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      SOX9 promotes epithelial-mesenchymal transition via the Hippo-YAP signaling pathway in gastric carcinoma cells

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          Abstract

          SRY-box 9 (SOX9) is overexpressed in a number of human tumors, including gastric cancer (GC). However, the function of SOX9 in the development of GC remains unknown. In the present study, SOX9 activated the Hippo-yes-associated protein (YAP) signaling pathway to enhance the epithelial-mesenchymal transition in GC cell lines. The results suggested that SOX9 knockdown inhibited invasion, proliferation and migration of GC cells. Furthermore, SOX9 silencing upregulated the expression of E-cadherin, an epithelial marker, and downregulated the expression of mesenchymal markers, including snail family transcriptional repressor 1, vimentin and N-cadherin. SOX9 overexpression increased the expression of the aforementioned markers. SOX9 significantly affected YAP phosphorylation and total YAP protein levels, suggesting that SOX9 is involved in the Hippo-YAP signaling pathway. The current study revealed that SOX9 may be involved in the pathogenesis of GC, and further elucidation of the pathways involved may support the development of novel therapeutic options for the treatment of GC.

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          Most cited references45

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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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            The Hippo signaling pathway in stem cell biology and cancer.

            The Hippo signaling pathway, consisting of a highly conserved kinase cascade (MST and Lats) and downstream transcription coactivators (YAP and TAZ), plays a key role in tissue homeostasis and organ size control by regulating tissue-specific stem cells. Moreover, this pathway plays a prominent role in tissue repair and regeneration. Dysregulation of the Hippo pathway is associated with cancer development. Recent studies have revealed a complex network of upstream inputs, including cell density, mechanical sensation, and G-protein-coupled receptor (GPCR) signaling, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway in stem cell biology and its potential implications in tissue homeostasis and cancer.
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              Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks

              Epithelial-to-mesenchymal transition (EMT) is a key step in development, wound healing, and cancer development. It involves cooperation of signaling pathways, such as transformation growth factor-β (TGF-β), Sonic Hedgehog (SHH), and WNT pathways. These signaling pathways crosstalk to each other and converge to key transcription factors (e.g., SNAIL1) to initialize and maintain the process of EMT. The functional roles of multi-signaling pathway crosstalks in EMT are sophisticated and, thus, remain to be explored. In this review, we focused on three major signal transduction pathways that promote or regulate EMT in carcinoma. We discussed the network structures, and provided a brief overview of the current therapy strategies and drug development targeted to these three signal transduction pathways. Finally, we highlighted systems biology approaches that can accelerate the process of deconstructing complex networks and drug discovery.
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                Author and article information

                Journal
                Oncol Lett
                Oncol Lett
                OL
                Oncology Letters
                D.A. Spandidos
                1792-1074
                1792-1082
                July 2019
                21 May 2019
                21 May 2019
                : 18
                : 1
                : 599-608
                Affiliations
                [1 ]Department of Gastroenterology, Medical Center for Digestive Diseases, People's Hospital of Lianshui, Huaian, Jiangsu 223400, P.R. China
                [2 ]Department of Gastroenterology, Medical Center for Digestive Diseases, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
                Author notes
                Correspondence to: Professor Aijun Zhou, Department of Gastroenterology, Medical Center for Digestive Diseases, People's Hospital of Lianshui, 6 Red Sun Road, Huaian, Jiangsu 223400, P.R. China, E-mail: zhouaijundr@ 123456163.com
                [*]

                Contributed equally

                Article
                OL-0-0-10387
                10.3892/ol.2019.10387
                6546990
                31289532
                dabd930e-4537-4cdd-af00-f30b81cd0907
                Copyright: © Zhou et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 30 August 2017
                : 12 April 2019
                Categories
                Articles

                Oncology & Radiotherapy
                sry-box 9,migration and invasion,epithelial-mesenchymal transition,hippo-yes-associated protein signaling,gastric carcinoma cells

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