Hepatitis C virus core protein interacts with Snail and histone deacetylases to promote the metastasis of hepatocellular carcinoma
Hepatitis C virus core protein interacts with Snail and histone deacetylases to promote the metastasis of hepatocellular carcinoma
复制标题
丙型肝炎病毒核心蛋白与Snail和组蛋白脱乙酰酶相互作用促进肝细胞癌转移
DOI：
10.1038/onc.2015.428
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发表时间：
2016-07-14
期刊：
影响因子：
8
通讯作者：
Tang, N.
中科院分区：
文献类型：
--
作者：
Nie, D.;Shan, X.;Tang, N.
转录抑制因子Snail下调E-钙粘蛋白与转移潜能的获得相关。尽管丙型肝炎病毒（HCV）核心蛋白与肝癌发生有关，但目前尚不清楚Snail是否参与HCV核心蛋白诱导的E-钙粘蛋白失调。在此，我们研究了HCV核心诱导E-钙粘蛋白抑制的机制以及Snail在HCV核心介导的侵袭和转移中的作用。我们发现，HCV感染，特别是HCV核心表达，有效地诱导上皮间质转化（EMT）在肝癌细胞通过抑制E-钙粘蛋白。HCV core与Snail相互作用，增强了Snail与E-cadherin启动子区E-box的结合，导致E-cadherin启动子活性降低。我们发现，HCV核心，蜗牛，和组蛋白去乙酰化酶HDAC 1/HDAC 2在E-钙粘蛋白启动子形成一个共阻遏复合物。此外，HCV核心显示通过激活PI 3 K/Akt/GSK 3 β途径稳定Snail。沉默Snail表达恢复了E-钙粘蛋白的表达，并抑制了体内HCV核心促进的肿瘤生长和远处肺转移。总的来说，这些结果表明，HCV核心通过与转录抑制因子复合物Snail/HDAC在E-钙粘蛋白启动子处相互作用诱导EMT，这导致E-钙粘蛋白抑制和肝癌细胞侵袭力增加。这些发现增加了对肝癌转移调节因素的理解，并可能最终导致HCV相关肝癌新治疗策略的发展。
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/GSK3 beta 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.