HBx通过β-arrestin1/Akt调控c-Jun在肝癌中的作用机制研究

Persistent inflammation caused by hepatitis B virus (HBV) infection impacts the pathogenesis of hepatocellular carcinoma (HCC), one of the most deathly diseases worldwide. The X protein of HBV (HBx) is known to play a key role in HBV infection and HCC development. While HBx transcriptionally up-regulates β-arrestin1 gene expression in hepatocytes to stimulate inflammatory responses. β-arrestin1 is ubiquitous expressed scaffolding proteins that regulate G-protein-coupled receptor signaling and signal transduction. Here, we showed that HBx markedly induces β-arrestin1 expression, which in turn upregulated c-Jun in hepatoma cells, a key regulator of HCC development. Based on these findings, we proposed a novel cascade consisting of HBx, β-arrestin1, Akt and c-Jun that mechanistically links HBV infection and HCC development. In this applying project, the mechanism of HBx-induced HCC development in vivo will be investigated by HBx transgenic mice. A β-arrestin1/Akt/c-Jun signaling pathway in HCC development in vivo by β-arrestin1 knockout mice will be delineated. The role of HBx on β-arrestin-1/Akt/c-Jun cascade and their expressions in human HCC tissues will be studied. Through the in vivo data generated from well-established genetically modified mouse models (HBx, β-arrestin1), the identification of a novel molecular cascade that is essential for the transformation of hepatocytes will be important for the discovery of therapeutic targets against HCC.

HBx是引起乙肝相关性肝癌的重要分子之一。我们的研究已发现β-arrestin1通过Akt在乙肝相关性肝癌中发挥重要作用(Yang Y, et al. Nat Commun. 2015)，进一步的研究又发现HBx通过上调β-arrestin1来调控c-Jun/p53。基于上述前期工作基础，本研究拟用HBx转基因小鼠及β-arrestin1基因敲除小鼠的肝癌模型，研究HBx通过β-arrestin1/Akt在肝细胞癌变中对c-Jun/p53的调控作用并揭示其机制，同时，通过细胞研究分析其信号通路，并进行临床组织样本验证，结果将为乙肝相关性肝癌的治疗提供理论依据及药物靶点。

原发性肝癌（hepatocellular carcinoma, HCC）是常见恶性肿瘤之一，尽管近年来肝癌的基础研究和临床研究都取得了巨大进展，但是肝癌的防治效果并不尽如人意，乙肝感染后肝细胞癌变的机制仍不清楚是重要的原因之一。我们既往的研究已经证实β-arrestin1 (ARRB1)在肝癌发生、发展中发挥重要作用，但其在肝癌的作用有待进一步的研究。本项目利用β-arrestin1 (ARRB1)基因缺陷小鼠，通过DEN建立小鼠肝癌模型，以证明了ARRB1通过ERK通路，调控Snail/EMT信号通路促进肝癌的侵袭和转移，同时利用肝癌细胞系研究相关的信号调控，进一步在通过已保存的病人肝癌及癌旁组织样本，与正常肝组织进行对比，验证上述相关作用机制。相关试验结果证实了炎症因子TNF-α诱导的ARRB1升高，促进了ERK的磷酸化，通过增加Snail表达，激活下游EMT通路，导致N-cadherin及Vimentin表达升高，增强了肝癌细胞的侵袭、转移。通过本研究，揭示ARRB1相关性肝癌发生、发展的新机制，为肝癌的防治策略制定提供科学依据。