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      Aquaporin 3 promotes epithelial-mesenchymal transition in gastric cancer

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          Abstract

          Background

          Gastric carcinoma (GC) is a common and lethal malignancy, and epithelial-mesenchymal transition (EMT) is believed to contribute to invasive and metastatic tumor growth. Aquaporin 3 (AQP3) is overexpressed in human GC tissues, while human epidermal growth factor (EGF) and hepatocyte growth factor, which can induce EMT, are able to up-regulate AQP3 expression, subsequently promoting GC cell migration and proliferation. The purpose of this study was to investigate the effects of AQP3 on EMT in human GC.

          Methods

          AQP3 and EMT-related proteins were detected by immunohistochemistry in human GC specimens and their clinical significance evaluated. AQP3 knockdown was attempted using small interfering RNAs, while EGF was used to up-regulate AQP3 expression. Western blotting, real-time quantitative polymerase chain reaction assays and immunofluorescence were used to evaluate changes in expression of AQP3 and EMT-related proteins in the SGC7901 and MGC803 human GC cell lines.

          Results

          AQP3 up-expression was associated with EMT-related proteins in human GC specimens, which correlated with poor prognosis for GC. AQP3 modulated GC cell proliferation, migration and invasion in vitro, and induced E-cadherin repression. AQP3 also up-regulated the expression of vimentin and fibronectin in vitro. The PI3K/AKT/SNAIL signaling pathway was likely involved in the induction of EMT by AQP3 in GC.

          Conclusions

          AQP3 promotes EMT in human cases of GC, allowing us to understand the mechanisms of AQP3 in GC progression, thus providing a potential strategy for its treatment.

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          Most cited references17

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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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            EMT as the ultimate survival mechanism of cancer cells.

            Epithelial cancers make up the vast majority of cancer types and, during the transition from benign adenoma to malignant carcinoma and metastasis, epithelial tumor cells acquire a de-differentiated, migratory and invasive behavior. This process of epithelial-mesenchymal transition (EMT) goes along with dramatic changes in cellular morphology, the loss and remodeling of cell-cell and cell-matrix adhesions, and the gain of migratory and invasive capabilities. EMT itself is a multistage process, involving a high degree of cellular plasticity and a large number of distinct genetic and epigenetic alterations, as fully differentiated epithelial cells convert into poorly differentiated, migratory and invasive mesenchymal cells. In the past years, a plethora of genes have been identified that are critical for EMT and metastasis formation. Notably, the EMT process not only induces increased cancer cell motility and invasiveness but also allows cancer cells to avoid apoptosis, anoikis, oncogene addiction, cellular, senescence and general immune defense. Notably, EMT seems to play a critical role in the generation and maintenance of cancer stem cells, highly consistent with the notion that metastatic cells carry the ability to initiate new tumors. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Aquaporins--new players in cancer biology.

              The aquaporins (AQPs) are small, integral-membrane proteins that selectively transport water across cell plasma membranes. A subset of AQPs, the aquaglyceroporins, also transport glycerol. AQPs are strongly expressed in tumor cells of different origins, particularly aggressive tumors. Recent discoveries of AQP involvement in cell migration and proliferation suggest that AQPs play key roles in tumor biology. AQP1 is ubiquitously expressed in tumor vascular endothelium, and AQP1-null mice show defective tumor angiogenesis resulting from impaired endothelial cell migration. AQP-expressing cancer cells show enhanced migration in vitro and greater local tumor invasion, tumor cell extravasation, and metastases in vivo. AQP-dependent cell migration may involve AQP-facilitated water influx into lamellipodia at the front edge of migrating cells. The aquaglyceroporin AQP3, which is found in normal epidermis and becomes upregulated in basal cell carcinoma, facilitates cell proliferation in different cell types. Remarkably, AQP3-null mice are resistant to skin tumorigenesis by a mechanism that may involve reduced tumor cell glycerol metabolism and ATP generation. Together, the data suggest that AQP expression in tumor cells and tumor vessels facilitates tumor growth and spread, suggesting AQP inhibition as a novel antitumor therapy.
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                Author and article information

                Contributors
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central
                0392-9078
                1756-9966
                2014
                3 May 2014
                : 33
                : 1
                : 38
                Affiliations
                [1 ]Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, 210029 Nanjing, Jiangsu, China
                [2 ]Department of Internal Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
                [3 ]Department of Pathology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
                [4 ]School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
                Article
                1756-9966-33-38
                10.1186/1756-9966-33-38
                4036310
                24887009
                27b76750-b4a1-407c-bb4d-ed39e0306598
                Copyright © 2014 Chen et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 March 2014
                : 28 April 2014
                Categories
                Research

                Oncology & Radiotherapy
                gastric cancer,aquaporin 3,epithelial-mesenchymal transition,e-cadherin,vimentin

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