Nie D, Shan X, Nie L, Duan Y, Chen Z, Yang Y, Li Z, Tian L, Gao Q, Shan Y, Tang N
The Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
Oncogene. 2016 Jul 14;35(28):3626-35. doi: 10.1038/onc.2015.428. Epub 2015 Nov 9.
Downregulation of E-cadherin by the transcriptional repressor Snail is associated with acquisition of metastatic potential. Although hepatitis C virus (HCV) core protein has been implicated in hepatocarcinogenesis, it is unclear whether Snail is involved in HCV core-induced dysregulation of E-cadherin. Herein, we investigated the mechanism by which HCV core induces E-cadherin repression and the role of Snail in HCV core-mediated invasiveness and metastasis. We found that HCV infection, especially HCV core expression, effectively induced the epithelial-mesenchymal transition (EMT) in hepatoma cells by repressing E-cadherin. HCV core interacted with Snail and enhanced its binding to the E-box in the promoter region of E-cadherin, leading to decreased E-cadherin promoter activity. We found that HCV core, Snail, and the histone deacetylases HDAC1/HDAC2 formed a co-repressor complex at the E-cadherin promoter. Moreover, HCV core was shown to stabilize Snail through activation of the PI3K/Akt/GSK3β pathway. Silencing Snail expression restored E-cadherin expression and inhibited HCV core-promoted tumor growth and distant lung metastasis in vivo. Collectively, these results demonstrated that HCV core induced EMT by interacting with the transcriptional repressor complex Snail/HDACs at the E-cadherin promoter, which led to E-cadherin repression and increased invasiveness of hepatoma cells. These findings increase understanding of factors regulating metastasis in hepatoma and may ultimately lead to the development of novel treatment strategies for HCV-associated hepatocellular carcinoma.
转录抑制因子Snail对E-钙黏蛋白的下调与转移潜能的获得有关。尽管丙型肝炎病毒（HCV）核心蛋白与肝癌发生有关，但尚不清楚Snail是否参与HCV核心蛋白诱导的E-钙黏蛋白失调。在此，我们研究了HCV核心蛋白诱导E-钙黏蛋白抑制的机制以及Snail在HCV核心蛋白介导的侵袭和转移中的作用。我们发现HCV感染，尤其是HCV核心蛋白的表达，通过抑制E-钙黏蛋白有效地诱导肝癌细胞发生上皮-间质转化（EMT）。HCV核心蛋白与Snail相互作用并增强其与E-钙黏蛋白启动子区域E盒的结合，导致E-钙黏蛋白启动子活性降低。我们发现HCV核心蛋白、Snail和组蛋白去乙酰化酶HDAC1/HDAC2在E-钙黏蛋白启动子处形成共抑制复合物。此外，HCV核心蛋白通过激活PI3K/Akt/GSK3β信号通路使Snail稳定。沉默Snail表达可恢复E-钙黏蛋白表达，并在体内抑制HCV核心蛋白促进的肿瘤生长和远处肺转移。总体而言，这些结果表明，HCV核心蛋白通过在E-钙黏蛋白启动子处与转录抑制复合物Snail/HDACs相互作用诱导EMT，从而导致E-钙黏蛋白抑制并增加肝癌细胞的侵袭性。这些发现增进了对肝癌转移调控因素的理解，并最终可能导致开发针对HCV相关肝细胞癌的新治疗策略。
