SOCS3表观沉默在HBV诱发肝癌过程中的生物学功能研究

Chronic HBV infection and chronic liver disease that progresses from hepatitis to cirrhosis are major risk factors for the development of HCC. Interleukin-6 (IL-6) has been demonstrated to be involved in Hepatitis B virus (HBV)-associated hepatocarcinogenesis through activation of STAT3 pathway. The sustained activation of IL-6/STAT3 pathway is frequently associated with repression of SOCS3, which is both a target gene and a negative regulator of STAT3. However, the silencing mechanism of SOCS3 in HCC remains to be elucidated. Our preliminary work showed that the repression of SOCS3 and sustained activation of IL-6/STAT3 pathway in HBV-producing HCC cells were caused by HBV-induced mitochondrial ROS accumulation. Mechanistic studies revealed that ROS-mediated epigenetic modification resulted in the silencing of SOCS3. Further studies revealed that the transcription repressor, Snail, could bind to SOCS3 promoter, suggesting that Snail might mediate the epigenetic silencing of SOCS3. In this project, we will elucidate the mechanism of Snail-mediated epigenetic silencing of SOCS3 and study the effect of SOCS3 on HBV-induced hepatocarcinogenesis. Moreover, we will enlarge the number of clinical HCC samples to analyze the potential prognostic value of SOCS3 and Snail. Our study will benefit the evaluation of SOCS3 and Snail as potential prognostic factors of HCC.

乙型肝炎病毒（HBV）感染是肝癌的主要诱因之一，其致病机理仍有待进一步阐明。HBV感染导致IL-6/STAT3信号通路的持续激活。SOCS3作为STAT3的靶基因和负调控因子，其表达在多种肿瘤中均被表观沉默。我们的前期研究发现HBV诱导的活性氧（ROS）积累可促进SOCS3启动子甲基化，从而下调其表达。运用蛋白质组学技术结合生物信息学分析，我们筛选出SOCS3的潜在调控因子Snail。在此基础上，本项目拟阐明Snail介导SOCS3表观沉默的分子机制；结合细胞和动物模型阐明SOCS3在HBV诱导肝癌发生过程中的生物学功能；明确SOCS3和Snail作为预后标记物联合使用在HBV相关肝癌中的病理学意义。通过本项目的实施，有望明确抑癌因子SOCS3和Snail作为肝癌预后标记物的潜在应用价值。

乙型肝炎病毒（HBV）感染是肝癌的主要诱因之一，其致病机理仍有待进一步阐明。HBV感染导致IL-6/STAT3信号通路的持续激活。SOCS3作为STAT3的靶基因和负调控因子，其表达在多种肿瘤中均被表观沉默。我们的前期研究发现HBV诱导的活性氧（ROS）积累可促进SOCS3启动子甲基化，从而下调其表达。运用蛋白质组学技术结合生物信息学分析，我们筛选出SOCS3的潜在调控因子Snail。在此基础上，本项目阐明了Snail介导SOCS3表观沉默的分子机制；结合细胞和动物模型阐明了SOCS3在HBV诱导肝癌发生过程中的生物学功能；明确了SOCS3和Snail作为预后标记物联合使用在HBV相关肝癌中的病理学意义。通过本项目的实施，阐明了抑癌因子SOCS3表观沉默的机制并明确了抑癌因子SOCS3和Snail作为肝癌预后标记物的潜在应用价值。