, RISC complexes were immunopurified in Jurkat cells over-expressing miR-21 following lentiviral trasduction as well as in Jurkat control cells lines. A parallel immunoprecipitation using isotype-matched rat IgG was performed as a control. AGO2 associated mRNAs were profiled by microarray (GEO: GSE37212). AGO2 bound miRNAs were profiled by RNA-seq. PMID:27054165

  20. Expression and significance of miR-21 in multiple myeloma patients.

    PubMed

    Wang, J H; Zhou, W W; Liu, B X; Man, D L; Yang, Z D; Liu, F R; Shang, H

    2016-01-01

    The aim of the present study is to examine the expression level of peripheral mir-21 in multiple myeloma (MM) patients and to determine its clinical significance. MM patients (30), monoclonal gammopathy of undetermined significance (MGUS) patients (14), and normal controls (20) were recruited to determine the serum level of β2-MG, IgA and IgM, IgG, λ, κ, TP, ALB, Hb, LDH, and Ca(2+). Gene expression of mir-21 was quantified by SYBR green real-time fluorescent quantitative PCR. We found that the expression level of serum mir-21 in the MM group was significantly higher than the MGUS group and the NC group (P < 0.01). According to the ISS installment, the level of mir-21, lgG, κ, and ALB in the MM group in stage I differed from that in stages II and III. The level of IgA, β2-MG in stage III was higher as compared with stage I and II (P < 0.05 and P < 0.01).The levels of mir-21, κ, (κ+λ), IgG, (IgG + IgA + IgM), and β2-MG in MM patients were positively correlated with ALB (P < 0.01). Based on the results, miR-21 plays an important role as an oncogene. Mir-21 may be important in the occurrence, development, and disease prognosis of MM. PMID:26909911

  1. STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation.

    PubMed

    Singh, Mohini; Garg, Neha; Venugopal, Chitra; Hallett, Robin; Tokar, Tomas; McFarlane, Nicole; Mahendram, Sujeivan; Bakhshinyan, David; Manoranjan, Branavan; Vora, Parvez; Qazi, Maleeha; Arpin, Carolynn C; Page, Brent; Haftchenary, Sina; Rosa, David A; Lai, Ping-Shan; Gómez-Biagi, Rodolfo F; Ali, Ahmed M; Lewis, Andrew; Geletu, Mulu; Murty, Naresh K; Hassell, John A; Jurisica, Igor; Gunning, Patrick T; Singh, Sheila K

    2015-09-29

    Brain metastases (BM) represent the most common tumor to affect the adult central nervous system. Despite the increasing incidence of BM, likely due to consistently improving treatment of primary cancers, BM remain severely understudied. In this study, we utilized patient-derived stem cell lines from lung-to-brain metastases to examine the regulatory role of STAT3 in brain metastasis initiating cells (BMICs). Annotation of our previously described BMIC regulatory genes with protein-protein interaction network mapping identified STAT3 as a novel protein interactor. STAT3 knockdown showed a reduction in BMIC self-renewal and migration, and decreased tumor size in vivo. Screening of BMIC lines with a library of STAT3 inhibitors identified one inhibitor to significantly reduce tumor formation. Meta-analysis identified the oncomir microRNA-21 (miR-21) as a target of STAT3 activity. Inhibition of miR-21 displayed similar reductions in BMIC self-renewal and migration as STAT3 knockdown. Knockdown of STAT3 also reduced expression of known downstream targets of miR-21. Our studies have thus identified STAT3 and miR-21 as cooperative regulators of stemness, migration and tumor initiation in lung-derived BM. Therefore, STAT3 represents a potential therapeutic target in the treatment of lung-to-brain metastases. PMID:26314961

  2. Expression of programmed cell death protein 4 (PDCD4) and miR-21 in urothelial carcinoma

    SciTech Connect

    Fischer, Nicolas; Goeke, Friederike; Splittstoesser, Vera; Lankat-Buttgereit, Brigitte; Mueller, Stefan C.; Ellinger, Joerg

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer The tumor suppressor gene PDCD4 is down-regulated in many tumorous entities. Black-Right-Pointing-Pointer We investigate the impact of PDCD4 and its regulating factor miR-21 in urothelial carcinoma. Black-Right-Pointing-Pointer We confirm PDCD4 as a tumor suppressor gene and it could be a diagnostic marker for this tumor. -- Abstract: Background: We investigated the role of the programmed cell death 4 (PDCD4) tumor suppressor gene in specimens of transitional cell carcinoma and of healthy individuals. Methods: PDCD4 immunohistochemical expression was investigated in 294 cases in histologically proven transitional cell carcinoma in different tumorous stages (28 controls, 122 non-muscle invasive urothelial carcinoma, stages Tis-T1, 119 invasive transitional cell carcinoma stages T2-T4 and 25 metastases). MiR-21 expression, an important PDCD4 regulator, was assessed with real-time PCR analysis and showed inverse correlation to tissue PDCD4 expression. Results: Nuclear and cytoplasmatic PDCD4 immunostaining decreased significantly with histopathological progression of the tumor (p < 0001). Controls showed strong nuclear and cytoplasmatic immunohistochemical staining. MiR-21 up regulation in tissue corresponded to PDCD4 suppression. Conclusions: These data support a decisive role for PDCD4 down regulation in transitional cell carcinoma and confirm miR-21 as a negative regulator for PDCD4. Additionally, PDCD4 immunohistochemical staining turns out to be a possible diagnostic marker for transitional cell carcinoma.

  3. STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation

    PubMed Central

    Singh, Mohini; Garg, Neha; Venugopal, Chitra; Hallett, Robin; Tokar, Tomas; McFarlane, Nicole; Mahendram, Sujeivan; Bakhshinyan, David; Manoranjan, Branavan; Vora, Parvez; Qazi, Maleeha; Arpin, Carolynn C.; Page, Brent; Haftchenary, Sina; Rosa, David A.; Lai, Ping-Shan; Gómez-Biagi, Rodolfo F.; Ali, Ahmed M.; Lewis, Andrew; Geletu, Mulu; Murty, Naresh K.; Hassell, John A.; Jurisica, Igor; Gunning, Patrick T.; Singh, Sheila K.

    2015-01-01

    Brain metastases (BM) represent the most common tumor to affect the adult central nervous system. Despite the increasing incidence of BM, likely due to consistently improving treatment of primary cancers, BM remain severely understudied. In this study, we utilized patient-derived stem cell lines from lung-to-brain metastases to examine the regulatory role of STAT3 in brain metastasis initiating cells (BMICs). Annotation of our previously described BMIC regulatory genes with protein-protein interaction network mapping identified STAT3 as a novel protein interactor. STAT3 knockdown showed a reduction in BMIC self-renewal and migration, and decreased tumor size in vivo. Screening of BMIC lines with a library of STAT3 inhibitors identified one inhibitor to significantly reduce tumor formation. Meta-analysis identified the oncomir microRNA-21 (miR-21) as a target of STAT3 activity. Inhibition of miR-21 displayed similar reductions in BMIC self-renewal and migration as STAT3 knockdown. Knockdown of STAT3 also reduced expression of known downstream targets of miR-21. Our studies have thus identified STAT3 and miR-21 as cooperative regulators of stemness, migration and tumor initiation in lung-derived BM. Therefore, STAT3 represents a potential therapeutic target in the treatment of lung-to-brain metastases. PMID:26314961

  4. Androgens downregulate miR-21 expression in breast cancer cells underlining the protective role of androgen receptor

    PubMed Central

    Donà, Ada; Rizza, Pietro; Aquila, Saveria; Avena, Paola; Lanzino, Marilena; Pellegrino, Michele; Vivacqua, Adele; Tucci, Paola; Morelli, Catia; Andò, Sebastiano; Sisci, Diego

    2016-01-01

    Although the protective role of androgen receptor (AR) in breast cancer (BC) is well established, the mechanisms involved remains largely unexplored. MicroRNAs play fundamental roles in many biological processes, including tumor cell development and metastasis. Herein, we report that androgens reduce BC cells proliferation acting as a negative modulator of the onco-miRNA-21. The synthetic androgen miboleron (Mib) decreases BC cell proliferation induced by miR-21 over-expression and AR knockdown evidenced the requirement of AR in the down-regulation of miR-21 expression. These effects seem to be a general mechanism occurring in BC tissues. Chromatin immune-precipitation (ChIP) analysis disclosed the binding of AR to a specific ARE sequence in miR-21 proximal promoter and recognizes the recruitment of HDAC3 as component for AR-mediated transcriptional repression. Such event is associated to a significantly reduced PolII binding in Mib treated extracts confirming that activated AR is a transcriptional repressor of miR-21 expression, providing further insight into the protective role of androgens in breast cancer cells. Collectively, our data and the widespread AR expression in primary and metastatic breast tumours, suggest a careful examination of the therapeutic potential of androgens also in potentiating the effectiveness of anti-oestrogen adjuvant therapies. PMID:26862856

  5. Androgens downregulate miR-21 expression in breast cancer cells underlining the protective role of androgen receptor.

    PubMed

    Casaburi, Ivan; Cesario, Maria Grazia; Donà, Ada; Rizza, Pietro; Aquila, Saveria; Avena, Paola; Lanzino, Marilena; Pellegrino, Michele; Vivacqua, Adele; Tucci, Paola; Morelli, Catia; Andò, Sebastiano; Sisci, Diego

    2016-03-15

    Although the protective role of androgen receptor (AR) in breast cancer (BC) is well established, the mechanisms involved remains largely unexplored. MicroRNAs play fundamental roles in many biological processes, including tumor cell development and metastasis. Herein, we report that androgens reduce BC cells proliferation acting as a negative modulator of the onco-miRNA-21.The synthetic androgen miboleron (Mib) decreases BC cell proliferation induced by miR-21 over-expression and AR knockdown evidenced the requirement of AR in the down-regulation of miR-21 expression. These effects seem to be a general mechanism occurring in BC tissues.Chromatin immune-precipitation (ChIP) analysis disclosed the binding of AR to a specific ARE sequence in miR-21 proximal promoter and recognizes the recruitment of HDAC3 as component for AR-mediated transcriptional repression. Such event is associated to a significantly reduced PolII binding in Mib treated extracts confirming that activated AR is a transcriptional repressor of miR-21 expression, providing further insight into the protective role of androgens in breast cancer cells.Collectively, our data and the widespread AR expression in primary and metastatic breast tumours, suggest a careful examination of the therapeutic potential of androgens also in potentiating the effectiveness of anti-oestrogen adjuvant therapies. PMID:26862856

  6. MiR-21 promotes intrahepatic cholangiocarcinoma proliferation and growth in vitro and in vivo by targeting PTPN14 and PTEN

    PubMed Central

    Wang, Li-Juan; He, Chen-Chen; Sui, Xin; Cai, Meng-Jiao; Zhou, Cong-Ya; Ma, Jin-Lu; Wu, Lei; Wang, Hao; Han, Su-Xia; Zhu, Qing

    2015-01-01

    Intrahepatic cholangiocarcinoma (ICC) constitutes the second-most common primary hepatic malignancy. MicroRNAs (miRNAs) play important roles in the pathogenesis of ICC. However, the clinical significance of miR-21 levels in ICC remains unclear. Here, we investigated the role of miR-21 in ICC and found that its expression was significantly upregulated in serum of ICC patients. Serum miR-21 levels robustly distinguished ICC patients from control subjects. Further experiments showed that inhibition of miR-21 suppressed ICC cell proliferation in vitro and tumor growth in vivo. Specifically, inhibition of miR-21 induced cell cycle arrest and apoptosis. Moreover, PTPN14 and PTEN were identified as direct and functional targets of miR-21. Finally, we showed high expression levels of miR-21 were closely related to adverse clinical features, diminished survival, and poor prognosis in ICC patients. This study revealed functional and mechanistic links between miR-21 and tumor suppressor genes, PTPN14 and PTEN, in the pathogenesis of ICC. MiR-21 not only plays important roles in the regulation of cell proliferation and tumor growth in ICC, but is also a diagnostic and prognostic marker, and a potential therapeutic target for ICC. PMID:25803229

  7. Imaging Dendrimer-Grafted Graphene Oxide Mediated Anti-miR-21 Delivery With an Activatable Luciferase Reporter.

    PubMed

    Wang, Fu; Zhang, Beilei; Zhou, Lin; Shi, Yaru; Li, Zhiqiang; Xia, Yuqiong; Tian, Jie

    2016-04-13

    MicroRNAs (miRNAs) are a class of post-transcriptional gene regulators involved in various physiological processes including carcinogenesis, and they have emerged as potential targets for tumor theranostics. However, the employment of antisense oligonucleotides, termed anti-miRs, for antagonizing miRNA functions in vivo has largely been impeded by a lack of effective delivery carriers. Here, we describe the development of polyamidoamine (PAMAM) dendrimer and polyethylene glycol (PEG)-functionalized nanographene oxide (NGO) conjugate (NGO-PEG-dendrimer) for the efficient delivery of anti-miR-21 into non-small-cell lung cancer cells. To monitor the delivery of anti-miR-21 into cells and tumors, we also constructed an activatable luciferase reporter (Fluc-3xPS) containing three perfectly complementary sequences against miR-21 in the 3' untranslated region (UTR) of the reporter. Compared with bare dendrimer and Lipofectamine 2000 (Lipo2000), NGO-PEG-dendrimer showed considerably lower cytotoxicity and higher transfection efficiency. As demonstrated by in vitro bioluminescence imaging and Western blotting assays, NGO-PEG-dendrimer effectively delivered anti-miR-21 into the cytoplasm and resulted in the upregulation of luciferase intensity and PTEN target protein expression in a dose-dependent manner. Moreover, transfection with anti-miR-21 by NGO-PEG-dendrimer led to stronger inhibition of cell migration and invasion than did bare dendrimer or Lipo2000 transfection. The intravenous delivery of anti-miR-21 via NGO-PEG-dendrimer induced a significant increase in the bioluminescence signal within the Fluc-3xPS reporter-transplanted tumor areas. These results suggest that NGO-PEG-dendrimer could be an efficient and a potential nanocarrier for delivering RNA oligonucleotides. In addition, the strategy of combining NGO-PEG-dendrimer with an activatable luciferase reporter allows the image-guided monitoring of the delivery process, which can provide insights into the RNA

  8. The R21C Mutation in Cardiac Troponin I Imposes Differences in Contractile Force Generation between the Left and Right Ventricles of Knock-In Mice.

    PubMed

    Liang, Jingsheng; Kazmierczak, Katarzyna; Rojas, Ana I; Wang, Yingcai; Szczesna-Cordary, Danuta

    2015-01-01

    We investigated the effect of the hypertrophic cardiomyopathy-linked R21C (arginine to cysteine) mutation in human cardiac troponin I (cTnI) on the contractile properties and myofilament protein phosphorylation in papillary muscle preparations from left (LV) and right (RV) ventricles of homozygous R21C(+/+) knock-in mice. The maximal steady-state force was significantly reduced in skinned papillary muscle strips from the LV compared to RV, with the latter displaying the level of force observed in LV or RV from wild-type (WT) mice. There were no differences in the Ca(2+) sensitivity between the RV and LV of R21C(+/+) mice; however, the Ca(2+) sensitivity of force was higher in RV-R21C(+/+) compared with RV-WT and lower in LV- R21C(+/+) compared with LV-WT. We also observed partial loss of Ca(2+) regulation at low [Ca(2+)]. In addition, R21C(+/+)-KI hearts showed no Ser23/24-cTnI phosphorylation compared to LV or RV of WT mice. However, phosphorylation of the myosin regulatory light chain (RLC) was significantly higher in the RV versus LV of R21C(+/+) mice and versus LV and RV of WT mice. The difference in RLC phosphorylation between the ventricles of R21C(+/+) mice likely contributes to observed differences in contractile force and the lower tension monitored in the LV of HCM mice. PMID:25961037

  9. Anti-inflammatory effects of miR-21 in the macrophage response to peritonitis.

    PubMed

    Barnett, Rebecca Elise; Conklin, Daniel J; Ryan, Lindsey; Keskey, Robert C; Ramjee, Vikram; Sepulveda, Ernesto A; Srivastava, Sanjay; Bhatnagar, Aruni; Cheadle, William G

    2016-02-01

    We investigated the role of microRNA-21 in the macrophage response to peritonitis; microRNA-21 expression increases in peritoneal macrophages after lipopolysaccharide stimulation but is delayed until 48 hours after cecal ligation and puncture. MicroRNA-21-null mice and bone marrow-derived cell lines were exposed to cecal ligation and puncture or lipopolysaccharide, and survival, microRNA-21 levels, target messenger RNAs and proteins, and cytokines were assayed. Macrophages were also transfected with microRNA-21 mimics and antagomirs, and similar endpoints were measured. Survival in microRNA-21-null mice was significantly decreased after lipopolysaccharide-induced peritonitis but unchanged after cecal ligation and puncture compared with similarly treated wild-type mice. MicroRNA-21 expression, tumor necrosis factor-α, interleukin 6, and programmed cell death protein 4 levels were increased after lipopolysaccharide addition in peritoneal cells. Pelino1 and sprouty (SPRY) messenger RNAs were similarly increased early, whereas programmed cell death protein 4 messenger RNA was decreased after lipopolysaccharide, and all microR-21 target messenger RNAs were subsequently decreased by 24 hours after lipopolysaccharide. Transfection with mimics and antagomirs led to appropriate responses in microRNA-21 and tumor necrosis factor-α. Knockdown of microRNA-21 in bone marrow-derived cells showed increased tumor necrosis factor-α and decreased interleukin 10 in response to lipopolysaccharide. Target proteins were unaffected by knockdown as was extracellular signal-regulated kinase; however, the nuclear factor κB p65 subunit was increased after lipopolysaccharide in the microRNA-21 knockout cells. In contrast, there was little change in these parameters after cecal ligation and puncture induction between null and wild-type mice. MicroRNA-21 is beneficial to survival in mice following lipopolysaccharide peritonitis. Overexpression of microRNA-21 decreased tumor necrosis factor

  10. Inhibiting miR-21 attenuates experimental hepatic fibrosis by suppressing both the ERK1 pathway in HSC and hepatocyte EMT.

    PubMed

    Wu, Kaiming; Ye, Changhong; Lin, Lin; Chu, Yimin; Ji, Meng; Dai, Weiping; Zeng, Xin; Lin, Yong

    2016-08-01

    MicroRNA-21 (miR-21) has emerged as a critical regulatory molecule and an important serum marker in hepatic fibrogenesis. The aim of the present study was to investigate the role of inhibiting miR-21 on hepatic fibrosis treatment. Serum miR-21 levels in 60 healthy individuals and 180 patients with different stages of liver cirrhosis were examined, miR-21 levels in normal or cirrhotic human liver tissues (n=10 each) were also detected. An adenoviral vector (Ad-TuD-21) carrying the sponging ToughDecoy (TuD)-RNA sequence against miR-21 was constructed to reduce miR-21 expression efficiently in vitro and in vivo Histological and immunohistological examinations were performed to evaluate the inhibitory effects and mechanism of Ad-TuD-21 delivery into carbon tetrachloride (CCl4) induced hepatic fibrosis rats by targeting extracellular signal-regulated kinase 1 (ERK1) signalling in hepatic stellate cells (HSC) and hepatocyte epithelial-mesenchymal transition (EMT). Our results revealed that enhanced miR-21 levels in cirrhotic patients were related to the severity and activity of liver cirrhosis. Ad-TuD-21 administered to liver fibrosis rats could remarkably suppress profibrotic gene expression, cause histological improvements in liver and attenuate hepatic fibrosis significantly. More importantly, after Ad-TuD-21 treatment, inhibition of both the ERK1 signalling pathway in HSC and hepatocyte EMT was confirmed, which paralleled the enhancement of miR-21 target genes-sprouty2 (SPRY2) and hepatocyte nuclear factor 4α (HNF4α)-expression in vivo These data demonstrated that miR-21 is a key regulator to promote hepatic fibrogenesis, and sponging miR-21 expression may present a novel potentially therapeutic option for hepatic fibrosis. PMID:27226339

  11. MiR-21a-5p suppresses bisphenol A-induced pre-adipocyte differentiation by targeting map2k3 through MKK3/p38/MAPK.

    PubMed

    Xie, Xiuwen; Song, Jia; Li, Gang

    2016-04-22

    Childhood obesity is a metabolic disease characterized by accumulation of excessive fat. Bisphenol A (BPA), a potential obesogen compound, possesses an estrogen mimetic activity and endocrine disruption effect. MicroRNA-21a-5p (miR-21a-5p) is reported to regulate the adipogenic differentiation. Our study showed that miR-21a-5p overexpression significantly decreased the red lipid droplets and triglyceride level in BPA-induced 3T3-L1 cells. BPA induced the mRNA and protein expression levels of PPARγ, C/EBPα and adiponectin, and the induction was inhibited by miR-21a-5p mimics transfection. MiR-21a-5p mimics inhibited the GR activity, GR phosphorylation (S220, S21a-5p2, and S234), and the activation of p38/MAPK pathway, which are elevated by BPA treatment in 3T3-L1 cells. MiR-21a-5p overexpression inhibited the protein level of MKK3, but not in the mRNA level. Luciferase activity assay showed that miR-21a-5p directly targeted map2k3 3'-UTR. MKK3 overexpression attenuated the effect of miR-21a-5p mimics transfection on 3T3-L1 differentiation. We also assessed the body weight, fat mass and the content of serum lipid in rats subcutaneous injected with BPA and miR-21a-5p mimics. MiR-21a-5p overexpression attenuated BPA-induced obesity in vivo. These findings suggested that miR-21a-5p inhibited BPA induced adipocyte differentiation by targeting map2k3 through MKK3/p38/MAPK in 3T3-L1 cells, providing a potential therapeutic strategy for BPA induced obesity. PMID:26996129

  12. Induction of a M/sub r/ 21,000 polypeptide in an Arthrobacter Sp. by dye-sensitized photooxidation

    SciTech Connect

    Franzi, J.J.

    1985-01-01

    Irradiation of aerobic cultures of an Arthrobacter species with near-UV light and oxygen induced synthesis of a cell surface protein, M/sub r/ 21,000 polypeptide. Visible light, oxygen and a sensitizing dye were also effective in induction. Far-UV light, bleomycin and nalidixic acid, all inducers of the recA protein in Escherichia coli, were ineffective inducers of this protein. Furthermore, X-irradiation and radical-generating oxidants failed to induce synthesis of the M/sub r/ 21,000 polypeptide. DNA binding dyes proved to be capable of inducing synthesis of this protein or inhibiting dye-mediated stimulation of synthesis of this protein. For example, dGdC-specific dyes (e.g. methylene blue, neutral red, acridine orange or ethidium bromide) were efficient inducers of the M/sub r/ 21,000 polypeptide. Also methylene blue and neutral red were more efficient inducers than were acridine orange or ethidium bromide, which could be explained by the greater dGdC specificity and, possibly by the greater photoreactivity of methylene blue and neutral red. dAdT-specific dyes such as methyl green or daunomycin effectively inhibited dye-mediated induction. Rose bengal is an anionic dye which does not bind to DNA but does mediate the photooxidation of deoxyguanosine residues in DNA. It is an efficient inducer of the M/sub r/ 21,000 polypeptide. Induction with this dye is nearly eliminated when novobiocin, an inhibitor of DNA gyrase (topoisomerase II) which mediates relaxation, is added in conjunction with rose bengal.

  13. Identification of a novel PPARβ/δ/miR-21-3p axis in UV-induced skin inflammation.

    PubMed

    Degueurce, Gwendoline; D'Errico, Ilenia; Pich, Christine; Ibberson, Mark; Schütz, Frédéric; Montagner, Alexandra; Sgandurra, Marie; Mury, Lionel; Jafari, Paris; Boda, Akash; Meunier, Julien; Rezzonico, Roger; Brembilla, Nicolò Costantino; Hohl, Daniel; Kolios, Antonios; Hofbauer, Günther; Xenarios, Ioannis; Michalik, Liliane

    2016-01-01

    Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control mouse cutaneous repair and UV-induced skin cancer development. Here, we describe a novel PPARβ/δ-dependent molecular cascade involving TGFβ1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders. PMID:27250636

  14. p-SMAD2/3 and DICER promote pre-miR-21 processing during pressure overload-associated myocardial remodeling.

    PubMed

    García, Raquel; Nistal, J Francisco; Merino, David; Price, Nathan L; Fernández-Hernando, Carlos; Beaumont, Javier; González, Arantxa; Hurlé, María A; Villar, Ana V

    2015-07-01

    Transforming growth factor-β (TGF-β) induces miR-21 expression which contributes to fibrotic events in the left ventricle (LV) under pressure overload. SMAD effectors of TGF-β signaling interact with DROSHA to promote primary miR-21 processing into precursor miR-21 (pre-miR-21). We hypothesize that p-SMAD-2 and -3 also interact with DICER1 to regulate the processing of pre-miR-21 to mature miR-21 in cardiac fibroblasts under experimental and clinical pressure overload. The subjects of the study were mice undergoing transverse aortic constriction (TAC) and patients with aortic stenosis (AS). In vitro, NIH-3T3 fibroblasts transfected with pre-miR-21 responded to TGF-β1 stimulation by overexpressing miR-21. Overexpression and silencing of SMAD2/3 resulted in higher and lower production of mature miR-21, respectively. DICER1 co-precipitated along with SMAD2/3 and both proteins were up-regulated in the LV from TAC-mice. Pre-miR-21 was isolated bound to the DICER1 maturation complex. Immunofluorescence analysis revealed co-localization of p-SMAD2/3 and DICER1 in NIH-3T3 and mouse cardiac fibroblasts. DICER1-p-SMAD2/3 protein-protein interaction was confirmed by in situ proximity ligation assay. Myocardial up-regulation of DICER1 constituted a response to pressure overload in TAC-mice. DICER mRNA levels correlated directly with those of TGF-β1, SMAD2 and SMAD3. In the LV from AS patients, DICER mRNA was up-regulated and its transcript levels correlated directly with TGF-β1, SMAD2, and SMAD3. Our results support that p-SMAD2/3 interacts with DICER1 to promote pre-miR-21 processing to mature miR-21. This new TGFβ-dependent regulatory mechanism is involved in miR-21 overexpression in cultured fibroblasts, and in the pressure overloaded LV of mice and human patients. PMID:25887159

  15. Regulator role of HPV E7 protein on miR-21 expression in cervical carcinoma cells and its functional implication

    PubMed Central

    Kong, Qingqin; Wang, Wenfeng; Li, Ping

    2015-01-01

    Cervical cancer is the second leading malignant tumor in women. Human papillomavirus 16 (HPV16) is one risk factor for cervical cancer, with its expressed E7 protein can facilitate the transformation of cervical epithelial cells. MicroRNA-21 (miR-21) is one important tumor growth regulatory factor involving in angiogenesis, tumor invasion and metastasis. This study thus aimed to investigate the role of high-risk HPV16 E7 protein in regulating miR-21 expression in cervical carcinoma and its related functions. Hela cells were transfected with pcDNA-HPV16 E7 expressing vectors. The expression level of E7 was determined by Western blotting, while miR-21 level was quantified by real-time PCR. The alternation of tumor cell proliferation is determined by transfecting miR-21 inhibitor into E7-overexpressing Hela cells. Cell apoptosis was studied by caspase-3 assay, while cell invasion was illustrated in Transwell chamber. The overexpression of HPV E7 protein facilitated the expression of miR-21, which potentiated Hela cell proliferation and invasion. The inhibition of miR-21 in E7-overexpressin Hela cells can inhibit both proliferation and invasion, but without significant effects on caspase-3 activity. HPV16 E7 protein can up-regulate host miR-21 expression, thus elevating cervical carcinoma cell growth, proliferation and invasion. Therefore, E7 protein is one critical factor in occurrence and progression of cervical carcinoma. PMID:26884851

  16. miR-21 Might be Involved in Breast Cancer Promotion and Invasion Rather than in Initial Events of Breast Cancer Development.

    PubMed

    Petrović, Nina

    2016-04-01

    Breast cancer (BC) is a heterogeneous disease that develops into a large number of varied phenotypes. One of the features used in its classification and therapy selection is invasiveness. MicroRNA-21 (miR-21) is considered to be an important element of BC invasiveness, and miR-21 levels are frequently increased in different tumor types compared with normal tissue, including the breast. Experimental and literature research has highlighted that miR-21 was always significantly elevated in every study that included invasive breast carcinomas compared with healthy breast tissue. The main goal of this research was to specify the predominant role of miR-21 in the different phases of BC pathogenesis, i.e. whether it was involved in the early (initiation), later (promotion), or late (propagation, progression) phases. Our second goal was to explain the roles of miR-21 targets in BC by an in silico approach and literature review, and to associate the importance of miR-21 with particular phases of BC pathogenesis through the action of its target genes. Analysis has shown that changes in miR-21 levels might be important for the later and/or late phases of breast cancerogenesis rather than for the initial early phases. Targets of miR-21 (TIMP3, PDCD4, PTEN, TPM1 and RECK) are also primarily involved in BC promotion and progression, especially invasion, angiogenesis and metastasis. miR-21 expression levels could perhaps be used in conjunction with the standard diagnostic parameters as an indicator of BC presence, and to indicate a phenotype likely to show early invasion/metastasis detection and poor prognosis. PMID:26891730

  17. Association of percentile ranking with citation impact and productivity in a large cohort of de novo NIMH-funded R01 grants.

    PubMed

    Doyle, J M; Quinn, K; Bodenstein, Y A; Wu, C O; Danthi, N; Lauer, M S

    2015-09-01

    Previous reports from National Institutes of Health and National Science Foundation have suggested that peer review scores of funded grants bear no association with grant citation impact and productivity. This lack of association, if true, may be particularly concerning during times of increasing competition for increasingly limited funds. We analyzed the citation impact and productivity for 1755 de novo investigator-initiated R01 grants funded for at least 2 years by National Institute of Mental Health between 2000 and 2009. Consistent with previous reports, we found no association between grant percentile ranking and subsequent productivity and citation impact, even after accounting for subject categories, years of publication, duration and amounts of funding, as well as a number of investigator-specific measures. Prior investigator funding and academic productivity were moderately strong predictors of grant citation impact. PMID:26033238

  18. miR-15b and miR-21 as Circulating Biomarkers for Diagnosis of Glioma

    PubMed Central

    Ivo D’Urso, Pietro; Fernando D’Urso, Oscar; Damiano Gianfreda, Cosimo; Mezzolla, Valeria; Storelli, Carlo; Marsigliante, Santo

    2015-01-01

    Malignant gliomas are lethal primary intracranial tumors. To date, little information on the role of deregulated genes in gliomas have been identified. As the involvement of miRNAs in the carcinogenesis is well known, we carried out a pilot study to identify, as potential biomarkers, differentially expressed microRNAs in blood samples of patients affected by glioma. We studied the miRNAs’ expression, by means of microarray and Real-Time PCR, in 30 blood samples from glioma patients and in 82 blood samples of patients suffering from: (a) various neurological disorders (n=30), (b) primary B-lymphoma of the Central Nervous System (PCNSL, n=36) and (c) secondary brain metastases (n=16). By quantitative real time reverse-transcriptase polymerase chain reaction (qRT-PCR), we identified significantly increased levels of two candidate biomarkers, miR-15b and miR-21, in blood of patients affected by gliomas. ROC analysis of miR-15b biomarker levels allowed to differentiate patients with tumour from patients without glioma. Furthermore, combined expression analyses of miR15b and miR-21 distinguished between patients with and without glioma (90% sensitivity and 100% specificity). In addition, a decrement in the expression levels of miR-16 characterized glioblastomas compared to low grade and anaplastic gliomas. In conclusion, this pilot study suggest that it’s possible to identify the disease state by meaning miR-15b and miR-21 markers in blood, while miR-16 can be used to distinguish glioblastoma from other grade gliomas. They can potentially be used as biomarkers for non-invasive diagnosis of gliomas; further studies are mandatory to confirm our preliminary findings. PMID:27047250

  19. The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer.

    PubMed

    Sahay, Debashish; Leblanc, Raphael; Grunewald, Thomas G P; Ambatipudi, Srikant; Ribeiro, Johnny; Clézardin, Philippe; Peyruchaud, Olivier

    2015-08-21

    Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA1-6). While blockage of LPA1in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA1/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA1 or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA1 in patients with basal breast carcinomas. PMID:26098771

  20. The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer

    PubMed Central

    Sahay, Debashish; Leblanc, Raphael; Grunewald, Thomas G. P.; Ambatipudi, Srikant; Ribeiro, Johnny; Clézardin, Philippe; Peyruchaud, Olivier

    2015-01-01

    Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA1-6). While blockage of LPA1 in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA1/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA1 or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA1 in patients with basal breast carcinomas. PMID:26098771

  1. Exosomal miR-21 derived from arsenite-transformed human bronchial epithelial cells promotes cell proliferation associated with arsenite carcinogenesis.

    PubMed

    Xu, Yuan; Luo, Fei; Liu, Yi; Shi, Le; Lu, Xiaolin; Xu, Wenchao; Liu, Qizhan

    2015-07-01

    Intercellular communications within the cancer microenvironment coordinate the assembly of various cell types. Exosomes are mediators of intercellular communication in immune signaling, tumor promotion, stress responses, and angiogenesis. The present research aimed to determine whether miRNAs secreted from human bronchial epithelial (HBE) cells transformed by 1.0 μM arsenite are transferred into normal HBE cells and are functionally active in the recipient cells. The results show that miR-21 is involved in exosome-mediated intercellular communication between neoplastic and normal HBE cells. Exosomes derived from transformed HBE cells stimulated proliferation of normal HBE cells, whereas exosomes from miR-21 depleted cells failed to stimulate proliferation. In normal HBE cells, the expression of phosphatase and tensin homolog, a target gene for miR-21, was increased by exosomal miR-21, indicating that exogenous miRNAs, via exosomal transport, function-like endogenous miRNAs. Concordantly, specific reduction of miR-21 content in exosome-producing transformed cells abolished the stimulation of proliferation by exosomes. Collectively, the data indicate that transformed HBE cells release exosomes containing miR-21, stimulating proliferation in neighboring normal HBE cells and supporting the concept that exosomal miRNAs are involved in cell-cell communication during carcinogenesis induced by environmental chemicals. PMID:24912785

  2. Curcumin modulates chronic myelogenous leukemia exosomes composition and affects angiogenic phenotype via exosomal miR-21.

    PubMed

    Taverna, Simona; Fontana, Simona; Monteleone, Francesca; Pucci, Marzia; Saieva, Laura; De Caro, Viviana; Cardinale, Valeria Giunta; Giallombardo, Marco; Vicario, Emanuela; Rolfo, Christian; Leo, Giacomo De; Alessandro, Riccardo

    2016-05-24

    Tumor derived exosomes are vesicles which contain proteins and microRNAs that mediate cell-cell communication and are involved in angiogenesis and tumor progression. Curcumin derived from the plant Curcuma longa, shows anticancer effects. Exosomes released by CML cells treated with Curcumin contain a high amount of miR-21 that is shuttled into the endothelial cells in a biologically active form. The treatment of HUVECs with CML Curcu-exosomes reduced RhoB expression and negatively modulated endothelial cells motility. We showed that the addition of CML control exosomes to HUVECs caused an increase in IL8 and VCAM1 levels, but Curcu-exosomes reversed these effects thus attenuating their angiogenic properties. This antiangiogenic effect was confirmed with in vitro and in vivo vascular network formation assays. SWATH analysis of the proteomic profile of Curcu-exosomes revealed that Curcumin treatment deeply changes their molecular properties, in particular, Curcumin induces a release of exosomes depleted in pro-angiogenic proteins and enriched in proteins endowed with anti-angiogenic activity. Among the proteins differential expressed we focused on MARCKS, since it was the most modulated protein and a target of miR-21. Taken together our data indicated that also Curcumin attenuates the exosome's ability to promote the angiogenic phenotype and to modulate the endothelial barrier organization. PMID:27050372

  3. Relative prognostic value of the Dukes and the Jass systems in rectal cancer. Findings from the National Surgical Adjuvant Breast and Bowel Projects (Protocol R-01)

    PubMed

    Fisher, E R; Robinsky, B; Sass, R; Fisher, B

    1989-11-01

    A comparison of the prognostic values of the Dukes and Jass systems were performed with 722 patients with rectal cancer enrolled in the National Surgical Adjuvant Breast and Bowel Projects, protocol R-01. The Jass system revealed four prognostic groups when all patients or only Dukes' B and C cases were examined; however, the magnitude of differences between groups I and II and III and IV were small. Dukes' classification, as defined in this study, revealed five prognostic groups. A statistically strong association between the Jass and Dukes systems was observed. Although histologic grade permitted further prognostic discrimination of all Dukes stages except A, only the Jass system allowed for the subdivision of C cases with up to four nodes positive for metastases. Those in that group had survival rates comparable to B cases (no nodal involvement) when scores of I and II were found. The distributions of the patients in the extremes of the Jass and Dukes systems (C2 as defined) were almost similar. The findings indicate that the Jass system is a valid prognostic method for patients with rectal carcinoma. In this material, however, it basically allowed for only two major prognostic groups whereas five were noted by the Dukes method. These results, as well as the more objective nature of Dukes' classification, warrant its continued use for prognosis and therapeutic decisions for patients with rectal cancer. PMID:2478350

  4. miR-21 expression and clinical outcome in locally advanced pancreatic cancer: exploratory analysis of the pancreatic cancer Erbitux, radiotherapy and UFT (PERU) trial

    PubMed Central

    Khan, Khurum; Cunningham, David; Peckitt, Clare; Barton, Sarah; Tait, Diana; Hawkins, Maria; Watkins, David; Starling, Naureen; Rao, Sheela; Begum, Ruwaida; Thomas, Janet; Oates, Jacqui; Guzzardo, Vincenza; Fassan, Matteo; Braconi, Chiara; Chau, Ian

    2016-01-01

    Background Locally advanced pancreatic cancer (LAPC) is associated with high mortality, and biomarker-driven treatment approach is currently lacking. This study evaluated safety and efficacy of a combination approach of chemotherapy followed by chemo-radiotherapy (CRT) +/− cetuximab, and the prognostic role of miR-21 in patients with LAPC treated with a multimodality approach. Patients and Methods This was a randomised phase II trial in which patients with inoperable LAPC were offered gemcitabine and capecitabine (GEM-CAP) for 16 weeks. Patients with stable disease or response after GEM-CAP were randomised to capecitabine or UFT plus radiotherapy (RT) (A), or capecitabine or UFT plus cetuximab plus RT (B). The primary outcome of the study was overall survival (OS). Clinical outcome was compared according to baseline circulating miR-21 levels. Results 17 patients were enrolled and treated with GEM-CAP, with 13 patients achieving disease control and being randomised to arms A (n:7) and B (n:6). After a median follow-up of 61.2 months, median progression free survival (PFS) was 10.4 months and 12.7 months, median OS was 15.8 months and 22.0 months in arms A and B respectively (p > 0.05). Patients with high baseline plasma miR-21 had worse PFS (3.5 vs. 12.7 months; p:0.032) and OS (5.1 vs 15.3 months; p:0.5) compared to patients with low miR-21. Circulating miR-21 levels reflected miR-21 expression within the tissues. Conclusions Addition of Cetuximab to CRT following induction chemotherapy did not improve survival. High miR-21 baseline plasma expression was associated with poor clinical outcome in LAPC patients treated with induction chemotherapy followed by chemo-radiotherapy. PMID:26862857

  5. Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype.

    PubMed

    Li, Ling; Li, Chao; Wang, Shaoxin; Wang, Zhaohui; Jiang, Jian; Wang, Wei; Li, Xiaoxia; Chen, Jin; Liu, Kun; Li, Chunhua; Zhu, Guiquan

    2016-04-01

    Hypoxia is a common feature of solid tumors and is associated with aggressiveness and poor patient outcomes. Exosomes, initially considered to be cellular "garbage dumpsters," are now implicated in mediating interactions with the cellular environment. However, the mechanisms underlying the association between exosomes and hypoxia during cancer progression remain poorly understood. In this study, we found that exosomes derived from hypoxic oral squamous cell carcinoma (OSCC) cells increased the migration and invasion of OSCC cells in a HIF-1α and HIF-2α-dependent manner. Given that exosomes have been shown to transport miRNAs to alter cellular functions, we performed miRNA sequencing of normoxic and hypoxic OSCC-derived exosomes. Of the 108 miRNAs that were differentially expressed, miR-21 stood out as one of the most significantly upregulated miRNAs under hypoxic conditions. miR-21 depletion in hypoxic OSCC cells led to decreased miR-21 levels in exosomes and significantly reduced cell migration and invasion. Conversely, restoration of miR-21 expression in HIF-1α and HIF-2α-depleted exosomes rescued OSCC cell migration and invasion. Moreover, exosomal miR-21 markedly enhanced snail and vimentin expression, while significantly decreasing E-cadherin levels in OSCC cells, in vitro and in vivo Finally, circulating exosomal miR-21 levels were closely associated with HIF-1α/HIF-2α expression, T stage, and lymph node metastasis in patients with OSCC. In conclusion, our findings suggest that the hypoxic microenvironment may stimulate tumor cells to generate miR-21-rich exosomes that are delivered to normoxic cells to promote prometastatic behaviors and prompt further investigation into the therapeutic value of exosome inhibition for cancer treatment. Cancer Res; 76(7); 1770-80. ©2016 AACR. PMID:26992424

  6. ERK8 is a novel HuR kinase that regulates tumour suppressor PDCD4 through a miR-21 dependent mechanism

    PubMed Central

    Liwak-Muir, Urszula; Dobson, Christine C.; Naing, Thet; Wylie, Quinlan; Chehade, Lucia; Baird, Stephen D.; Chakraborty, Pranesh K.; Holcik, Martin

    2016-01-01

    Programmed cell death 4 (PDCD4) is a tumour suppressor implicated in cancer development and progression and was recently identified as a repressor of cap-independent translation of specific genes involved in the regulation of apoptosis. We show that the RNA-binding protein HuR binds to the PDCD4 3′UTR to protect it from miR-21-induced silencing. However, following H2O2 treatment, PDCD4 mRNA is degraded via miR-21 binding. Importantly, we identify HuR as a novel substrate of the ERK8 kinase pathway in response to H2O2 treatment. We show that phosphorylation of HuR by ERK8 prevents it from binding to PDCD4 mRNA and allows miR-21-mediated degradation of PDCD4. PMID:26595526

  7. Evaluation of Plasma miR-21 and miR-152 as Diagnostic Biomarkers for Common Types of Human Cancers

    PubMed Central

    Chen, Hankui; Liu, Helu; Zou, Hanqing; Chen, Rui; Dou, Yuhong; Sheng, Shile; Dai, Shengming; Ai, Junmei; Melson, Joshua; Kittles, Rick A.; Pirooznia, Mehdi; Liptay, Michael J.; Borgia, Jeffrey A.; Deng, Youping

    2016-01-01

    Stable blood based miRNA species have allowed for the differentiation of patients with various types of cancer. Therefore, specific blood-based miRNA might be considered as a methodology which could be informative of the presence of cancer potentially from multiple distinct organ sites. Recently, miR-21 has been identified as an “oncomir” in various tumors while miR-152 as a tumor suppressor. In this study, we investigated whether circulating miR-21 and miR-152 can be used for early detection of lung cancer (LuCa), colorectal carcinoma (CRC), breast cancer (BrCa) and prostate cancer (PCa), with distinguishing cancer from various benign lesions on these organ sites. We measured the two miRNA levels by using real-time RT-PCR in plasma samples from a total of 204 cancer patients, 159 various benign lesions, and 228 normal subjects. We observed significantly elevated expression of miR-21 and miR-152 in LuCa, CRC, and BrCa when compared with normal controls. We also found upregulation of plasma miR-21 and miR-152 levels in patients with benign lesions of lung and breast, as compared to normal controls, respectively. No significant expression variation of the two miRNAs was observed in PCa or prostatic benign lesions as compared to healthy controls. Receiver operating characteristic (ROC) analyses revealed that miR-21 and/or miR-152 can discriminate LuCa, CRC and BrCa from normal controls. Our results suggest that plasma miR-21 and miR-152 may serve as non-specific noninvasive biomarkers for early screening of LuCa, CRC, and BrCa, but not PCa. PMID:26958084

  8. Star-branched amphiphilic PLA-b-PDMAEMA copolymers for co-delivery of miR-21 inhibitor and doxorubicin to treat glioma.

    PubMed

    Qian, Xiaomin; Long, Lixia; Shi, Zhendong; Liu, Chaoyong; Qiu, Mingzhe; Sheng, Jing; Pu, Peiyu; Yuan, Xubo; Ren, Yu; Kang, Chunsheng

    2014-02-01

    The combined treatment of chemotherapeutant and microRNA (miR) has been proven to be a viable strategy for enhancing chemosensitivity due to its synergistic effect for tumor therapy. However, the co-delivery of drugs and genes remains a major challenge as they lack efficient co-delivery carriers. In this study, three amphiphilic star-branched copolymers comprising polylactic acid (PLA) and polydimethylaminoethyl methacrylate (PDMAEMA) with AB3, (AB3)2,and (AB3)3 molecular architectures were synthesized respectively by a combination of ring-opening polymerization, atom transfer radical polymerization, and click chemistry via an "arm-first" approach. The star copolymers possessed a low critical micelle concentration (CMC) and formed nano-sized micelles with positive surface charges in water as well as exhibiting a much lower cytotoxicity than PEI 25 kDa. Nevertheless, their gene transfection efficiency and tumor inhibition ability showed a remarkable dependence on their molecular architecture. The (AB3)3 architecture micelle copolymer exhibited the highest transfection efficiency, about 2.5 times higher than PEI. In addition, after co-delivering DOX and miR-21 inhibitor (miR-21i) into LN229 glioma cells, the micelles could mediate escaping miR-21i from lysosome degradation and the release of DOX to the nucleus, which significantly decreased the miR-21 expression. Moreover, co-delivery of DOX and miR-21i surprisingly exhibited an anti-proliferative efficiency compared with DOX or the miR-21i treatment alone. These results demonstrated that amphiphilic star-branched copolymers are highly promising for their combinatorial delivery of genes and hydrophobic therapeutants. PMID:24332459

  9. Opposing roles of miR-21 and miR-29 in the progression of fibrosis in Duchenne muscular dystrophy.

    PubMed

    Zanotti, Simona; Gibertini, Sara; Curcio, Maurizio; Savadori, Paolo; Pasanisi, Barbara; Morandi, Lucia; Cornelio, Ferdinando; Mantegazza, Renato; Mora, Marina

    2015-07-01

    Excessive extracellular matrix deposition progressively replacing muscle fibres is the endpoint of most severe muscle diseases. Recent data indicate major involvement of microRNAs in regulating pro- and anti-fibrotic genes. To investigate the roles of miR-21 and miR-29 in muscle fibrosis in Duchenne muscle dystrophy, we evaluated their expression in muscle biopsies from 14 patients, and in muscle-derived fibroblasts and myoblasts. In Duchenne muscle biopsies, miR-21 expression was significantly increased, and correlated directly with COL1A1 and COL6A1 transcript levels. MiR-21 expression was also significantly increased in Duchenne fibroblasts, more so after TGF-β1 treatment. In Duchenne fibroblasts the expression of miR-21 target transcripts PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SPRY-1 (Sprouty homolog 1) was significantly reduced; while collagen I and VI transcript levels and soluble collagen production were significantly increased. MiR-29a and miR-29c were significantly reduced in Duchenne muscle and myoblasts, and miR-29 target transcripts, COL3A1, FBN1 and YY1, significantly increased. MiR-21 silencing in mdx mice reduced fibrosis in the diaphragm muscle and in both Duchenne fibroblasts and mdx mice restored PTEN and SPRY-1 expression, and significantly reduced collagen I and VI expression; while miR-29 mimicking in Duchenne myoblasts significantly decreased miR-29 target transcripts. These findings indicate that miR-21 and miR-29 play opposing roles in Duchenne muscle fibrosis and suggest that pharmacological modulation of their expression has therapeutic potential for reducing fibrosis in this condition. PMID:25892183

  10. Circulating miR-21 and miR-29a as Markers of Disease Severity and Etiology in Cholestatic Pediatric Liver Disease

    PubMed Central

    Goldschmidt, Imeke; Thum, Thomas; Baumann, Ulrich

    2016-01-01

    Circulating microRNAs have been investigated as markers of disease severity in a variety of conditions. We examined whether circulating miR-21 and miR-29a could serve as markers of hepatic fibrosis and disease etiology in children with various liver diseases. Circulating miR-21 and miR-29a were determined in 58 children (21 female, age 0.1–17.8 (median 9.8) years)) with chronic liver disease and compared to histological grading of hepatic fibrosis. 22 healthy children served as controls for circulating miRNAs. Levels of circulating miR-21 appeared to be age-dependent in healthy children. Children with biliary atresia had significantly higher levels of miR-21 compared both to healthy controls and to age-matched children with other cholestatic liver disease. Circulating miR-29a levels in biliary atresia children did not differ from healthy controls, but tended to be higher than in age-matched children with other cholestatic liver disease. Neither miR-21 nor miR-29a correlated well with hepatic fibrosis. Circulating miR-21 and miR-29a levels can potentially serve as non-invasive diagnostic markers to differentiate biliary atresia from other cholestatic disease in infancy. They do not appear suitable as non-invasive markers for the degree of hepatic fibrosis in an unselected cohort of children with various liver diseases. The discriminating effect regarding neonatal cholestasis should be followed up in a prospective longitudinal study. PMID:26927196

  11. MiR-21 controls in situ expansion of CCR6⁺ regulatory T cells through PTEN/AKT pathway in breast cancer.

    PubMed

    Hu, Yan; Wang, Chunhong; Li, Yongju; Zhao, Juanjuan; Chen, Chao; Zhou, Ya; Tao, Yijin; Guo, Mengmeng; Qin, Nalin; Ren, Tao; Wen, Zhenke; Xu, Lin

    2015-09-01

    Our recent evidence showed that prior expansion of CCR6(+) Foxp3(+) regulatory T cells (Tregs) was important for their dominant enrichment in tumor tissue, which was closely related to poor prognosis of breast cancer patients. However, the underlying regulation mechanism of expansion of CCR6(+) Tregs in situ remains largely unknown. In this study, we reported that miR-21 was highly expressed in CCR6(+) Tregs in tumor tissues from a murine breast cancer model. And silencing of miR-21 could significantly reduce the proliferation of CCR6(+) Tregs in vitro. Adoptive cell-transfer assay further showed that silencing of miR-21 could alter the enrichment of CCR6(+) Tregs in the tumor mass and endow effectively antitumor effect of CD8(+) T cells using a murine breast cancer model. Mechanistic evidence showed that silencing of miR-21 enhanced the expression of its target phosphatase and tensin homolog deleted on chromosome ten (PTEN) and subsequently altered the activation of Akt pathway, which was ultimately responsible for reduced proliferation activity of CCR6(+) Tregs. Finally, we further revealed that miR-21 was also highly expressed on CCR6(+) Tregs in clinical breast cancer patients. Therefore, miR-21 can act as a fine tuner in the regulation of PTEN/Akt pathway transduction in the expansion of CCR6(+) Tregs in tumor sites and provided a novel insight into the development of therapeutic strategies for promoting T-cell immunity by regulating distinct subset of Tregs through targeting specific miRNAs. PMID:25735723

  12. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1

    PubMed Central

    Au Yeung, Chi Lam; Co, Ngai-Na; Tsuruga, Tetsushi; Yeung, Tsz-Lun; Kwan, Suet-Ying; Leung, Cecilia S.; Li, Yong; Lu, Edward S.; Kwan, Kenny; Wong, Kwong-Kwok; Schmandt, Rosemarie; Lu, Karen H.; Mok, Samuel C.

    2016-01-01

    Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer. PMID:27021436

  13. Sequential co-delivery of miR-21 inhibitor followed by burst release doxorubicin using NIR-responsive hollow gold nanoparticle to enhance anticancer efficacy.

    PubMed

    Ren, Yu; Wang, Ruirui; Gao, Lizhang; Li, Ke; Zhou, Xuan; Guo, Hua; Liu, Chaoyong; Han, Donglin; Tian, Jianguo; Ye, Qing; Hu, Ye Tony; Sun, Duxin; Yuan, Xubo; Zhang, Ning

    2016-04-28

    Previous literature and our study showed the delivery sequence of microRNA inhibitor and chemotherapeutic compounds achieve distinct therapeutic anticancer efficacy. Yet, it is challenging to use nanoparticle to achieve sequential drug delivery. In the current study, we designed sequential co-delivery system using a near-infrared-radiation (NIR) responsive hollow gold nanoparticle (HGNPs) to achieve sequential release of microRNA inhibitor (miR-21i)/doxirubicin(Dox) in order to achieve synergistic efficacy. PAMAM modified HGNPs was used to encapsulate miR-21i and Dox. Upon entering tumor cells, miRNA-21i was released first to sensitize the cancer cells, the subsequent burst release of Dox was achieved by NIR triggered collapse of HGNPs. This sequential delivery of miRNA-21i and Dox produced a synergistic apoptotic response, thereby enhancing anticancer efficacy by 8-fold and increasing anti-cancer stem cell activity by 50-fold. The sequential delivery of miR-21i and Dox using HGNPs under NIR after intravenous administration showed high tumor accumulation and significantly improved efficacy, which was 4-fold compared to free Dox group. These data suggested that the sequential co-delivery of miR-21i followed by burst release Dox using NIR-responsive HGNPs sensitized cancer cells to chemotherapeutic compound, which provided a novel concept for co-delivery miRNA inhibitors and chemotherapeutic compounds to enhance their efficacy. PMID:26956593

  14. miR-21-5p renal expression is associated with fibrosis and renal survival in patients with IgA nephropathy

    PubMed Central

    Hennino, Marie-Flore; Buob, David; Van der Hauwaert, Cynthia; Gnemmi, Viviane; Jomaa, Zacharie; Pottier, Nicolas; Savary, Grégoire; Drumez, Elodie; Noël, Christian; Cauffiez, Christelle; Glowacki, François

    2016-01-01

    IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis, whose prognosis is highly variable. Interstitial fibrosis is a strong independent prognosis factor. Among microRNA involved in renal fibrogenesis, only few have been investigated in IgAN. In the context of IgAN, we aimed to analyze the role of miR-21-5p, miR-214-3p and miR-199a-5p, three established “fibromiRs” involved in renal fibrosis. Fifty-six IgAN biopsy specimens were retrospectively scored according to Oxford classification. Renal expression of miR-21-5p, miR-214-3p and miR-199a-5p were significantly associated with T score (miR-21-5p T0 RQ median = 1.23, T1 RQ = 3.01, T2 RQ = 3.90; miR-214-5p T0 RQ = 1.39, T1 RQ = 2.20, T2 RQ = 2.48; miR-199a-5p T0 RQ = 0.76, T1 RQ = 1.41, T2 RQ = 1.87). miR-21-5p expression was associated with S score (S0 RQ median = 1.31, S1 RQ = 2.65), but not miR-214-3p nor miR-199a-5p. In our cohort, poor renal survival was associated with high blood pressure, proteinuria and elevated creatininemia, as well as T and S scores. Moreover, renal expression of miR-21-5p, miR-214-3p were associated with renal survival. In conclusion, miR-21-5p, miR-214-3p and miR-199a-5p are three “fibromiRs” involved in renal fibrosis in the course of IgAN and miR-21-5p and miR-214-3p are associated with renal survival. PMID:27264483

  15. miR-21-5p renal expression is associated with fibrosis and renal survival in patients with IgA nephropathy.

    PubMed

    Hennino, Marie-Flore; Buob, David; Van der Hauwaert, Cynthia; Gnemmi, Viviane; Jomaa, Zacharie; Pottier, Nicolas; Savary, Grégoire; Drumez, Elodie; Noël, Christian; Cauffiez, Christelle; Glowacki, François

    2016-01-01

    IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis, whose prognosis is highly variable. Interstitial fibrosis is a strong independent prognosis factor. Among microRNA involved in renal fibrogenesis, only few have been investigated in IgAN. In the context of IgAN, we aimed to analyze the role of miR-21-5p, miR-214-3p and miR-199a-5p, three established "fibromiRs" involved in renal fibrosis. Fifty-six IgAN biopsy specimens were retrospectively scored according to Oxford classification. Renal expression of miR-21-5p, miR-214-3p and miR-199a-5p were significantly associated with T score (miR-21-5p T0 RQ median = 1.23, T1 RQ = 3.01, T2 RQ = 3.90; miR-214-5p T0 RQ = 1.39, T1 RQ = 2.20, T2 RQ = 2.48; miR-199a-5p T0 RQ = 0.76, T1 RQ = 1.41, T2 RQ = 1.87). miR-21-5p expression was associated with S score (S0 RQ median = 1.31, S1 RQ = 2.65), but not miR-214-3p nor miR-199a-5p. In our cohort, poor renal survival was associated with high blood pressure, proteinuria and elevated creatininemia, as well as T and S scores. Moreover, renal expression of miR-21-5p, miR-214-3p were associated with renal survival. In conclusion, miR-21-5p, miR-214-3p and miR-199a-5p are three "fibromiRs" involved in renal fibrosis in the course of IgAN and miR-21-5p and miR-214-3p are associated with renal survival. PMID:27264483

  16. MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes

    PubMed Central

    Yan, Li; Cao, Rui; Liu, YuanBo; Wang, LianZhao; Pan, Bo; Lv, XiaoYan; Jiao, Hu; Zhuang, Qiang; Sun, XueJian; Xiao, Ran

    2016-01-01

    Keloid is the abnormal wound healing puzzled by the aggressive growth and high recurrence rate due to its unrevealed key pathogenic mechanism. MicroRNAs contribute to a series of biological processes including epithelial-mesenchymal transition (EMT) and cells stemness involved in fibrotic disease. Here, using microRNAs microarray analysis we found mir-21-5p was significantly up-regulated in keloid epidermis. To investigate the role of miR-21-5p in keloid pathogenesis, we transfected miR-21-5p mimic or inhibitor in keloid keratinocytes and examined the abilities of cell proliferation, apoptosis, migration and invasion, the expressions of EMT-related markers vimentin and E-cadherin and stem-like cells-associated markers CD44 and ALDH1, and the involvement of PTEN and the signaling of AKT and ERK. Our results demonstrated that up-regulation or knockdown of miR-21-5p significantly increased or decreased the migration, invasion and sphere-forming abilities of keloid keratinocytes, and the phenotype of EMT and cells stemness were enhanced or reduced as well. Furthermore, PTEN and p-AKT were shown to participate in the regulation of miR-21-5p on EMT phenotypes and stemness signatures of keloid keratinocytes, which might account for the invasion and recurrence of keloids. This molecular mechanism of miR-21-5p on keloid keratinocytes linked EMT with cells stemness and implicated novel therapeutic targets for keloids. PMID:27596120

  17. Detection of Drug-Induced Acute Kidney Injury in Humans Using Urinary KIM-1, miR-21, -200c, and -423.

    PubMed

    Pavkovic, Mira; Robinson-Cohen, Cassianne; Chua, Alicia S; Nicoara, Oana; Cárdenas-González, Mariana; Bijol, Vanesa; Ramachandran, Krithika; Hampson, Lucy; Pirmohamed, Munir; Antoine, Daniel J; Frendl, Gyorgy; Himmelfarb, Jonathan; Waikar, Sushrut S; Vaidya, Vishal S

    2016-07-01

    Drug-induced acute kidney injury (AKI) is often encountered in hospitalized patients. Although serum creatinine (SCr) is still routinely used for assessing AKI, it is known to be insensitive and nonspecific. Therefore, our objective was to evaluate kidney injury molecule 1 (KIM-1) in conjunction with microRNA (miR)-21, -200c, and -423 as urinary biomarkers for drug-induced AKI in humans. In a cross-sectional cohort of patients (n = 135) with acetaminophen (APAP) overdose, all 4 biomarkers were significantly (P < .004) higher not only in APAP-overdosed (OD) patients with AKI (based on SCr increase) but also in APAP-OD patients without clinical diagnosis of AKI compared with healthy volunteers. In a longitudinal cohort of patients with malignant mesothelioma receiving intraoperative cisplatin (Cp) therapy (n = 108) the 4 biomarkers increased significantly (P < .0014) over time after Cp administration, but could not be used to distinguish patients with or without AKI. Evidence for human proximal tubular epithelial cells (HPTECs) being the source of miRNAs in urine was obtained first, by in situ hybridization based confirmation of increase in miR-21 expression in the kidney sections of AKI patients and second, by increased levels of miR-21, -200c, and -423 in the medium of cultured HPTECs treated with Cp and 4-aminophenol (APAP degradation product). Target prediction analysis revealed 1102 mRNA targets of miR-21, -200c, and -423 that are associated with pathways perturbed in diverse pathological kidney conditions. In summary, we report noninvasive detection of AKI in humans by combining the sensitivity of KIM-1 along with mechanistic potentials of miR-21, -200c, and -423. PMID:27122240

  18. Effects of exercise training together with tamoxifen in reducing mammary tumor burden in mice: Possible underlying pathway of miR-21.

    PubMed

    Khori, Vahid; Amani Shalamzari, Sadegh; Isanejad, Amin; Alizadeh, Ali Mohammad; Alizadeh, Shaban; Khodayari, Saeed; Khodayari, Hamid; Shahbazi, Shirin; Zahedi, Ali; Sohanaki, Hamid; Khaniki, Mahmood; Mahdian, Reza; Saffari, Mojtaba; Fayad, Raja

    2015-10-15

    Exercise training has an anti-tumor effect and can reduce tumor growth; however, the exact underlying mechanisms of its protective effects are still obscure. MicroRNA (miR)-21 is a predictor in cancer survival, and has a potential use as an indicator of therapeutic outcome in breast malignancies. Forty-eight female BALB/c mice were equally divided into six groups to investigate the effects of interval exercise training with tamoxifen on miR-21 expression and its possible assumed mechanisms in an estrogen receptor-positive breast cancer model. ELISA, immunohistochemistry, western blot, qRT-PCR assays were performed at the end of the study. Tumor size was significantly declined in exercise training and tamoxifen groups compared to tumor group (P<0.05). Expression of miR-21 was significantly down-regulated in trained and tamoxifen treated mice in comparison with tumor group (P<0.05). Exercise training was as effective as tamoxifen treatment in decreasing serum estradiol and ER-α expression (P<0.05). Exercise training and tamoxifen reduced tumor IL-6 levels, NF-kB and STAT3 expressions, and up-regulated TPM1 and PDCD4 expressions (P<0.05). Both exercise and tamoxifen had synergistic effects in reducing miR-21 and Bcl-2, and up-regulating PDCD4 expression. Results showed that interval exercise training may reduce mammary tumor burden in mice through possible underlying pathway of miR-21. PMID:26300395

  19. MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes.

    PubMed

    Yan, Li; Cao, Rui; Liu, YuanBo; Wang, LianZhao; Pan, Bo; Lv, XiaoYan; Jiao, Hu; Zhuang, Qiang; Sun, XueJian; Xiao, Ran

    2016-01-01

    Keloid is the abnormal wound healing puzzled by the aggressive growth and high recurrence rate due to its unrevealed key pathogenic mechanism. MicroRNAs contribute to a series of biological processes including epithelial-mesenchymal transition (EMT) and cells stemness involved in fibrotic disease. Here, using microRNAs microarray analysis we found mir-21-5p was significantly up-regulated in keloid epidermis. To investigate the role of miR-21-5p in keloid pathogenesis, we transfected miR-21-5p mimic or inhibitor in keloid keratinocytes and examined the abilities of cell proliferation, apoptosis, migration and invasion, the expressions of EMT-related markers vimentin and E-cadherin and stem-like cells-associated markers CD44 and ALDH1, and the involvement of PTEN and the signaling of AKT and ERK. Our results demonstrated that up-regulation or knockdown of miR-21-5p significantly increased or decreased the migration, invasion and sphere-forming abilities of keloid keratinocytes, and the phenotype of EMT and cells stemness were enhanced or reduced as well. Furthermore, PTEN and p-AKT were shown to participate in the regulation of miR-21-5p on EMT phenotypes and stemness signatures of keloid keratinocytes, which might account for the invasion and recurrence of keloids. This molecular mechanism of miR-21-5p on keloid keratinocytes linked EMT with cells stemness and implicated novel therapeutic targets for keloids. PMID:27596120

  20. Upregulation of miR-21 by Ghrelin Ameliorates Ischemia/Reperfusion-Induced Acute Kidney Injury by Inhibiting Inflammation and Cell Apoptosis.

    PubMed

    Zhang, Wanzhe; Shu, Liliang

    2016-08-01

    Renal ischemia-reperfusion (I/R) injury can be caused by cardiac surgery, renal vascular obstruction, and kidney transplantation, mainly leading to acute kidney injury (AKI), which is complicated by lack of effective preventative and therapeutic strategies. Ghrelin has recently been reported to possess anti-inflammatory properties in several types of cells; however, little attention has been given to the role of ghrelin in I/R-induced AKI. The aim of this study is to explore the role of ghrelin in I/R-induced AKI. In this study, an I/R-induced rat AKI model and a hypoxia-induced NRK-52E cell I/R model were successfully constructed. Ghrelin expression was increased significantly in these rat and cell models. After enhancing ghrelin level by injecting exogenous ghrelin into rats or transfecting a ghrelin-pcDNA3.1 vector into renal tubular epithelial cells, we observed that I/R-induced AKI can be ameliorated by ghrelin, as shown by alterations in histology, as well as changes in serum creatinine (SCr) level, cell apoptosis, and the levels of inflammatory factors. Based on the importance of microRNA-21 (miR-21) in renal disease and the modulation effect of ghrelin on miR-21 in gastric epithelial cells, we tested whether miR-21 participates in the protective effect of ghrelin on I/R-induced AKI. Ghrelin could upregulate the PI3K/AKT signaling pathway by increasing the miR-21 level, which led to the protective effect of ghrelin on I/R-induced AKI by inhibiting the inflammatory response and renal tubular epithelial cell apoptosis. Our research identifies that ghrelin can ameliorate I/R-induced AKI by upregulating miR-21, which advances the understanding of mechanisms by which ghrelin ameliorates I/R-induced AKI. PMID:27152763

  1. Formulation of Anti-miR-21 and 4-Hydroxytamoxifen Co-loaded Biodegradable Polymer Nanoparticles and Their Antiproliferative Effect on Breast Cancer Cells

    PubMed Central

    2015-01-01

    Breast cancer is the second leading cause of cancer-related death in women. The majority of breast tumors are estrogen receptor-positive (ER+) and hormone-dependent. Neoadjuvant anti-estrogen therapy has been widely employed to reduce tumor mass prior to surgery. Tamoxifen is a broadly used anti-estrogen for early and advanced ER+ breast cancers in women and the most common hormone treatment for male breast cancer. 4-Hydroxytamoxifen (4-OHT) is an active metabolite of tamoxifen that functions as an estrogen receptor antagonist and displays higher affinity for estrogen receptors than that of tamoxifen and its other metabolites. MicroRNA-21 (miR-21) is a small noncoding RNA of 23 nucleotides that regulates several apoptotic and tumor suppressor genes and contributes to chemoresistance in numerous cancers, including breast cancer. The present study investigated the therapeutic potential of 4-OHT and anti-miR-21 coadministration in an attempt to combat tamoxifen resistance, a common problem often encountered in anti-estrogen therapy. A biodegradable poly(d,l-lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG-COOH) copolymer was utilized as a carrier to codeliver 4-OHT and anti-miR-21 to ER+ breast cancer cells. 4-OHT and anti-miR-21 co-loaded PLGA-b-PEG nanoparticles (NPs) were developed using emulsion-diffusion evaporation (EDE) and water-in-oil-in-water (w/o/w) double emulsion methods. The EDE method was found to be best method for 4-OHT loading, and the w/o/w method proved to be more effective for coloading NPs with anti-miR-21 and 4-OHT. The optimal NPs, which were prepared using the double emulsion method, were evaluated for their antiproliferative and apoptotic effects against MCF7, ZR-75-1, and BT-474 human breast cancer cells as well as against 4T1 mouse mammary carcinoma cells. We demonstrated that PLGA-b-PEG NP encapsulation significantly extended 4-OHT’s stability and biological activity compared to that of free 4-OHT. MTT assays indicated that

  2. The expression of miR-21 and miR-143 is deregulated by the HPV16 E7 oncoprotein and 17β-estradiol.

    PubMed

    Gómez-Gómez, Yazmín; Organista-Nava, Jorge; Ocadiz-Delgado, Rodolfo; García-Villa, Enrique; Leyva-Vazquez, Marco Antonio; Illades-Aguiar, Berenice; Lambert, Paul F; García-Carrancá, Alejandro; Gariglio, Patricio

    2016-08-01

    MicroRNAs (miRNAs) are a class of non-coding RNAs that negatively regulate their target mRNAs at a posttranscriptional level, thereby affecting crucial processes in cancer development. However, little is known about the molecular events that control expression of miRNAs in cervical cancer (CC). HPV16 E7 oncoprotein in conjunction with estrogen are sufficient to produce high grade cervical dysplasia and invasive cervical malignancies in a mouse model. In the present study, we determined the potential role that the E7 oncoprotein and 17β-estradiol (E2) play in the deregulation of miR-21 and miR-143 expression levels by these two risk factors. We found that, while the expression of miR-21 was upregulated and the expression of miR-143 was downregulated by the HPV16 E7 oncoprotein in vivo, and in vitro and that E2 treatment is also implicated in the deregulation of these important miRNAs in vivo. Sustained upregulation of miR-21 resulted in suppression of PTEN expression, and repression of miR-143 increased the mRNA and protein levels from Bcl-2. These results suggested that HPV type 16 E7 oncoprotein and E2 play an important role in regulating miR-21 and miR-143 expression. We have observed similar results in CC patients containing HPV16 sequences, suggesting that these miRNAs could serve as diagnostic biomarkers in CC. The present study highlights the roles of miRNAs in cervical tissue and implicates these important molecules in cervical carcinogenesis. PMID:27278606

  3. Differential expression of miR200a-3p and miR21 in grade II–III and grade IV gliomas

    PubMed Central

    Berthois, Yolande; Delfino, Christine; Metellus, Philippe; Fina, Frederic; Nanni-Metellus, Isabelle; Al Aswy, Hayat; Pirisi, Victor; Ouafik, L’Houcine; Boudouresque, Françoise

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain tumor and is among the deadliest of human cancers. Dysregulation of microRNAs (miRNAs) expression is an important step in tumor progression as miRNAs can act as tumor suppressors or oncogenes and may affect cell sensitivity to chemotherapy. Whereas the oncogenic miR21 has been shown to be overexpressed in gliomas, the expression and function of the tumor-supressor miR200a in GBMs remains unknown. In this study, we show that miR21 is upregulated in grade IV (GBMs) vs. grade II–III (LGs) gliomas, confirming that miR21 expression level is correlated with tumor grade, and that it may be considered as a marker of tumor progression. Conversely, miR200a is demonstrated for the first time to be downregulated in GBMs compared with LGs, and overexpression of miR200a in GBM cells is shown to promote TMZ-sensitivity. Interestingly, miR200a but not miR21 expression level is significantly higher in TMZ-responsive vs. -unresponsive tumoral glial cells in primary culture. Furthermore, miR200a appears negatively correlated with the expression of the DNA repair enzyme O6-methylguanine methyltransferase (MGMT), and the inhibition of MGMT activity results in an increase of miR200a expression in GBM cells. Taken together, these data strongly suggest that miR200a is likely to act as a crucial antitumoral factor regarding glioma progression. Interplay between miR200a and MGMT should be considered as potential mechanism involved in therapeutic response. PMID:24755707

  4. Aberrant expression of miR-127, miR-21 and miR-16 in placentas of deceased cloned sheep.

    PubMed

    Ni, Wei; You, Shuang; Cao, Yang; Li, Cunyuan; Wei, Junchuang; Wang, Dawei; Qiao, Jun; Zhao, Xinxia; Hu, Shengwei; Quan, Renzhe

    2016-04-01

    Placental deficiencies are associated with developmental abnormalities of animal produced by somatic cell nuclear transfer (SCNT). It is reported that aberrant expression of microRNAs (miRNAs) in the common placenta is associated with fetal growth restriction and placental deficiencies. However, an understanding of the expression and function of miRNAs in the placentas of cloned animal is lacking. In this study, we characterized the expression of five growth-associated miRNAs (miR-127, miR-16, miR-21, miR-93 and miR-182) in placentas of deceased transgenic cloned sheep (deceased group, n=7), live transgenic cloned sheep (live group, n=5) and conventionally produced sheep (control group, n=10). Expression levels of miR-127 (P<0.01), miR-21 (P<0.01) and miR-16 (P<0.05) were significantly up-regulated in the placentas of deceased group compared to that of control group. In contrast, the expression of these miRNAs was largely normal in the placentas of live group, except for the expression of miR-21. Furthermore, we confirmed that retrotransposon-like gene (Rtl1), a key gene in placental development, was down-regulated by miR-127 as a target in placenta cells. Our results suggested that the abnormal expression of miR-127, miR-21 and miR-16 in placentas of deceased sheep, through dysregulation of target genes, may result in developmental deficiencies of transgenic cloned sheep. PMID:27033933

  5. Effect of Corilagin on the miR-21/smad7/ERK signaling pathway in a schistosomiasis-induced hepatic fibrosis mouse model.

    PubMed

    Yang, Fan; Wang, Yao; Xue, Jun; Ma, Qian; Zhang, Juan; Chen, Yun-Fei; Shang, Zhen-Zhong; Li, Quan-Qiang; Zhang, Shu-Ling; Zhao, Lei

    2016-08-01

    This study sought to investigate the anti-fibrotic effect of Corilagin via interference with the miR-21/smad7/ERK signaling pathway in a schistosomiasis-induced hepatic fibrosis mouse model. Mice were infected with Schistosoma japonicum cercaria to establish the mouse model of schistosomiasis-induced hepatic fibrosis. At four weeks after infection, the groups were given different medications. The living conditions were observed. Real-time PCR was employed to detect the mRNA levels of miR-21, smad7 and connective tissue growth factor (CTGF), and western blotting was used to examine the protein levels of smad7, CTGF, smad1, p-smad1, smad2, p-smad2, ERK1/2, p-ERK1/2 and TGF-β receptor I. Immunohistochemistry was used to examine the expression of CTGF. Compared with the model group, increasing concentrations of Corilagin improved the quality of life, inhibited the mRNA expression of miR-21, promoted smad7 protein expression, and inhibited CTGF protein expression (p<0.05 or 0.01). Moreover, Corilagin significantly reduced the protein levels of p-smad1, p-smad2, p-ERK1/2, and TGF-β receptor I (p<0.05 or 0.01). CTGF staining in the cytoplasm was markedly decreased by Corilagin (p<0.05 or 0.01). In conclusion, Corilagin inhibited schistosomiasis-induced hepatic fibrosis via the miR21/smad7/ERK pathway in this animal model. PMID:26946098

  6. Aberrant miR-21 and miR-200b expression and its pro-fibrotic potential in hypertrophic scars.

    PubMed

    Zhou, Renpeng; Zhang, Qi; Zhang, Yun; Fu, Shibo; Wang, Chen

    2015-12-10

    The post-traumatic hypertrophic scar (HS) is a fibrotic disease with excessive extracellular matrix (ECM) production by fibroblasts in response to tissue injury. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNA in hypertrophic scar formation is unclear. Abnormal expression of miRNA in fibrosis has been investigated in several studies. The transforming growth factor β1 (TGF-β1) promotes fibroblasts proliferation, the synthesis of collagen and other extracellular matrix, and ultimately leads to the formation of the HS by inducing excessive deposition of ECM. We identified two miRNAs whose expression was correlated with fibrotic diseases: miR-21 and miR-200b. This study further confirmed that after stimulation with TGF-β1, the expression of miR-21 was increased, whereas the mRNA level of SMAD7 was decreased in fibroblasts. TGF-β1 reduced the expression of miR-200b, while it augmented that of Zinc finger E-box-binding homeobox 1(Zeb1). Our experiments demonstrated that the expression of miR-21 and miR-200b are related to a disorder, and the TGF-β/miR-21/Smad7 and TGF-β/miR200b/Zeb1 pathways might participate in the pathogenesis of HS. Thus, a novel, beyond the traditional methods, approach for HS treatment via miRNA therapeutics could have been provided. PMID:26500110

  7. Gemcitabine Sensitivity Can Be Induced in Pancreatic Cancer Cells through Modulation of miR-200 and miR-21 Expression by Curcumin or Its Analogue CDF

    PubMed Central

    Ali, Shadan; Ahmad, Aamir; Banerjee, Sanjeev; Padhye, Subhash; Dominiak, Kristin; Schaffert, Jacqueline M.; Wang, Zhiwei; Philip, Philip A.; Sarkar, Fazlul H.

    2010-01-01

    Curcumin induces cancer cell growth arrest and apoptosis in vitro, but its poor bioavailability in vivo limits its antitumor efficacy. We have previously evaluated the bioavailability of novel analogues of curcumin compared with curcumin, and we found that the analogue CDF exhibited greater systemic and pancreatic tissue bioavailability. In this study, we evaluated the effects of CDF or curcumin alone or in combination with gemcitabine on cell viability and apoptosis in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer (PC) cell lines. Mechanistic investigations revealed a significant reduction in cell viability in CDF-treated cells compared with curcumin-treated cells, which were also associated with the induction of apoptosis, and these results were consistent with the downregulation of Akt, cyclooxygenase-2, prostaglandin E2, vascular endothelial growth factor, and NF-κB DNA binding activity. We have also documented attenuated expression of miR-200 and increased expression of miR-21 (a signature of tumor aggressiveness) in gemcitabine-resistant cells relative to gemcitabine-sensitive cells. Interestingly, CDF treatment upregulated miR-200 expression and downregulated the expression of miR-21, and the downregulation of miR-21 resulted in the induction of PTEN. These results prompt further interest in CDF as a drug modality to improve treatment outcome of patients diagnosed with PC as a result of its greater bioavailability in pancreatic tissue. PMID:20388782

  8. Down-regulation of miR-21 Induces Differentiation of Chemoresistant Colon Cancer Cells and Enhances Susceptibility to Therapeutic Regimens.

    PubMed

    Yu, Yingjie; Sarkar, Fazlul H; Majumdar, Adhip P N

    2013-04-01

    MicroRNAs are endogenous posttranscriptional modulators that negatively control the expression of their target genes and play an important role in the development and progression of many malignancies, including colorectal carcinoma. In particular, expression of microRNA-21 (miR-21) is greatly increased in chemotherapy-resistant (CR) colon cancer cells that are enriched in undifferentiated cancer stem/stem-like cells (CSCs/CSLCs). We hypothesize that miR-21 plays a critical role in regulating differentiation of CR colon cancer cells. Indeed, we observed that downregulation of miR-21 in CR colon cancer cells (HCT-116 or HT-29) by antisense miR-21 induced differentiation, as evidenced by marked increases in cytokeratin-20 (CK-20) expression and alkaline phosphatase activity. These changes were accompanied by a significant reduction in the expression of colon CSC/CSLC marker CD44, colonosphere formation, and T-cell factor/lymphoid enhancer factor (TCF/LEF) activity but increased the expression of proapoptotic programmed cell death 4 gene. Induction of differentiation greatly increased sensitivity of CR colon cancer cells to the growth inhibitory properties of all three regimens tested: 5-fluorouracil + oxaliplatin (FUOX), difluorinated curcumin (CDF), and the combination of CDF and FUOX. However, the magnitude of inhibition of growth by either CDF (75%) alone or CDF + FUOX (80%) was much higher than that observed with only FUOX (40%). Growth inhibition by CDF and CDF + FUOX in differentiating CR colon cancer cells was associated with a 98% to 99% reduction in the expression of CD44 and epidermal growth factor receptor (EGFR). However, down-regulation of CK-20 in CR colon cancer cells produced no significant change in cellular growth in the absence or presence of FUOX, when compared with the corresponding controls. The current observation suggests that CDF and CDF + FUOX are highly effective in inhibiting growth and reducing colon CSCs/CSLCs in anti-miR-21-induced

  9. Differential regulation of miR-146a/FAS and miR-21/FASLG axes in autoimmune lymphoproliferative syndrome due to FAS mutation (ALPS-FAS).

    PubMed

    Marega, Lia Furlaneto; Teocchi, Marcelo Ananias; Dos Santos Vilela, Maria Marluce

    2016-08-01

    Most cases of autoimmune lymphoproliferative syndrome (ALPS) have an inherited genetic defect involving apoptosis-related genes of the FAS pathway. MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs playing a role in the control of gene expression. This is the first report on miRNAs in ALPS patients. We studied a mother and son carrying the same FAS cell surface death receptor (FAS) mutation, but with only the son manifesting the signs and symptoms of ALPS-FAS. The aim was to analyse, by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), the peripheral blood mononuclear cells (PBMC) relative expression of miR-146a and miR-21, including their passenger strands and respective targets (FAS and FASLG). In comparison with healthy matched control individuals, miR-21-3p was over-expressed significantly (P = 0·0313) in the son, with no significant change in the expression of miR-146a, miR-146a-3p and miR-21. In contrast, the mother had a slight under-expression of the miR-146a pair and miR-21-3p (P = 0·0625). Regarding the miRNA targets, FAS was up-regulated markedly for the mother (P = 0·0078), but down-regulated for the son (P = 0·0625), while FASLG did not have any significant alteration. Taken together, our finding clearly suggests a role of the miR-146a/FAS axis in ALPS-FAS variable expressivity in which FAS haploinsufficiency seems to be compensated only in the mother who had the miR-146a pair down-regulated. As only the son had the major clinical manifestations of ALPS-FAS, miR-21-3p should be investigated as playing a critical role in ALPS physiopathology, including the development of lymphoma. PMID:27060458

  10. Up-regulation of miR-21 and miR-23a Contributes to As2 O3 -induced hERG Channel Deficiency.

    PubMed

    Zhao, Xin; Shi, Yuan-Qi; Yan, Cai-Chuan; Feng, Pan-feng; Wang, Xue; Zhang, Rui; Zhang, Xiao; Li, Bao-Xin

    2015-06-01

    Arsenic trioxide (As2O3) is used to treat acute pro-myelocytic leukaemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As2O3 can damage the hERG current via disturbing its trafficking to cellular membrane. Consistent with these findings, in this study, we reported that As2O3 inhibited hERG channel at both protein and mRNA levels and damaged hERG current but did not affect channel kinetics. Further, we demonstrated that As2O3 up-regulated miR-21 and miR-23a expression in hERG-HEK293 cells and neonatal cardiomyocytes. In addition, knock-down of miR-21 by its specific antisense molecules AMO-21 was able to rescue Sp1 and hERG inhibition caused by As2O3. Consistently, phosphorylation of NF-κB, the upstream regulatory factor of miR-21, was significantly up-regulated by As2O3 . This finding revealed that regulation of the NF-κB-miR-21-Sp1 signalling pathway is a novel mechanism for As2O3-induced hERG inhibition. Meanwhile, the expression of Hsp90 and hERG was rescued by transfection with AMO-23a. And the hERG channel inhibition induced by As2O3 was rescued after being transfected with AMO-23a, which may be a molecular mechanism for the role of As2O3 in hERG trafficking deficiency. In brief, our study revealed that miR-21 and miR-23a are involved in As2O3-induced hERG deficiency at transcriptional and transportational levels. This discovery may provide a novel mechanism of As2O3-induced hERG channel deficiency, and these miRNAs may serve as potential therapeutic targets for the handling of As2O3 cardiotoxicity. PMID:25395240

  11. AC1MMYR2 impairs high dose paclitaxel-induced tumor metastasis by targeting miR-21/CDK5 axis.

    PubMed

    Ren, Yu; Zhou, Xuan; Yang, Juan-Juan; Liu, Xia; Zhao, Xiao-hui; Wang, Qi-xue; Han, Lei; Song, Xin; Zhu, Zhi-yan; Tian, Wei-ping; Zhang, Lun; Mei, Mei; Kang, Chun-sheng

    2015-07-01

    Paclitaxel (taxol) is a widely used chemo-drug for many solid tumors, while continual taxol treatment is revealed to stimulate tumor dissemination. We previously found that a small molecule inhibitor of miR-21, termed AC1MMYR2, had the potential to impair tumorigenesis and metastasis. The aim of this study was to investigate whether combining AC1MMYR2 with taxol could be explored as a means to limit tumor metastasis. Here we showed that abnormal activation of miR-21/CDK5 axis was associated with breast cancer lymph node metastasis, which was also contribute to high dose taxol-induced invasion and epithelial mesenchymal transition (EMT) in both breast cancer cell line MDA-MB-231 and glioblastoma cell line U87VIII. AC1MMYR2 attenuated CDK5 activity by functional targeting CDK5RAP1, CDK5 activator p39 and target p-FAK(ser732). A series of in vitro assays indicated that treatment of AC1MMYR2 combined with taxol suppressed tumor migration and invasion ability in both MDA-MB-231 and U87VIII cell. More importantly, combination therapy impaired high-dose taxol induced invadopodia, and EMT markers including β-catenin, E-cadherin and vimentin. Strikingly, a significant reduction of lung metastasis in mice was observed in the AC1MMYR2 plus taxol treatment. Taken together, our work demonstrated that AC1MMYR2 appeared to be a promising strategy in combating taxol induced cancer metastasis by targeting miR-21/CDK5 axis, which highlighted the potential for development of therapeutic modalities for better clinic taxol application. PMID:25827073

  12. microRNA fingerprinting of CLL patients with chromosome 17p deletion identify a miR-21 score that stratifies early survival

    PubMed Central

    Rossi, Simona; Shimizu, Masayoshi; Barbarotto, Elisa; Nicoloso, Milena S.; Dimitri, Federica; Sampath, Deepa; Fabbri, Muller; Lerner, Susan; Barron, Lynn L.; Rassenti, Laura Z.; Jiang, Li; Xiao, Lianchun; Hu, Jianhua; Secchiero, Paola; Zauli, Giorgio; Volinia, Stefano; Negrini, Massimo; Wierda, William; Kipps, Thomas J.; Plunkett, William; Coombes, Kevin R.; Abruzzo, Lynne V.

    2010-01-01

    Aberrant expression of microRNAs (miRNAs) has been associated with clinical outcome in patients with chronic lymphocytic leukemia (CLL). To identify a powerful and easily assessable miRNA bio-marker of prognosis and survival, we performed quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling in 104 CLL patients with a well-defined chromosome 17p status, and we validated our findings with miRNA microarray data from an independent cohort of 80 patients. We found that miR-15a, miR-21, miR-34a, miR-155, and miR-181b were differentially expressed between CLLs with chromosome 17p deletion and CLLs with normal 17p and normal karyotype, and that miR-181b was down-regulated in therapy-refractory cases. miR-21 expression levels were significantly higher in patients with poor prognosis and predicted overall survival (OS), and miR-181b expression levels significantly predicted treatment-free survival. We developed a 21FK score (miR-21 qRT-PCR, fluorescence in situ hybridization, Karyotype) to stratify patients according to OS and found that patients with a low score had a significantly longer OS time. When we evaluated the relative power of the 21FK score with the most used prognostic factors, the score was the most significant in both CLL cohorts. We conclude that the 21FK score represents a useful tool for distinguishing between good-prognosis and poor-prognosis CLL patients. PMID:20393129

  13. Up-regulation of miR-21 and 146a expression and increased DNA damage frequency in a mouse model of polycystic ovary syndrome (PCOS)

    PubMed Central

    Salimi-Asl, Mohammad; Mozdarani, Hossein; Kadivar, Mehdi

    2016-01-01

    Introduction: Polycystic ovary syndrome (PCOS), a multigenic endocrine disorder, is highly associated with low-grade chronic inflammation, however its etiology remains unclear. In this study, we employed dehydroepiandrosterone (DHEA)-treated mice to reveal the molecular mechanism of inflammation and its correlation with oxidative stress in PCOS patients. Methods: miR-21 and miR-146a expression levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). DNA strand breakage frequency was measured using the single cell gel electrophoresis (SCGE) assay (comet assay) and micronucleus test (MN). CRP levels were measured by ELISA method and ESR values were measured by means of Micro-Dispette (Fisher No: 02-675-256) tubes according to the manufacturer’s instructions. Data were analyzed using one-way ANOVA in SPSS 21.0 software. Results: Our results showed that miR-21 and miR-146a as inflammation markers were upregulated in the sample group in comparison with control group. Erythrocyte sedimentation rate (ESR) and C- reactive protein (CRP) levels were also increased in mouse models of PCOS (p < 0.000). Micronucleated polychromatic erythrocyte (MNPCE) rates per 1000 polychromatic erythrocyte (PCE) significantly increased in DHEA treated mice (6.22 ± 3.28) in comparison with the controls (2.33 ± 2.23, p < 0.000). Moreover, mean arbitrary unit in DHEA treated animals (277 ± 92) was significantly higher than that in controls (184 ± 76, p = 0.005). Conclusion: To conclude, increased DNA strand breakage frequency and increased expression levels of miR-21 and miR-146a in DHEA administrated animals suggest that low grade chronic inflammation and oxidative stress can act as the main etiologies of PCOS. PMID:27525225

  14. FZD6, targeted by miR-21, represses gastric cancer cell proliferation and migration via activating non-canonical wnt pathway

    PubMed Central

    Yan, Jin; Liu, Tingyu; Zhou, Xiaoying; Dang, Yini; Yin, Chengqiang; Zhang, Guoxin

    2016-01-01

    FZD6 plays crucial roles in human tumorigenesis. However, its mechanism in regulating cancers has not been fully elucidated. In the study, we found that FZD6 repressed gastric cancer cell proliferation and migration via activating non-canonical wnt pathway. In addition, non-canonical wnt pathway ameliorated expression of canonical wnt pathway. We also demonstrated that the FZD6 was involved in miR-21-dependent effects in the canonical and non-canonical wnt pathways in gastric cancer. These findings provide a better understanding of the development and progression of gastric cancer and may be an important implication for future therapy. PMID:27347343

  15. PIK3R1 targeting by miR-21 suppresses tumor cell migration and invasion by reducing PI3K/AKT signaling and reversing EMT, and predicts clinical outcome of breast cancer

    PubMed Central

    YAN, LI-XU; LIU, YAN-HUI; XIANG, JIAN-WEN; WU, QI-NIAN; XU, LEI-BO; LUO, XIN-LAN; ZHU, XIAO-LAN; LIU, CHAO; XU, FANG-PING; LUO, DONG-LAN; MEI, PING; XU, JIE; ZHANG, KE-PING; CHEN, JIE

    2016-01-01

    We have previously shown that dysregulation of miR-21 functioned as an oncomiR in breast cancer. The aim of the present study was to elucidate the mechanisms by which miR-21 regulate breast tumor migration and invasion. We applied pathway analysis on genome microarray data and target-predicting algorithms for miR-21 target screening, and used luciferase reporting assay to confirm the direct target. Thereafter, we investigated the function of the target gene phosphoinositide-3-kinase, regulatory subunit 1 (α) (PIK3R1), and detected PIK3R1 coding protein (p85α) by immunohistochemistry and miR-21 by RT-qPCR on 320 archival paraffin-embedded tissues of breast cancer to evaluate the correlation of their expression with prognosis. First, we found that PIK3R1 suppressed growth, invasiveness, and metastatic properties of breast cancer cells. Next, we identified the PIK3R1 as a direct target of miR-21 and showed that it was negatively regulated by miR-21. Furthermore, we demonstrated that p85α overexpression phenocopied the suppression effects of antimiR-21 on breast cancer cell growth, migration and invasion, indicating its tumor suppressor role in breast cancer. On the contrary, PIK3R1 knockdown abrogated antimiR-21-induced effect on breast cancer cells. Notably, antimiR-21 induction increased p85α, accompanied by decreased p-AKT level. Besides, antimiR-21/PIK3R1-induced suppression of invasiveness in breast cancer cells was mediated by reversing epithelial-mesenchymal transition (EMT). p85α downregulation was found in 25 (7.8%) of the 320 breast cancer patients, and was associated with inferior 5-year disease-free survival (DFS) and overall survival (OS). Taken together, we provide novel evidence that miR-21 knockdown suppresses cell growth, migration and invasion partly by inhibiting PI3K/AKT activation via direct targeting PIK3R1 and reversing EMT in breast cancer. p85α downregulation defined a specific subgroup of breast cancer with shorter 5-year DFS and OS

  16. Inhibition of breast cancer cell motility with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFβ/miR-21 signaling

    PubMed Central

    Ma, Ruixia; Feng, Xiangling; Li, Wei; Piazza, Gary A.; Xi, Yaguang

    2016-01-01

    Compelling efficacy on intervention of tumorigenesis by nonsteroidal anti-inflammatory drugs (NSAIDs) has been documented intensively. However, the toxicities related to cyclooxygenase (COX) inhibition resulting in suppression of physiologically important prostaglandins limit their clinical use for human cancer chemoprevention. A novel derivative of the NSAID sulindac sulfide (SS), referred as sulindac sulfide amide (SSA), was recently developed, which lacks COX inhibitory activity, yet shows greater suppressive effect than SS on growth of various cancer cells. In this study, we focus on the inhibitory activity of SSA on breast tumor cell motility, which has not been studied previously. Our results show that SSA treatment at non-cytotoxic concentrations can specifically reduce breast tumor cell motility without influencing tumor cell growth, and the mechanism of action involves the suppression of TGFβ signaling by directly blocking Smad2/3 phosphorylation. Moreover, miR-21, a well-documented oncogenic miRNA for promoting tumor cell metastasis, was also found to be involved in inhibitory activity of SSA in breast tumor cell motility through the modulation of TGFβ pathway. In conclusion, we demonstrate that a non-COX inhibitory derivative of sulindac can inhibit breast tumor metastasis by a mechanism involving the TGFβ/miR-21 signaling axis. PMID:26769851

  17. Silencing of miR-21 by locked nucleic acid-lipid nanocapsule complexes sensitize human glioblastoma cells to radiation-induced cell death.

    PubMed

    Griveau, A; Bejaud, J; Anthiya, S; Avril, S; Autret, D; Garcion, E

    2013-10-01

    The recent discovery of microRNA (miRNA) as major post-transcriptional repressors prompt the interest of developing novel approaches to target miRNA pathways to improve therapy. In this context, although the most significant barrier to their widespread clinical use remains delivery, nuclease-resistant locked nucleic acid (LNA) that bind specifically and irreversibly to miRNA represent interesting weapons. Thus, by focusing on oncongenic miR-21 miRNA, which participate to cancer cell resistance to apoptotic signals, the aim of the present study was to investigate the possibility of silencing miRNA by LNA conjugated to lipid nanocapsules (LNCs) as miRNA-targeted nanomedicines in U87MG glioblastoma (GBM) cells. After synthesis of an amphiphilic lipopeptide affine for nucleic acids, a post-insertion procedure during the LNC phase inversion formulation process allowed to construct peptide-conjugated LNCs. Peptide-conjugated LNCs were then incubated with LNAs to allow the formation of complexes characterized in gel retardation assays and by their physicochemical properties. U87MG cell treatment by LNA-LNC complexes resulted in a marked reduction of miR-21 expression as assessed by RTqPCR. In addition, exposure of U87MG cells to LNA-LNC complexes followed by external beam radiation demonstrated a significant improvement of cell sensitivity to treatment and emphasizes the interest to investigate further this miRNA-targeted strategy. PMID:23732394

  18. Acupuncture Decreases NF-κB p65, miR-155, and miR-21 and Increases miR-146a Expression in Chronic Atrophic Gastritis Rats

    PubMed Central

    Zhang, Jialing; Huang, Kangbai; Zhong, Guoxin; Huang, Yong; Li, Suhe; Qu, Shanshan; Zhang, Jiping

    2016-01-01

    Acupuncture has been used to treat chronic atrophic gastritis (CAG) in traditional Chinese medicine (TCM) for centuries. In this study, we evaluated the effect of acupuncture at Zusanli (ST36), Zhongwan (CV12), and Pishu (BL20) acupoints on weight changes of rats, histological changes of gastric glands, and expressions changes of nuclear factor-kappa B (NF-κB) p65, microRNA- (miR-) 155, miR-21, and miR-146a in CAG rats induced by N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) combined with irregular diet. Consequently, we found that acupuncture treatment elevated body weight of rats significantly when compared to the model group. By observing histological changes, we found that the acupuncture group showed better improvement of gastric mucosa injury than the model group. Our results also demonstrated upregulation of NF-κB p65, miR-155, and miR-21 in gastric tissue of CAG rats and a positive correlation between miR-155 and miR-21. Relatively, expression of miR-146a was downregulated and negative correlation relationships between miR-146a and miR-155/miR-21 in CAG rats were observed. Additionally, expressions of NF-κB p65, miR-155, and miR-21 were downregulated and miR-146a was upregulated after acupuncture treatment. Taken together, our data imply that acupuncture can downregulate NF-κB p65, miR-155, and miR-21 and upregulate miR-146a expression in CAG rats. NF-κB p65, miR-155, miR-21, and miR-146a may play important roles in therapeutic effect of acupuncture in treating CAG. PMID:27293468

  19. Cell-Penetrating Poly(disulfide) Assisted Intracellular Delivery of Mesoporous Silica Nanoparticles for Inhibition of miR-21 Function and Detection of Subsequent Therapeutic Effects.

    PubMed

    Yu, Changmin; Qian, Linghui; Ge, Jingyan; Fu, Jiaqi; Yuan, Peiyan; Yao, Samantha C L; Yao, Shao Q

    2016-08-01

    The design of drug delivery systems capable of minimal endolysosomal trapping, controlled drug release, and real-time monitoring of drug effect is highly desirable for personalized medicine. Herein, by using mesoporous silica nanoparticles (MSNs) coated with cell-penetrating poly(disulfide)s and a fluorogenic apoptosis-detecting peptide (DEVD-AAN), we have developed a platform that could be uptaken rapidly by mammalian cells via endocytosis-independent pathways. Subsequent loading of these MSNs with small molecule inhibitors and antisense oligonucleotides resulted in intracellular release of these drugs, leading to combination inhibition of endogenous miR-21 activities which was immediately detectable by the MSN surface-coated peptide using two-photon fluorescence microscopy. PMID:27325284

  20. Dicer1 imparts essential survival cues in Notch-driven T-ALL via miR-21-mediated tumor suppressor Pdcd4 repression.

    PubMed

    Junker, Fabian; Chabloz, Antoine; Koch, Ute; Radtke, Freddy

    2015-08-20

    The modulatory function of individual microRNAs (miRNAs) in Notch-driven T-cell acute lymphoblastic leukemias (T-ALLs) has recently been established. Although protumorigenic and tumor-suppressive miRNAs are implicated in disease onset in murine models of Notch-driven T-cell leukemia, whether Dicer1-processed miRNAs are essential for Notch-driven T-ALL is currently unknown. Here we used conditional and inducible genetic loss-of-function approaches to test whether the development and maintenance of Notch-driven T-ALL was dependent on Dicer1 function. Mice with specific inactivation of both Dicer1 alleles in the T-cell lineage did not develop Notch-driven T-ALL. In contrast, loss of 1 functional Dicer1 allele did not significantly perturb T-ALL onset and tumor progression. Inducible inactivation of Dicer1 in early stage polyclonal T-ALL cells was sufficient to abrogate T-ALL progression in leukemic mice, whereas late-stage monoclonal T-ALL cells were counterselected against loss of Dicer1. Lineage-tracing experiments revealed that Dicer1 deficiency led to the induction of apoptosis in T-ALL cells, whereas cell cycle progression remained unaltered. Through microarray-based miRNA profiling, we identified miR-21 as a previously unrecognized miRNA deregulated in both mouse and human T-ALL. Herein, we demonstrate that miR-21 regulates T-ALL cell survival via repression of the tumor suppressor Pdcd4. PMID:25979949

  1. Expression and Localization of microRNAs in Perinatal Rat Pancreas: Role of miR-21 in Regulation of Cholesterol Metabolism

    PubMed Central

    Gaarn, Louise W.; Bagge, Annika; Pedersen, Lykke; Dahmcke, Christina M.; Nielsen, Jens H.; Dalgaard, Louise T.

    2011-01-01

    Objective To investigate the expression of pancreatic microRNAs (miRNAs) during the period of perinatal beta-cell expansion and maturation in rats, determine the localization of these miRNAs and perform a pathway analysis with predicted target mRNAs expressed in perinatal pancreas. Research Design and Methods RNA was extracted from whole pancreas at embryonic day 20 (E20), on the day of birth (P0) and two days after birth (P2) and hybridized to miRNA microarrays. Differentially expressed miRNAs were verified by northern blotting and their pancreatic localization determined by in situ hybridization. Pathway analysis was done using regulated sets of mRNAs predicted as targets of the miRNAs. Possible target genes were tested using reporter-gene analysis in INS-1E cells. Results Nine miRNAs were differentially expressed perinatally, seven were confirmed to be regulated at the level of the mature miRNA. The localization studies showed endocrine localization of six of these miRNAs (miR-21, -23a, -29a, -125b-5p, -376b-3p and -451), and all were expressed in exocrine cells at one time point at least. Pathways involving metabolic processes, terpenoid and sterol metabolism were selectively affected by concomitant regulation by miRNAs and mRNAs, and Srebf1 was validated as a target of miR-21. Conclusions The findings suggest that miRNAs are involved in the functional maturation of pancreatic exocrine and endocrine tissue following birth. Pathway analysis of target genes identify changes in sterol metabolism around birth as being selectively affected by differential miRNA expression during this period. PMID:22022489

  2. Circulating miR-21, miR-378, and miR-940 increase in response to an acute exhaustive exercise in chronic heart failure patients

    PubMed Central

    Das, Saumya; Wang, Lemin; Jiang, Jinfa; Li, Guanghe; Xu, Jiahong; Yao, Jianhua; Wang, Hongbao; Dai, Yue; Xiao, Junjie

    2016-01-01

    Congestive heart failure (CHF) is a major cause of hospitalizations, morbidity, and mortality in Western societies. In addition to optimal medical and device therapy, exercise training is an important adjunct treatment option for CHF patients. MicroRNAs (miRNAs, miRs) participate in a variety of physiological and pathological processes. Dynamic regulation of circulating miRNAs during exercise in healthy persons and athletes has recently been documented, however, the response of circulating miRNAs to exercise in CHF patients is undetermined. Twenty-eight CHF patients underwent a symptom-limited incremental cardiopulmonary exercise test on a bicycle ergometer using a standardized exercise protocol of revised Ramp10 programs at Shanghai Tongji Hospital. Blood samples were collected before and immediately after an acute exercise session. RNA was extracted from the serum and selected miRNAs were determined using quantitative polymerase chain reactions. Moreover, inflammatory and muscle damage markers were determined by enzyme linked immunosorbent assays. We found that serum miR-21, miR-378 and miR-940 levels were significantly up-regulated immediately following an acute exercise while the rest were not changed. In addition, no robust correlation was identified between changes of these miRNAs and exercise capacity, muscle damage or inflammation. In conclusion, serum miR-21, miR-378, and miR-940 increase in response to an acute exhaustive exercise in CHF patients. Further studies are needed to clarify the potential use of circulating miRNAs as biomarkers of exercise adaptation in CHF patients, and if they have any use as prognostic markers of cardiovascular outcomes. PMID:26799589

  3. Arsenic-exposed Keratinocytes Exhibit Differential microRNAs Expression Profile; Potential Implication of miR-21, miR-200a and miR-141 in Melanoma Pathway

    PubMed Central

    Gonzalez, Horacio; Lema, Carolina; Kirken, Robert A.; Maldonado, Rosa A.; Varela-Ramirez, Armando; Aguilera, Renato J.

    2016-01-01

    Long-term exposure to arsenic has been linked to cancer in different organs and tissues, including skin. Here, non-malignant human keratinocytes (HaCaT) were exposed to arsenic and its effects on microRNAs (miRNAs; miR) expression were analyzed via miRCURY LNA array analyses. A total of 30 miRNAs were found differentially expressed in arsenic-treated cells, as compared to untreated controls. Among the up-regulated miRNAs, miR-21, miR-200a and miR-141, are well known to be involved in carcinogenesis. Additional findings confirmed that those three miRNAs were indeed up-regulated in arsenic-stimulated keratinocytes as demonstrated by quantitative PCR assay. Furthermore, bioinformatics analysis of both potential cancer-related pathways and targeted genes affected by miR-21, miR-200a and/or miR-141 was performed. Results revealed that miR-21, miR-200a and miR-141 are implicated in skin carcinogenesis related with melanoma development. Conclusively, our results indicate that arsenic-treated keratinocytes exhibited alteration in the miRNAs expression profile and that miR-21, miR-200a and miR-141 could be promising early biomarkers of the epithelial phenotype of cancer cells and they could be potential novel targets for melanoma therapeutic interventions. PMID:27054085

  4. Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling, and miR-21 expression, processes involved in the EMT and malignant transformation of human bronchial epithelial cells

    SciTech Connect

    Luo, Fei; Xu, Yuan; Ling, Min; Zhao, Yue; Xu, Wenchao; Liang, Xiao; Jiang, Rongrong; Wang, Bairu; Bian, Qian; Liu, Qizhan

    2013-11-15

    Arsenite is an established human carcinogen, and arsenite-induced inflammation contributes to malignant transformation of cells, but the molecular mechanisms by which cancers are produced remain to be established. The present results showed that, evoked by arsenite, secretion of interleukin-6 (IL-6), a pro-inflammatory cytokine, led to the activation of STAT3, a transcription activator, and to increased levels of a microRNA, miR-21. Blocking IL-6 with anti-IL-6 antibody and inhibiting STAT3 activation reduced miR-21 expression. For human bronchial epithelial cells, cultured in the presence of anti-IL-6 antibody for 3 days, the arsenite-induced EMT and malignant transformation were reversed. Thus, IL-6, acting on STAT3 signaling, which up-regulates miR-21in an autocrine manner, contributes to the EMT induced by arsenite. These data define a link from inflammation to EMT in the arsenite-induced malignant transformation of HBE cells. This link, mediated through miRNAs, establishes a mechanism for arsenite-induced lung carcinogenesis. - Highlights: • Arsenite evokes IL-6 secretion. • IL-6 autocrine mediates STAT3 signaling and up-regulates miR-21expression. • Inflammation is involved in arsenite-induced EMT.

  5. Effect of miR-19a and miR-21 on the JAK/STAT signaling pathway in the peripheral blood mononuclear cells of patients with systemic juvenile idiopathic arthritis

    PubMed Central

    LI, HONG-WEI; XIE, YING; LI, FENG; SUN, GUANG-CHAO; CHEN, ZHI; ZENG, HUA-SONG

    2016-01-01

    Overexpression of the components of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway are key factors of the pathogenic mechanisms underlying systematic juvenile idiopathic arthritis (SJIA). The present study aimed to investigate the association between microRNA (miR)-19a, miR-21 and the JAK/STAT signaling pathway. A total of 20 patients with SJIA were included in the study, and peripheral blood mononuclear cells (PBMCs) from 20 normal controls were also collected. RNAiso was used to extract total RNA, and the RNA was then reverse transcribed into cDNA. Primers were designed to detect the mRNA of miR-19a and miR-21, and U6 was set as the internal parameter. In addition, the mRNA of STAT3, suppressor of cytokine signaling 3 (SOCS3), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected, and β-actin was set as the internal parameter. Reverse transcription-quantitative polymerase chain reaction was performed to detect the expression levels of these proteins in patients with SJIA and control subjects, and non-parametric tests were used to analyze the statistical differences in 2−ΔΔCq between the two groups. The expression levels of miR-19a and miR-21 were significantly lower in the SJIA group compared with the control group (P<0.05). SOCS3, TNF-α and STAT3 were shown to be the target genes of miR-19a and miR-21, as determined by Targetscan. The expression levels of STAT3, SOCS3, TNF-α and IL-6 mRNA were significantly higher compared with those of the control group (P<0.05). In the PBMCs of sthe patients with SJIA, miR-19a and miR-21 expression levels were lower compared with those of the control group, and the JAK/STAT signaling pathway was activated, which indicated that miR-19a and miR-21 may participate in the activation of the JAK/STAT signaling pathway. PMID:27284344

  6. Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial.

    PubMed

    Müller, Volkmar; Gade, Stephan; Steinbach, Bettina; Loibl, Sibylle; von Minckwitz, Gunter; Untch, Michael; Schwedler, Kathrin; Lübbe, Kristina; Schem, Christian; Fasching, Peter A; Mau, Christine; Pantel, Klaus; Schwarzenbach, Heidi

    2014-08-01

    Trastuzumab and lapatinib are established treatments for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer with different mechanisms of action. The focus of this study is to investigate, whether altered expression levels of potentially relevant microRNAs (miRs) in serum are associated with response to trastuzumab or lapatinib. Circulating miR-21, miR-210, and miR-373 were quantified with TaqMan MicroRNA assays in serum of 127 HER2-postive breast cancer patients before and after neoadjuvant therapy and in 19 healthy controls. Patients received chemotherapy combined with either trastuzumab or lapatinib within the prospectively randomized Geparquinto trial. The association between miR levels and pathological response (pCR) to therapy and type of therapy was examined. Serum levels of miR-21 (p = 5.04e-08, p = 1.43e-10), miR-210 (p = 0.00151, p = 1.6e-05), and miR-373 (p = 7.87e-06, p = 1.75e-07) were significantly higher in patients before and after chemotherapy than in healthy women. Concentrations of miR-21 (p = 5.73e-08), miR-210 (p = 0.000724), and miR-373 (p = 0.00209) increased further after chemotherapy. A significant association of higher serum levels of miR-373 with advanced clinical tumor stage could be detected (p < 0.002). An association of miR-21 levels before (p = 0.0091) and after (p = 0.037) chemotherapy with overall survival of the patients could be detected, independent of type of anti-HER2 therapy. No association of circulating miRs with pCR was found. Our findings demonstrate a specific influence of neoadjuvant therapy on the serum levels of miR-21, miR-210, and miR-373 in breast cancer patients together with a prognostic value of miR-21. PMID:25086636

  7. Keratinization-associated miR-7 and miR-21 Regulate Tumor Suppressor Reversion-inducing Cysteine-rich Protein with Kazal Motifs (RECK) in Oral Cancer*

    PubMed Central

    Jung, Hyun Min; Phillips, Brittany L.; Patel, Rushi S.; Cohen, Donald M.; Jakymiw, Andrew; Kong, William W.; Cheng, Jin Q.; Chan, Edward K. L.

    2012-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs that posttranscriptionally regulate gene expression during many biological processes. Recently, the aberrant expressions of miRNAs have become a major focus in cancer research. The purpose of this study was to identify deregulated miRNAs in oral cancer and further focus on specific miRNAs that were related to patient survival. Here, we report that miRNA expression profiling provided more precise information when oral squamous cell carcinomas were subcategorized on the basis of clinicopathological parameters (tumor primary site, histological subtype, tumor stage, and HPV16 status). An innovative radar chart analysis method was developed to depict subcategories of cancers taking into consideration the expression patterns of multiple miRNAs combined with the clinicopathological parameters. Keratinization of tumors and the high expression of miR-21 were the major factors related to the poor prognosis of patients. Interestingly, a majority of the keratinized tumors expressed high levels of miR-21. Further investigations demonstrated the regulation of the tumor suppressor gene reversion-inducing cysteine-rich protein with kazal motifs (RECK) by two keratinization-associated miRNAs, miR-7 and miR-21. Transfection of miR-7 and miR-21-mimics reduced the expression of RECK through direct miRNA-mediated regulation, and these miRNAs were inversely correlated with RECK in CAL 27 orthotopic xenograft tumors. Furthermore, a similar inverse correlation was demonstrated in CAL 27 cells treated in vitro by different external stimuli such as trypsinization, cell density, and serum concentration. Taken together, our data show that keratinization is associated with poor prognosis of oral cancer patients and keratinization-associated miRNAs mediate deregulation of RECK which may contribute to the aggressiveness of tumors. PMID:22761427

  8. Tamoxifen-Induced Cell Death of Malignant Glioma Cells Is Brought About by Oxidative-Stress-Mediated Alterations in the Expression of BCL2 Family Members and Is Enhanced on miR-21 Inhibition.

    PubMed

    Harmalkar, Mugdha; Upraity, Shailendra; Kazi, Sadaf; Shirsat, Neelam Vishwanath

    2015-10-01

    High-grade gliomas are refractory to the current mode of treatment primarily due to their inherent resistance to cell death. Tamoxifen has been reported to inhibit growth and induce cell death of glioma cells in vitro, in an estrogen-receptor-independent manner. Delineating the molecular mechanism underlying tamoxifen-induced cell death of human glioma cells would help in identifying pathways/genes that could be targeted to induce tumor-cell-specific cell death. In the present study, tamoxifen was found to bring about autophagic cell death of human glioma cells that was accompanied by oxidative stress induction, JNK activation, downregulation of anti-autophagic BCL2 family members, viz. BCL2 and BCL-XL, and increased expression of the pro-autophagic members BCL-Xs and BAK. Oxidative stress induction appears to be primarily responsible for the tamoxifen-induced cell death since the cell death, JNK activation, and the alterations in the expression levels of BCL2 family members were abrogated on pretreatment with antioxidant vitamin E. MiR-21, an oncogenic miRNA, is known to be highly upregulated in malignant glioma. Inhibition of miR-21 activity was found to enhance tamoxifen-induced cell death of U87 MG malignant glioma cells. Tamoxifen treatment coupled with miR-21 inhibition could therefore be an effective strategy for the treatment of malignant gliomas. PMID:26109525

  9. Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis.

    PubMed

    Venturutti, L; Romero, L V; Urtreger, A J; Chervo, M F; Cordo Russo, R I; Mercogliano, M F; Inurrigarro, G; Pereyra, M G; Proietti, C J; Izzo, F; Díaz Flaqué, M C; Sundblad, V; Roa, J C; Guzmán, P; Bal de Kier Joffé, E D; Charreau, E H; Schillaci, R; Elizalde, P V

    2016-04-28

    Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another player in BC, has been recognized as a downstream mediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated novel direction of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3 binds to its response elements (GAS) at the ErbB-2 promoter to upregulate ErbB-2 transcription in metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displaying metastatic and non-metastatic ability, highlighting Stat3 general role as upstream regulator of ErbB-2 expression in BC. Moreover, we showed that Stat3 co-opts NErbB-2 function by recruiting ErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), a metastasis-promoting microRNA (miRNA). Using an ErbB-2 nuclear localization domain mutant and a constitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and also its direct role as transcription factor upregulate miR-21 in BC. This reveals a novel function of NErbB-2 as a regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate the expression of the metastasis-suppressor protein programmed cell death 4 (PDCD4), a validated miR-21 target. Using an in vivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 or miR-21 expression, we showed that both are downstream mediators of Stat3-driven metastasis. Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive BCs

  10. Stress-related alcohol consumption in heavy drinkers correlates with expression of miR-10a, miR-21 and components of the TAR-RNA binding protein (TRBP)-associated complex

    PubMed Central

    Beech, Robert D.; Leffert, Janine J.; Lin, Aiping; Hong, Kwangik A.; Hansen, Julie; Umlauf, Sheila; Mane, Shrikant; Zhao, Hongyu; Sinha, Rajita

    2014-01-01

    Background Alterations in stress-related gene-expression may play a role in stress-related drinking and the risk for alcohol dependence. Methods Microarrays were used to measure changes in gene-expression in peripheral blood in non-smoking, social drinking subjects exposed to three types of personalized imagery: neutral, stressful (but not alcohol-related), and alcohol-related cues. Gene-expression was measured at baseline, immediately after, and 1 hour after stimulus presentation. Subjects were allowed to drink up to 750cc of beer in a “taste-test” following stimulus presentation in each imagery condition, and the amount of beer consumed was recorded. Gene-expression levels were compared in 2 groups of non-smoking subjects (n=11/group): heavy drinkers (HD, defined as regular alcohol use over the past year of at least 8 standard drinks/week for women and at least 15 standard drinks/week for men), and moderate drinkers (MD, defined as up to 7 standard drinks/week for women and 14 standard drinks/week for men). Expression of microRNA10 (miR-10a) and microRNA 21 (miR-21) was assessed by quantitative real-time PCR (qRT-PCR). Results After correction for multiple testing (FDR<0.05), 79 genes were identified that changed by > 1.3 fold in the HD group, but not the MD group, following exposure to stress. No changes were observed for any of these genes in either group following exposure to neutral or alcohol-related imagery. Pathway analysis suggested that many of these genes, form part of the TAR-RNA binding protein (TRBP)-associated complex and are positively regulated by miR-10a and MiR-21. Expression of both miR-10a and miR-21 was up-regulated following psychological stress in HD, but not MD subjects, however the differences between groups were not statistically significant. Expression levels of both microRNAs was correlated (miR-10a, R2= 0.59, miR-21 R2= 0.57) with amount drunk in HD, but not MD subjects. Conclusions Expression of miR-10a, miR-21 and several of

  11. Hypoxia-Induced Aggressiveness of Pancreatic Cancer Cells Is Due to Increased Expression of VEGF, IL-6 and miR-21, Which Can Be Attenuated by CDF Treatment

    PubMed Central

    Bao, Bin; Ali, Shadan; Ahmad, Aamir; Azmi, Asfar S.; Li, Yiwei; Banerjee, Sanjeev; Kong, Dejuan; Sethi, Seema; Aboukameel, Amro; Padhye, Subhash B.; Sarkar, Fazlul H.

    2012-01-01

    Hypoxia is known to play critical roles in cell survival, angiogenesis, tumor invasion, and metastasis. Hypoxia mediated over-expression of hypoxia-inducible factor (HIF) has been shown to be associated with therapeutic resistance, and contributes to poor prognosis of cancer patients. Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance. However, the precise molecular mechanism(s) by which hypoxia/HIF drives these events are not fully understood. Here, we show, for the first time, that hypoxia leads to increased expression of VEGF, IL-6, and CSC signature genes Nanog, Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis, and the formation of pancreatospheres, concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer (PC) cells. The treatment of PC cells with CDF, a novel synthetic compound inhibited the production of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 and miR-210 under hypoxia. CDF also led to decreased cell migration/invasion, angiogenesis, and formation of pancreatospheres under hypoxia. Moreover, CDF decreased gene expression of miR-21, miR-210, IL-6, HIF-1α, VEGF, and CSC signatures in vivo in a mouse orthotopic model of human PC. Collectively, these results suggest that the anti-tumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become a novel, and effective anti-tumor agent for PC therapy. PMID:23272057

  12. Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures.

    PubMed

    van Scheppingen, J; Iyer, A M; Prabowo, A S; Mühlebner, A; Anink, J J; Scholl, T; Feucht, M; Jansen, F E; Spliet, W G; Krsek, P; Zamecnik, J; Buccoliero, A M; Giordano, F; Genitori, L; Kotulska, K; Jozwiak, S; Jaworski, J; Liszewska, E; van Vliet, E A; Aronica, E

    2016-06-01

    Tuberous sclerosis complex (TSC) is a genetic disease presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Abnormal activation of various inflammatory pathways has been observed in astrocytes in brain lesions associated with TSC. Increasing evidence supports the involvement of microRNAs in the regulation of astrocyte-mediated inflammatory response. To study the role of inflammation-related microRNAs in TSC, we employed real-time PCR and in situ hybridization to characterize the expression of miR21, miR146a, and miR155 in TSC lesions (cortical tubers and subependymal giant cell astrocytomas, SEGAs). We observed an increased expression of miR21, miR146a, and miR155 in TSC tubers compared with control and perituberal brain tissue. Expression was localized in dysmorphic neurons, giant cells, and reactive astrocytes and positively correlated with IL-1β expression. In addition, cultured human astrocytes and SEGA-derived cell cultures were used to study the regulation of the expression of these miRNAs in response to the proinflammatory cytokine IL-1β and to evaluate the effects of overexpression or knockdown of miR21, miR146a, and miR155 on inflammatory signaling. IL-1β stimulation of cultured glial cells strongly induced intracellular miR21, miR146a, and miR155 expression, as well as miR146a extracellular release. IL-1β signaling was differentially modulated by overexpression of miR155 or miR146a, which resulted in pro- or anti-inflammatory effects, respectively. This study provides supportive evidence that inflammation-related microRNAs play a role in TSC. In particular, miR146a and miR155 appear to be key players in the regulation of astrocyte-mediated inflammatory response, with miR146a as most interesting anti-inflammatory therapeutic candidate. PMID:27014996

  13. Grant R01CA172627 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  14. Grant R01CA120933 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  15. Grant R01CA182076 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  16. Grant R01CA163683 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  17. Grant R01CA180949 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  18. Grant R01CA172444 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  19. Grant R01AT006885 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  20. Grant R01CA180087 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  1. Grant R01CA192124 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  2. Grant R01CA160880 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  3. Grant R01CA196854 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  4. Grant R01CA168292 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  5. Grant R01CA163803 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  6. Grant R01CA195723 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  7. Grant R01CA182969 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  8. Grant R01CA132927 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  9. Grant R01CA194617 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  10. Grant R01CA182905 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  11. Grant R01CA137178 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  12. Grant R01CA187027 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  13. Grant R01CA187160 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  14. Grant R01CA159976 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  15. Grant R01CA165309 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  16. Grant R01CA183869 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  17. Grant R01CA181242 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  18. Grant R01AT007003 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  19. Grant R01CA169398 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  20. Grant R01CA182284 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  1. Grant R01CA185301 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  2. Grant R01CA134620 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  3. Grant R01CA155301 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  4. Grant R01CA164782 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  5. Grant R01CA128134 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  6. Grant R01CA148817 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  7. Grant R01CA155297 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  8. Grant R01CA179511 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  9. Grant R01CA132951 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  10. Grant R01CA098286 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  11. Grant R01CA154489 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  12. Grant R01CA170549 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  13. Grant R01CA107408 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  14. Grant R01CA190092 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  15. Grant R01CA163293 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  16. Grant R01CA196200 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  17. Grant R01CA179949 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  18. Grant R01CA172576 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  19. Grant R01CA133050 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  20. Grant R01CA169175 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  1. Grant R01CA179992 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  2. Grant R01CA164574 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  3. Grant R01CA172517 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  4. Grant R01AG041869 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  5. Grant R01AT008108 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  6. Grant R01AI093723 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  7. Grant R01CA161534 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  8. Grant R01CA157469 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  9. Grant R01CA140605 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  10. Grant R01NS046606 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  11. Grant R01CA151304 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  12. Grant R01CA138800 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  13. Grant R01CA148966 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  14. Grant R01CA163103 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  15. Grant R01AT005295 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  16. Grant R01NR014068 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  17. Grant R01CA140561 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  18. Grant R01CA087546 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  19. Grant R01EB019337 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  20. Grant R01CA152799 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  1. Grant R01CA200423 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  2. Grant R01CA188038 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  3. Grant R01CA177995 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  4. Grant R01CA174683 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  5. Grant R01CA177562 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  6. Grant R01CA190776 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  7. Grant R01CA193522 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  8. Grant R01AT006860 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  9. Grant R01CA190610 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  10. Grant R01CA183296 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  11. Grant R01CA190710 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  12. Grant R01CA195708 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  13. Grant R01CA184926 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  14. Grant R01CA196639 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  15. Grant R01CA166011 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  16. Grant R01CA166590 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  17. Grant R01AT007429 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  18. Grant R01CA094076 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  19. Grant R01CA105266 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  20. Grant R01CA196692 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  1. Grant R01CA184820 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  2. Grant R01CA162401 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  3. Grant R01CA158668 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  4. Grant R01CA026582 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  5. Grant R01CA084233 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  6. Grant R01CA166557 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  7. Grant R01CA080946 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  8. Grant R01CA158319 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  9. Grant R01CA166710 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  10. Grant R01CA124481 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  11. Grant R01CA162139 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  12. Grant R01CA151494 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  13. Grant R01CA184027 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  14. NCI/DCCPS R21 Program Announcements

    Cancer.gov

    The Division of Cancer Control and Population Sciences funds a large portfolio of grants and contracts. The portfolio currently includes approximately 800 grants valued at nearly $450 million. Here we provide a listing of funding opportunities that are currently accepting applications. Please visit this page regularly as new funding opportunities are added upon approval by NCI.

  15. Down-regulation of TGF-b1, TGF-b receptor 2, and TGF-b-associated microRNAs, miR-20a and miR-21, in skin lesions of sulfur mustard-exposed Iranian war veterans.

    PubMed

    Valizadeh, Mohadeseh; Mirzaei, Behnaz; Tavallaei, Mahmood; Noorani, Mohammad Reza; Amiri, Mojtaba; Soroush, Mohammad Reza; Mowla, Seyed Javad

    2015-01-01

    Sulfur mustard (SM) affects divergent cellular pathways including cell cycle, apoptosis, necrosis, and inflammatory responses. SM-induced lesions in skin include late-onset hyper-pigmentation, xerosis, and atrophy. It seems that TGF-b signaling pathway is a major player for SM pathogenesis. Here, we have employed a real-time polymerase chain reaction (PCR) approach to evaluate the expression alterations of all TGF-b variants and their receptors in skin biopsies obtained from 10 Iran-Iraq war veterans. Using specific LNA primers, the expression alteration of a TGF-bR2 regulator, miR-20a, and TGF-b downstream target, miR-21, was also assessed in the same samples Our real-time PCR data revealed a significant down-regulation of TGF-b1 and TGF-bR2, the major mediators of TGF-b signaling pathway, in skin biopsies of SM-exposed patients (p = 0.0015 and p = 0.0115, respectively). Down-regulation of TGF-b signaling pathway seems to contribute in severe inflammation observed in SM-exposed patients' tissues. MiR-20a and miR-21, as two important TGF-b associated microRNAs (miRNAs), were also down-regulated in SM-exposed skin lesions, compared to those of control group (p = 0.0003). Based on our findings, these miRNAs could be directly or indirectly involve in the pathogenesis of SM. Altogether, our data suggest the suitability of TGF-b1, TGF-bR2, as well as miR-20a and miR-21 as potential biomarkers for diagnosis and treatment of SM-exposed patients. PMID:26498464

  16. Grant R21CA182941 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  17. Grant R21DK105476 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  18. Grant R21CA196954 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  19. Grant R21CA186853 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  20. Grant R21DK108781 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  1. Grant R21CA191761 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  2. Grant R21CA198049 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  3. Grant R21CA174594 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  4. Grant R21CA182861 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  5. Grant R21CA190021 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  6. Grant R21CA174541 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  7. Grant R21CA185460 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  8. Grant R21CA184788 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  9. Grant R21CA181901 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  10. Grant R21CA182111 | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.