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      miR-145 inhibits tumor growth and metastasis by targeting metadherin in high-grade serous ovarian carcinoma

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          Abstract

          High-grade serous ovarian carcinoma (HGSOC), the most common and aggressive subtype of epithelial ovarian cancer, is characterized by TP53 mutations and genetic instability. Using miRNA profiling analysis, we found that miR-145, a p53 regulated miRNA, was frequently down-regulated in HGSOC. miR-145 down-regulation was further validated in a large cohort of HGSOCs by qPCR. Overexpression of miR-145 in ovarian cancer cells significantly suppressed proliferation, migration and invasion in vitro and inhibited tumor growth and metastasis in vivo. Metadherin (MTDH) was subsequently identified as a direct target of miR-145, and was found to be significantly up-regulated in HGSOC. Furthermore, overexpression of MTDH rescued the inhibitory effects of miR-145 in ovarian cancer cells. Finally, we found that high level of MTDH expression correlated with poor prognosis of HGSOC. Therefore, lack of suppression of MTDH by miR-145 when p53 is dysfunctional leads to increased tumor growth and metastasis of HGSOC. Our study established a new link between p53, miR-145 and MTDH in the regulation of tumor growth and metastasis in HGSOC.

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          miR-145 and miR-143 Regulate Smooth Muscle Cell Fate Decisions

          Kimberly Cordes, Neil T. Sheehy, Mark White … (2009)
          SUMMARY microRNAs are regulators of myriad cellular events, but evidence for a single microRNA that can efficiently differentiate multipotent cells into a specific lineage or regulate direct reprogramming of cells into an alternate cell fate has been elusive. Here, we show that miR-145 and miR-143 are co-transcribed in multipotent cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem cell–derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2.5, and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4, myocardin, and Elk-1 to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.
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            MicroRNA expression profiles in serous ovarian carcinoma.

            Eun Nam, Heejei Yoon, Sang Kim … (2008)
            Although microRNAs have recently been recognized as riboregulators of gene expression, little is known about microRNA expression profiles in serous ovarian carcinoma. We assessed the expression of microRNA and the association between microRNA expression and the prognosis of serous ovarian carcinoma. Twenty patients diagnosed with serous ovarian carcinoma and eight patients treated for benign uterine disease between December 2000 and September 2003 were enrolled in this study. The microRNA expression profiles were examined using DNA microarray and Northern blot analyses. Several microRNAs were differentially expressed in serous ovarian carcinoma compared with normal ovarian tissues, including miR-21, miR-125a, miR-125b, miR-100, miR-145, miR-16, and miR-99a, which were each differentially expressed in >16 patients. In addition, the expression levels of some microRNAs were correlated with the survival in patients with serous ovarian carcinoma. Higher expression of miR-200, miR-141, miR-18a, miR-93, and miR-429, and lower expression of let-7b, and miR-199a were significantly correlated with a poor prognosis (P < 0.05). Our results indicate that dysregulation of microRNAs is involved in ovarian carcinogenesis and associated with the prognosis of serous ovarian carcinoma.
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              MicroRNAs in the p53 network: micromanagement of tumour suppression.

              Heiko Hermeking (2012)
              In recent years, microRNAs (miRNAs) have been identified as mediators of tumour suppression and stress responses exerted by the p53 tumour suppressor. p53-regulated miRNAs contribute to tumour suppression by controlling the expression of central components of multiple processes, including cell cycle progression, epithelial-mesenchymal transition, stemness, metabolism, cell survival and angiogenesis. The expression and activity of p53 itself is also under the control of miRNAs. Finally, genetic and epigenetic alterations identified in the p53-miRNA network indicate that these pathways are important for the initiation and progression of tumours. In the future, knowledge about the p53-miRNA network may be able to be exploited for diagnostic and therapeutic approaches in cancer prevention and treatment.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: November 2014
                Publication date (Electronic): 23 October 2014
                Volume: 5
                Issue: 21
                Pages: 10816-10829
                Affiliations
                1 Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, China
                2 Department of Cell Biology, Shandong University School of Medicine, Jinan, Shandong, China
                3 Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China
                4 Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
                5 Department of Pathology, Northwestern University School of Medicine, Chicago, IL, USA
                6 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
                Author notes
                Correspondence to: Beihua Kong, kongbeihua@ 123456sdu.edu.cn
                Article
                PMC ID: 4279412
                PubMed ID: 25333261
                SO-VID: d65866c6-0a15-4aad-923e-43789d809816
                Copyright © Copyright: © 2014 Dong et al.
                License:

                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
                Date received : 18 September 2014
                Date accepted : 25 September 2014
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: mir-145,mtdh,p53,hgsoc,metastasis
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: mir-145, mtdh, p53, hgsoc, metastasis

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