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      miR‐1 suppresses the proliferation and promotes the apoptosis of esophageal carcinoma cells by targeting Src

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          Abstract

          Nonreceptor tyrosine kinase c‐Src, also known as Src, is a potent oncogene involved in a series of biological processes including cell growth, differentiation, and apoptosis; however, its expression pattern and function in esophageal cancer is poorly addressed. In this study, abnormal overexpression of Src protein was observed in esophageal cancer tissues, which fuelled the speculation that microRNA‐mediated posttranscriptional regulatory mechanism might be involved. Bioinformatic analyses were applied to identify miRNAs that could potentially target Src. miR‐1 was predicted and further validated as a direct repressor of Src. Moreover, we manipulated knockdown and overexpression experiment on TE‐1 and TE‐10 cells to demonstrate miR‐1 suppressed proliferation and promoted apoptosis in esophageal cancer cells by inhibiting Src. Taken together, this study underlines a negative regulatory mechanism in which miR‐1 serves as a suppressor of Src in esophageal cancer cells and may provide insights into novel therapeutic approaches for esophageal cancer.

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          Most cited references28

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          Prediction of mammalian microRNA targets.

          MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
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            MicroRNA biogenesis: coordinated cropping and dicing.

            V Kim (2005)
            The recent discovery of microRNAs (miRNAs) took many by surprise because of their unorthodox features and widespread functions. These tiny, approximately 22-nucleotide, RNAs control several pathways including developmental timing, haematopoiesis, organogenesis, apoptosis, cell proliferation and possibly even tumorigenesis. Among the most pressing questions regarding this unusual class of regulatory miRNA-encoding genes is how miRNAs are produced in cells and how the genes themselves are controlled by various regulatory networks.
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              Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy.

              Myotonic dystrophy is an RNA gain-of-function disease caused by expanded CUG or CCUG repeats, which sequester the RNA binding protein MBNL1. Here we describe a newly discovered function for MBNL1 as a regulator of pre-miR-1 biogenesis and find that miR-1 processing is altered in heart samples from people with myotonic dystrophy. MBNL1 binds to a UGC motif located within the loop of pre-miR-1 and competes for the binding of LIN28, which promotes pre-miR-1 uridylation by ZCCHC11 (TUT4) and blocks Dicer processing. As a consequence of miR-1 loss, expression of GJA1 (connexin 43) and CACNA1C (Cav1.2), which are targets of miR-1, is increased in both DM1- and DM2-affected hearts. CACNA1C and GJA1 encode the main calcium- and gap-junction channels in heart, respectively, and we propose that their misregulation may contribute to the cardiac dysfunctions observed in affected persons.
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                Author and article information

                Contributors
                wangtao_pumc@live.cn
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                16 October 2017
                December 2017
                : 6
                : 12 ( doiID: 10.1002/cam4.2017.6.issue-12 )
                : 2957-2965
                Affiliations
                [ 1 ] Department of Thoracic and Cardiovascular Surgery Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical School Nanjing Jiangsu 210008 China
                [ 2 ] Nanjing Medical University Affiliated Cancer Hospital Nanjing Jiangsu 210009 China
                [ 3 ] State Key Laboratory of Pharmaceutical Biotechnology Nanjing Advanced Institute of Life Sciences Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology Nanjing Jiangsu 210093 China
                [ 4 ] Department of Lymphoma Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center of Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin 300060 China
                [ 5 ] Nanjing Multicenter Biobank Biobank of Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical School Nanjing Jiangsu 210008 China
                Author notes
                [*] [* ] Correspondence:

                Tao Wang, Nanjing University, Hankou Road, Nanjing, Jiangsu 210093, China. Tel: +86‐025‐83304616; Fax: 8625‐8968‐0245; E‐mail: wangtao_pumc@ 123456live.cn

                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-0987-3647
                Article
                CAM41214
                10.1002/cam4.1214
                5727306
                29034995
                79c2039f-2606-464e-bca6-00baac06e79b
                © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 01 June 2017
                : 29 August 2017
                : 31 August 2017
                Page count
                Figures: 4, Tables: 0, Pages: 9, Words: 5134
                Funding
                Funded by: Natural Science Foundation of Jiangsu Province
                Award ID: BK20140601
                Categories
                Original Research
                Cancer Biology
                Original Research
                Custom metadata
                2.0
                cam41214
                December 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:13.12.2017

                Oncology & Radiotherapy
                apoptosis,esophageal cancer,mir‐1,proliferation,src
                Oncology & Radiotherapy
                apoptosis, esophageal cancer, mir‐1, proliferation, src

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