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      The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer

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          Abstract

          Recently, the long non-coding RNA (lncRNA) H19 has been identified as an oncogenic gene in multiple cancer types and elevated expression of H19 was tightly linked to tumorigenesis and cancer progression. However, the molecular basis for this observation has not been characterized in colorectal cancer (CRC) especially during epithelial to mesenchymal transition (EMT) progression. In our studies, H19 was characterized as a novel regulator of EMT in CRC. We found that H19 was highly expressed in mesenchymal-like cancer cells and primary CRC tissues. Stable expression of H19 significantly promotes EMT progression and accelerates in vivo and in vitro tumor growth. Furthermore, by using bioinformatics study and RNA immunoprecipitation combined with luciferase reporter assays, we demonstrated that H19 functioned as a competing endogenous RNA (ceRNA) for miR-138 and miR-200a, antagonized their functions and led to the de-repression of their endogenous targets Vimentin, ZEB1, and ZEB2, all of which were core marker genes for mesenchymal cells. Taken together, these observations imply that the lncRNA H19 modulated the expression of multiple genes involved in EMT by acting as a competing endogenous RNA, which may build up the missing link between the regulatory miRNA network and EMT progression.

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          Most cited references 51

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          Global cancer statistics, 2002.

           D Parkin,  F Bray,  J Ferlay (2005)
          Estimates of the worldwide incidence, mortality and prevalence of 26 cancers in the year 2002 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. The results are presented here in summary form, including the geographic variation between 20 large "areas" of the world. Overall, there were 10.9 million new cases, 6.7 million deaths, and 24.6 million persons alive with cancer (within three years of diagnosis). The most commonly diagnosed cancers are lung (1.35 million), breast (1.15 million), and colorectal (1 million); the most common causes of cancer death are lung cancer (1.18 million deaths), stomach cancer (700,000 deaths), and liver cancer (598,000 deaths). The most prevalent cancer in the world is breast cancer (4.4 million survivors up to 5 years following diagnosis). There are striking variations in the risk of different cancers by geographic area. Most of the international variation is due to exposure to known or suspected risk factors related to lifestyle or environment, and provides a clear challenge to prevention.
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            Epithelial-mesenchymal transitions in development and disease.

            The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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              A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?

              Here, we present a unifying hypothesis about how messenger RNAs, transcribed pseudogenes, and long noncoding RNAs "talk" to each other using microRNA response elements (MREs) as letters of a new language. We propose that this "competing endogenous RNA" (ceRNA) activity forms a large-scale regulatory network across the transcriptome, greatly expanding the functional genetic information in the human genome and playing important roles in pathological conditions, such as cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Affiliations
                1 School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, P.R. China
                2 Croucher Laboratory for Human Genomics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, P.R. China
                3 Guangzhou Institute of Advanced Technology, Chinese Academy of Sciences, Guangzhou, P.R. China
                4 Department of Infectious Diseases, Peking University Shenzhen Hospital, Shenzhen, P.R. China
                5 Department of Clinical Laboratory, Nanshan Affiliated Hospital of Guangdong Medical College, Shenzhen, P.R. China
                6 Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, P.R. China
                Author notes
                Correspondence to: Mary Miu-Yee Waye, mary-waye@ 123456cuhk.edu.hk
                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                8 September 2015
                5 June 2015
                : 6
                : 26
                : 22513-22525
                26068968 4673179
                Copyright: © 2015 Liang et al.

                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.

                Categories
                Research Paper

                Oncology & Radiotherapy

                lncrna, mirna sponges, cerna

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