IFIT3抑制肝脏炎-癌转化的作用和机制研究

肝脏慢性炎症是导致肝癌发生的主要因素，肝脏炎-癌转化的分子调控机制尚未彻底阐明。申请人此前首次发现IFIT3能够增强干扰素效应信号通路的活化，进而增强干扰素治疗肝癌的疗效（Hepatology,2017）。进一步我们发现IFIT3在肝癌组织中表达水平显著降低，且肝细胞特异性IFIT3基因敲除小鼠中，DEN诱导的肝脏炎-癌转化和肝细胞代偿性增殖显著增强，提示IFIT3可能通过调控肝细胞在炎症损伤后的增殖修复而抑制肝脏炎-癌转化及肝癌发生。初步机制研究还发现IFIT3或通过抑制IL-6诱导的STAT3磷酸化而抑制肿瘤发生，但仍待进一步探索。本课题拟深入探求IFIT3在调控肝细胞增殖和肝脏炎-癌转化中的作用机制，包括IFIT3如何参与调控肝脏炎症发生发展、肝脏炎症微环境中炎症因子效应，以及肝脏炎症所激发的肝细胞代偿性增殖及肿瘤发生过程，以期为肝脏炎-癌发生提出新机制，为肝癌治疗提供新的潜在靶点。

Chronic liver inflammation plays key role in the carcinogenesis of hepatocellular carcinoma (HCC). The molecular regulation of inflammation-induced carcinogenesis has not been fully explored. The applicant and team had demonstrated that IFIT3 could enhance the activation of interferon signaling pathway and further improve the therapeutic effect in HCC patients receiving interferon-α in previous work (Hepatology, 2017). In the meanwhile, severe reduction of the IFIT3 expression level in the tissue of hepatocellular carcinoma was found. Therefore, we further constructed hepatocyte specific IFIT3 knockout mice, and found that the hepatocyte-specific knockout of IFIT3 significantly enhanced the DEN-induced HCC, as well as enhanced compensatory proliferation of hepatocytes during the process, which implies that IFIT3 may suppress hepatic inflammation-induced carcinogenesis. Although furtherly we found that IFIT3 deficiency promoted STAT3 phosphorylation and activation after IL-6 stimulation, the mechanism still needs further study. Therefore, this research aims to explore the role and molecular mechanism of IFIT3 in regulating the proliferation of hepatocytes and the inflammation-induced carcinogenesis of HCC, including its involvement in the regulation of the development of liver inflammation, cytokine effector signaling pathway regulation in tumor microenvironment, and the process of inflammation-induced hepatocytes proliferation and carcinogenesis. The current research expects to provide new mechanisms for liver inflammation-induced carcinogenesis and novel potential targets of combination immunotherapy.