Effects of endosulfan on hepatoma cell adhesion: Epithelial-mesenchymal transition and anoikis resistance
Effects of endosulfan on hepatoma cell adhesion: Epithelial-mesenchymal transition and anoikis resistance
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DOI：
10.1016/j.tox.2012.05.008
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发表时间：
2012-10-09
期刊：
影响因子：
4.5
通讯作者：
Rahmani, Roger
中科院分区：
文献类型：
--
作者：
Peyre, Ludovic;Zucchini-Pascal, Nathalie;Rahmani, Roger
硫丹是一种农业中常用的有机氯农药，但在2011年被斯德哥尔摩公约列为持久性有机污染物（POP）。它的潜在毒性使其继续使用成为一个主要的公共卫生问题。尽管在实验动物中进行了研究，但硫丹对人类肝脏致癌作用的分子机制仍然知之甚少。在这项研究中，我们研究了硫丹对HepG2肝细胞的表型影响。首先，我们发现硫丹破坏了anoikis过程。事实上，暴露于硫丹的细胞最初对硫丹敏感，随后恢复了对这一过程的抵抗力。这一现象与上皮细胞向间充质细胞（EMT）的诱导过程平行发生，如以下所示：(1)肌动蛋白细胞骨架的重组以及FAK信号通路的激活；(2) E-cadherin表达的抑制；(3)蜗牛和蛞蝓的诱导；(4) WNT/ β -catenin通路的激活；(5)间质标志物（S100a4、vimentin、纤维连接蛋白、MMP-7）的诱导和重组。其次，尽管获得了间充质特性，但暴露于硫丹的HepG2细胞无法迁移。这种无法获得运动表型可能归因于ECM和细胞之间相互作用的破坏。综上所述，这些结果表明，硫丹通过诱导细胞脱离和部分EMT以及破坏anoikis过程，深刻地改变了肝细胞的表型。所有这些事件至少在一定程度上说明了硫丹在肝脏中的致癌潜力。2012爱思唯尔爱尔兰有限公司版权所有。
Endosulfan is an organochlorine pesticide commonly used in agriculture yet classified by the Stockholm Convention in 2011 as a persistent organic pollutant (POP). Its potential toxicity makes its continued use a major public health concern. Despite studies in laboratory animals, the molecular mechanisms underlying the carcinogenic effects of endosulfan in human liver remain poorly understood. In this study, we investigated the phenotypical effects of endosulfan on HepG2 liver cells. First, we found that endosulfan disrupted the anoikis process. Indeed, cells exposed to endosulfan were initially sensitized to anoikis and thereafter recovered their resistance to this process. This phenomenon occurred in parallel to the induction of the epithelial to mesenchymal (EMT) process, as demonstrated by: (1) reorganization of the actin cytoskeleton together with activation of the FAK signaling pathway; (2) repression of E-cadherin expression; (3) induction of Snail and Slug; (4) activation of the WNT/beta-catenin pathway; and (5) induction and reorganization of mesenchymal markers (S100a4, vimentin, fibronectin, MMP-7). Secondly, despite the acquisition of mesenchymal characteristics, HepG2 cells exposed to endosulfan failed to migrate. This incapacity to acquire a motile phenotype could be attributed to a disruption of the interaction between the ECM and the cells. Taken together, these results indicate that endosulfan profoundly alters the phenotype of liver cells by inducing cell detachment and partial EMT as well as disrupting the anoikis process. All these events account, at least in part, for the carcinogenic potential of endosulfan in liver. (c) 2012 Elsevier Ireland Ltd. All rights reserved.