Hepatitis C viral protein NS5A induces EMT and participates in oncogenic transformation of primary hepatocyte precursors
Hepatitis C viral protein NS5A induces EMT and participates in oncogenic transformation of primary hepatocyte precursors
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DOI：
10.1016/j.jhep.2012.06.027
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发表时间：
2012-11-01
影响因子：
25.7
通讯作者：
Hibner, Urszula
中科院分区：
文献类型：
--
作者：
Akkari, Leila;Gregoire, Damien;Hibner, Urszula
背景和目标：顶基极性是上皮结构和功能所必需的，是几种肿瘤相关病原体的目标，并且通常在癌变过程中受到干扰。丙型肝炎病毒（HCV）感染与肝细胞癌的高风险相关，通常在细胞形态的发育异常改变之前。我们研究的分子机制和HCV驱动的扰动上皮polarity.Methods的功能后果：我们使用生化，遗传学和细胞生物学方法来评估丙型肝炎病毒蛋白NS 5A对肝细胞和肝祖细胞的极性和功能的影响。转基因动物和异种移植模型在体内验证细胞culture.Results中获得的结果：我们发现，表达HCV-NS 5A的原代肝前体细胞和永生化肝细胞系引起了深刻的修改细胞极性，导致上皮间质转化（EMT）。NS 5A，无论是单独或在感染过程中的病毒蛋白的完整补体的情况下，通过激活Twist 2，EMT的转录调节因子。NS 5A的作用与TGF-β的作用是相加的，TGF-β是一种在患病肝脏中丰富的细胞因子，与HCV相关的病理学高度相关。此外，NS 5A与致癌Ras合作，产生转化，侵入性细胞，是高度致瘤性在vivo.Conclusions：我们的数据表明，在HCV感染的背景下，NS 5A有利于形成癌前病变破坏细胞极性和其他致癌事件与病毒蛋白合作，产生能动性和侵入性肿瘤细胞。(C)2012年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Apicobasal polarity, which is essential for epithelial structure and function, is targeted by several tumour-related pathogens and is generally perturbed in the course of carcinogenesis. Hepatitis C virus (HCV) infection is associated with a strong risk of hepatocellular carcinoma, typically preceded by dysplastic alterations of cell morphology. We investigated the molecular mechanisms and the functional consequences of HCV-driven perturbations of epithelial polarity.Methods:We used biochemical, genetic, and cell biology approaches to assess the impact of hepatitis C viral protein NS5A on the polarity and function of hepatocytes and hepatic progenitors. Transgenic animals and xenograft models served for in vivo validation of the results obtained in cell culture.Results: We found that expression of HCV-NS5A in primary hepatic precursors and in immortalized hepatocyte cell lines gave rise to profound modifications of cell polarity, leading to epithelial to mesenchymal transition (EMT). NS5A, either alone or in the context of the full complement of viral proteins in the course of infection, acted through activating Twist2, a transcriptional regulator of EMT. The effects of NS5A were additive to those of TGF-beta, a cytokine abundant in diseased liver and highly relevant to HCV-related pathology. Moreover, NS5A cooperates with oncogenic Ras, giving rise to transformed, invasive cells that are highly tumorigenic in vivo.Conclusions: Our data suggest that in the context of HCV infection, NS5A favors formation of preneoplastic lesions by disrupting cell polarity and additional oncogenic events cooperate with the viral protein to give rise to motile and invasive tumour cells. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.