EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition
EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition
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DOI：
10.1016/j.jhep.2014.03.033
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发表时间：
2014-08-01
影响因子：
25.7
通讯作者：
Fouassier, Laura
中科院分区：
文献类型：
--
作者：
Claperon, Audrey;Mergey, Martine;Fouassier, Laura
背景与目的：上皮-间质转化（EMT）是一个参与肿瘤进展的细胞过程。EMT的第一步是破坏E-钙粘蛋白介导的粘附连接。胆管癌（CCA）是一种因局部浸润和转移而预后不良的癌症，表现出EMT特征。EGFR是一种受体酪氨酸激酶，在CCA进展中起主要作用。该研究的目的是确定是否EMT是由表皮生长因子受体在CCA cells.Methods：在体内，E-cadherin的表达进行了分析，在100例患者的CCA肿瘤和相关的病理特征和表皮生长因子受体的表达，并在异种移植模型与吉非替尼，EGFR的抑制剂治疗的小鼠。结果：在人CCA中，E-cadherin在50%的肿瘤中出现胞浆定位，这与CCA的外周型、肿瘤大小、卫星结节的存在和EGFR过表达有关。在异种移植肿瘤中，E-钙粘蛋白显示出胞质模式，而用吉非替尼治疗小鼠恢复了E-钙粘蛋白的膜表达。在体外，EGF诱导CCA细胞的散射，导致从粘附连接的破坏。EGF处理的CCA细胞中观察到E-钙粘蛋白的内化和表达减少，以及β-连环蛋白的核转位。在这些细胞中，EMT-转录因子（即，Slug和Zeb-1）和间充质标志物（即，N-钙粘蛋白和α-SMA）被诱导，有利于通过细胞骨架重塑的细胞侵袭。所有这些作用被gefitinib.Conclusions抑制：EGF/EGFR轴触发EMT在CCA细胞突出的CCA进展中的关键作用，这一途径。(C)2014年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Epithelial-mesenchymal transition (EMT) is a cellular process involved in cancer progression. The first step of EMT consists in the disruption of E-cadherin-mediated adherens junctions. Cholangiocarcinoma (CCA), a cancer with a poor prognosis due to local invasion and metastasis, displays EMT features. EGFR, a receptor tyrosine kinase, plays a major role in CCA progression. The aim of the study was to determine if EMT is induced by EGFR in CCA cells.Methods: In vivo, the expression of E-cadherin was analysed in CCA tumours of 100 patients and correlated with pathological features and EGFR expression, and in a xenograft model in mice treated with gefitinib, an inhibitor of EGFR. In vitro, the regulation of EMT by EGFR was investigated in CCA cell lines.Results: In human CCA, a cytoplasmic localization of E-cadherin occurred in 50% of the tumours was associated with the peripheral type of CCA, tumour size, the presence of satellite nodules and EGFR overexpression. In xenografted tumours, E-cadherin displayed a cytoplasmic pattern whereas the treatment of mice with gefitinib restored the membranous expression of E-cadherin. In vitro, EGF induced scattering of CCA cells that resulted from the disruption of adherens junctions. Internalization and decreased expression of E-cadherin, as well as nuclear translocation of beta-catenin, were observed in EGF-treated CCA cells. In these cells, EMT-transcription factors (i.e., Slug and Zeb-1) and mesenchymal markers (i.e., N-cadherin and alpha-SMA) were induced, favoring cell invasiveness through cytoskeleton remodeling. All these effects were inhibited by gefitinib.Conclusions: The EGF/EGFR axis triggers EMT in CCA cells highlighting the key role of this pathway in CCA progression. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.