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Epithelial cell adhesion molecule overexpression regulates epithelial-mesenchymal transition, stemness and metastasis of nasopharyngeal carcinoma cells via the PTEN/AKT/mTOR pathway

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      Abstract

      Epithelial cell adhesion molecule (EpCAM) is known to be highly expressed in a variety of epithelial carcinomas, and it is involved in cell adhesion and proliferation. However, its expression profile and biological function in nasopharyngeal carcinoma (NPC) remains unclear. In this study, higher expression of EpCAM was found in NPC samples compared with non-cancer nasopharyngeal mucosa by qRT-PCR. Additionally, immunohistochemistry (IHC) analysis of NPC specimens from 64 cases showed that high EpCAM expression was associated with metastasis and shorter survival. Multivariate survival analysis identified high EpCAM expression as an independent prognostic factor. Ectopic EpCAM expression in NPC cells promoted epithelial-mesenchymal transition (EMT), induced a cancer stem cell (CSC)-like phenotype, and enhanced metastasis in vitro and in vivo without an effect on cell proliferation. Notably, EpCAM overexpression reduced PTEN expression and increased the level of AKT, mTOR, p70S6K and 4EBP1 phosphorylation. Correspondingly, an AKT inhibitor and rapamycin blocked the effect of EpCAM on NPC cell invasion and stem-like phenotypes, and siRNA targeting PTEN rescued the oncogenic activities in EpCAM knockdown NPC cells. Our data demonstrate that EpCAM regulates EMT, stemness and metastasis of NPC cells via the PTEN/AKT/mTOR pathway.

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      Most cited references 47

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      Continuous cultures of fused cells secreting antibody of predefined specificity.

       G Köhler,  C Milstein (1975)
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        Nuclear signalling by tumour-associated antigen EpCAM.

        EpCAM was found to be overexpressed on epithelial progenitors, carcinomas and cancer-initiating cells. The role of EpCAM in proliferation, and its association with cancer is poorly explained by proposed cell adhesion functions. Here we show that regulated intramembrane proteolysis activates EpCAM as a mitogenic signal transducer in vitro and in vivo. This involves shedding of its ectodomain EpEX and nuclear translocation of its intracellular domain EpICD. Cleavage of EpCAM is sequentially catalysed by TACE and presenilin-2. Pharmacological inhibition or genetic silencing of either protease impairs growth-promoting signalling by EpCAM, which is compensated for by EpICD. Released EpICD associates with FHL2, beta-catenin and Lef-1 to form a nuclear complex that contacts DNA at Lef-1 consensus sites, induces gene transcription and is oncogenic in immunodeficient mice. In patients, EpICD was found in nuclei of colon carcinoma but not of normal tissue. Nuclear signalling of EpCAM explains how EpCAM functions in cell proliferation.
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          The prevalence and prevention of nasopharyngeal carcinoma in China

          Nasopharyngeal carcinoma (NPC) has remarkable epidemiological features, including regional, racial, and familial aggregations. The aim of this review is to describe the epidemiological characteristics of NPC and to propose possible causes for the high incidence patterns in southern China. Since the etiology of NPC is not completely understood, approaches to primary prevention of NPC remain under consideration. This situation highlights the need to conduct secondary prevention, including improving rates of early detection, early diagnosis, and early treatment in NPC patients. Since the 1970's, high-risk populations in southern China have been screened extensively for early detection of NPC using anti–Epstein-Barr virus (EBV) serum biomarkers. This review summarizes several large screening studies that have been conducted in the high-incidence areas of China. Screening markers, high-risk age range for screening, time intervals for blood re-examination, and the effectiveness of these screening studies will be discussed. Conduction of prospective randomized controlled screening trials in southern China can be expected to maximize the cost-effectiveness of early NPC detection screening.
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            Author and article information

            Affiliations
            [1 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, State Key Laboratory of Oncology in South China, ; Guangzhou, China
            [2 ]Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
            [3 ]ISNI 0000 0004 1803 6191, GRID grid.488530.2, Department of Nasopharyngeal Carcinoma, , Sun Yat-Sen University Cancer Center, ; Guangzhou, China
            [4 ]Zhoukou Hospital of Traditional Chinese Medicine, Zhoukou, China
            [5 ]ISNI 0000 0004 1803 6191, GRID grid.488530.2, Department of Pathology, , Sun Yat-Sen University Cancer Center, ; Guangzhou, China
            [6 ]ISNI 0000 0000 8653 1072, GRID grid.410737.6, Cancer Center of Guangzhou Medical University, ; Guangzhou, China
            Contributors
            +86-20-8734-3308 , wanghy@mail.sysu.edu.cn
            +86-20-87342280 , maishj@sysucc.org.cn
            Journal
            Cell Death Dis
            Cell Death Dis
            Cell Death & Disease
            Nature Publishing Group UK (London )
            2041-4889
            5 January 2018
            5 January 2018
            January 2018
            : 9
            : 1
            29305578 5849035 13 10.1038/s41419-017-0013-8
            © The Author(s) 2018

            Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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            Cell biology

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