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      MiR-130b Is a Prognostic Marker and Inhibits Cell Proliferation and Invasion in Pancreatic Cancer through Targeting STAT3

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          Abstract

          Accumulating evidence indicates that microRNAs (miRNAs) are aberrantly expressed in human cancer and contribute to the tumorigenesis, but their roles in pancreatic cancer are still largely unknown. In this study, our data showed that miR-130b was significantly downregulated in 52 pairs of pancreatic cancer tissues and five cell lines. Furthermore, the deregulated miR-130b was correlated with worse prognosis, increased tumor size, late TNM stage, lymphatic invasion and distant metastasis. Multivariate analysis showed that miR-130b expression was a significant and independent prognostic predictor for pancreatic cancer patients. Functional studies indicated that the overexpression of miR-130b dramatically suppressed the proliferation of pancreatic cancer cells both in vitro and in vivo, which could be attributed to the induction of apoptosis and cell cycle arrest at S phase. Meanwhile, an overexpressed miR-130b remarkably inhibited the invasive ability of pancreatic cancer cells. Moreover, the dual luciferase assay revealed that STAT3 was directly targeted by miR-130b, which was further confirmed by the inverse expression of miR-130b and STAT3 in pancreatic cancer samples. Our findings suggested that miR-130b might have a considerable potential in prognosis identification and application of therapy for pancreatic cancer.

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          Most cited references26

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          Cancer statistics, 2009.

          Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are standardized by age to the 2000 United States standard million population. A total of 1,479,350 new cancer cases and 562,340 deaths from cancer are projected to occur in the United States in 2009. Overall cancer incidence rates decreased in the most recent time period in both men (1.8% per year from 2001 to 2005) and women (0.6% per year from 1998 to 2005), largely because of decreases in the three major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and in two major cancer sites in women (breast and colorectum). Overall cancer death rates decreased in men by 19.2% between 1990 and 2005, with decreases in lung (37%), prostate (24%), and colorectal (17%) cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2005 decreased by 11.4%, with decreases in breast (37%) and colorectal (24%) cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates has resulted in the avoidance of about 650,000 deaths from cancer over the 15-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years of age. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment.
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            MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma.

            Pancreatic ductal adenocarcinoma (PDAC) is known for its very poor overall prognosis. Accurate early diagnosis and new therapeutic modalities are therefore urgently needed. We used 377 feature microRNA (miRNA) arrays to investigate miRNA expression in normal pancreas, chronic pancreatitis, and PDAC tissues as well as PDAC-derived cell lines. A pancreatic miRNome was established comparing the data from normal pancreas with a reference set of 33 human tissues. The expression of miR-216 and -217 and lack of expression of miR-133a were identified as characteristic of pancreas tissue. Unsupervised clustering showed that the three pancreatic tissues types can be classified according to their respective miRNA expression profiles. We identified 26 miRNAs most prominently misregulated in PDAC and a relative quantitative reverse transcriptase-polymerase chain reaction index using only miR-217 and -196a was found to discriminate normal pancreas, chronic pancreatitis and cancerous tissues, establishing a potential utility for miRNAs in diagnostic procedures. Lastly, comparing differentially expressed genes from PDAC with predicted miRNA target genes for the top 26 miRNAs, we identified potential novel links between aberrant miRNA expression and known target genes relevant to PDAC biology. Our data provides novel insights into the miRNA-driven pathophysiological mechanisms involved in PDAC development and offers new candidate targets to be exploited both for diagnostic and therapeutic strategies.
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              Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer.

              Members of the signal transducers and activators of transcription (STAT) pathway, which were originally identified as key components linking cytokine signals to transcriptional events in cells, have recently been demonstrated to have a major role in cancer. They are cytoplasmic proteins that form functional dimers with each other when activated by tyrosine phosphorylation. Activated STAT proteins translocate to the nucleus to regulate expression of genes by binding to specific elements within gene promoters. Constitutive activation of the STAT family members Stat3 and Stat5, and/or loss of Stat1 signaling, is found in a large group of diverse tumors. Increasing evidence demonstrates that STAT proteins can regulate many pathways important in oncogenesis including cell-cycle progression, apoptosis, tumor angiogenesis, tumor-cell invasion and metastasis, and tumor-cell evasion of the immune system. Based on these findings, a growing effort is underway to target STAT proteins directly and indirectly for cancer therapy. This review will highlight STAT signaling pathways, STAT target genes involved in cancer, evidence for STAT activation in human cancers, and therapeutic strategies to target STAT molecules for anticancer therapy.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                10 September 2013
                : 8
                : 9
                : e73803
                Affiliations
                [1 ]Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                [2 ]Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, China
                [3 ]Department of Obstetrics and Gynecology, Zhejiang Provincial People’s Hospital, Hangzhou, China
                Medical University Graz, Austria
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GZ JGZ YS QQ YL BW KT SCD XL SZ YN CYW. Performed the experiments: JGZ YL BW KT. Analyzed the data: GZ JGZ. Contributed reagents/materials/analysis tools: GZ JGZ YS QQ YL BW KT SCD XL SZ QG CYW. Wrote the paper: GZ JGZ CYW.

                Article
                PONE-D-13-00387
                10.1371/journal.pone.0073803
                3769379
                24040078
                5dbc5b8e-9476-4e89-935f-dd2b6d19e5d9
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 December 2012
                : 24 July 2013
                Page count
                Pages: 10
                Funding
                This study was supported by grants from the National Science Foundation Committee (NSFC) of China (grant numbers 30972900 and 30600594). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article

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