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      Downregulation of miR-218 contributes to epithelial–mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling

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          Epithelial–mesenchymal transition (EMT) has been recognized as a key element of cell migration and invasion in lung cancer; however, the underlying mechanisms are not fully elucidated. Recently, emerging evidence suggest that miRNAs have crucial roles in control of EMT and EMT-associated traits such as migration, invasion and chemoresistance. Here, we found that miR-218 expression levels were significantly downregulated in lung cancer tissues compared with adjacent non-cancerous tissues, and the levels of miR-218 were significantly associated with histological grades and lymph node metastasis. Overexpression of miR-218 inhibited cell migration and invasion as well as the EMT process. Of particular importance, miR-218 was involved in the metastatic process of lung cancer cells in vivo by suppressing local invasion and distant colonization. We identified Slug and ZEB2 as direct functional targets of miR-218. Inverse correlations were observed between miR-218 levels and Slug/ZEB2 levels in cancer tissue samples. In addition, overexpression of miR-218 in H1299 increased chemosensitivity of cells to cisplatin treatment through suppression of Slug and ZEB2. These findings highlight an important role of miR-218 in the regulation of EMT-related traits and metastasis of lung cancer in part by modulation of Slug/ZEB2 signaling, and provide a potential therapeutic strategy by targeting miR-218 in NSCLC.

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          Most cited references 35

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          Cancer statistics, 2013

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            MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA.

             Pui W Kong,  Hua Yang,  L He (2008)
            Transforming growth factor beta (TGF-beta) signaling facilitates metastasis in advanced malignancy. While a number of protein-encoding genes are known to be involved in this process, information on the role of microRNAs (miRNAs) in TGF-beta-induced cell migration and invasion is still limited. By hybridizing a 515-miRNA oligonucleotide-based microarray library, a total of 28 miRNAs were found to be significantly deregulated in TGF-beta-treated normal murine mammary gland (NMuMG) epithelial cells but not Smad4 knockdown NMuMG cells. Among upregulated miRNAs, miR-155 was the most significantly elevated miRNA. TGF-beta induces miR-155 expression and promoter activity through Smad4. The knockdown of miR-155 suppressed TGF-beta-induced epithelial-mesenchymal transition (EMT) and tight junction dissolution, as well as cell migration and invasion. Further, the ectopic expression of miR-155 reduced RhoA protein and disrupted tight junction formation. Reintroducing RhoA cDNA without the 3' untranslated region largely reversed the phenotype induced by miR-155 and TGF-beta. In addition, elevated levels of miR-155 were frequently detected in invasive breast cancer tissues. These data suggest that miR-155 may play an important role in TGF-beta-induced EMT and cell migration and invasion by targeting RhoA and indicate that it is a potential therapeutic target for breast cancer intervention.
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              Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression.

              Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here, we address this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. Despite having widespread somatic genetic alterations, the metastasis-prone tumor cells retained a marked plasticity. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in three-dimensional culture that underwent epithelial-to-mesenchymal transition (EMT) following treatment with transforming growth factor-beta or injection into syngeneic mice. This transition was entirely dependent on the microRNA (miR)-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize, and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that tumor cell metastasis is regulated by miR-200 expression, which changes in response to contextual extracellular cues.

                Author and article information

                Nature Publishing Group
                04 May 2017
                13 February 2017
                : 36
                : 18
                : 2577-2588
                [1 ]Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
                [2 ]State Key Lab of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Cancer Center, Department of Pathology, Nanjing Medical University , Nanjing, China
                [3 ]Department of Oncology, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
                [4 ]Department of Pathology, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
                [5 ]Department of Pathology, Affiliated Drum Tower Hospital of Nanjing University Medical School , Nanjing, China
                [6 ]Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University , Philadelphia, PA, USA
                Author notes
                [* ]Department of Pathology, Nanjing Medical University , Nanjing 211166, China E-mail: binghjiang@ 123456yahoo.com or bhjiang@ 123456jefferson.edu (B-H. J.)
                [* ]Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University , 1020 Locust Street, Suite 334, Jefferson Alumni Hall, Philadelphia, PA 19107, USA. E-mail: Jun.he@ 123456jefferson.edu (J.H)

                These authors contributed equally to this work.

                Copyright © 2017 The Author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                Original Article

                Oncology & Radiotherapy


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