microRNA-199调控肝脏炎症IL-6效应信号通路及其在炎瘤转化中的作用和机制研究

HBV-related hepatocellular carcinoma (HCC) is especially prevalent in China. Molecular regulatory mechanisms of inflammation and carcinogenesis in the liver have attracted much attention in the research of HCC carcinogenesis. microRNAs play important roles in HCC carcinogenesis and progression. Previously, we have elucidated the miRNomes of human normal liver, hepatitis liver, cirrhosis liver, and HCC tissues, and found that miR-199 expression was enriched in human normal liver but significantly decreased in HCC tissues. The roles of miR-199 in HCC progression was investigated and published in Cancer Cell, 2011. However, the roles of miR-199 in HCC carcinogenesis remain elusive. Hence, we constructed the miR-199 conditional knockout mice, and found that hepatocyte specific deficiency of miR-199 significantly increased HCC carcinogenesis in the DEN-induced HCC carcinogenesis mouse model. Thus, we intend to investigate the roles of miR-199 in inflammation and carcinogenesis of HCC in this study, so as to suggest new mechanisms and intervention approaches in HCC carcinogenesis.

乙型肝炎相关肝癌是我国的重大疾病，肝脏炎瘤转化的分子调控机制是该领域研究中的重大科学问题。IL-6在肝脏炎瘤转化中发挥关键作用，其信号通路调控机制及效应目前受广泛关注。microRNA在炎症和肿瘤发生发展中发挥重要调控作用。课题组前期系统筛选了肝癌发生发展过程中人正常肝脏-肝炎-肝硬化-肝癌组织中的microRNA组改变，发现正常肝脏中富集表达的miR-199在肝癌中表达显著降低（发表于2011年Cancer Cell）。而miR-199在肝脏炎瘤转化，尤其是IL-6表达和效应中的调控功能目前未知。据此我们构建了miR-199条件敲除小鼠，在DEN诱导炎瘤转化模型下，发现肝细胞特异性miR-199敲除显著增强IL-6效应通路活化进而促进肝脏炎瘤转化。由此我们拟从IL-6效应通路调控机制的角度研究miR-199在肝脏炎瘤转化中的作用和机制，以期为肝癌发生提出新机制，为肝癌早期干预提供新思路。

microRNA在炎症和肿瘤发生发展中发挥重要调控作用。IL-6在肝脏炎瘤转化中发挥关键作用，其信号通路调控机制及效应目前受广泛关注。课题组前期系统筛选了肝癌发生发展过程中人正常肝脏-肝炎-肝硬化-肝癌组织中的microRNA组改变，发现正常肝脏中富集表达的miR-199在肝癌中表达显著降低。利用miR-199条件敲除小鼠和化学诱导炎瘤转化模型，本项目从IL-6效应通路调控机制的角度研究miR-199在肝脏炎瘤转化中的作用和机制，发现miR-199a-3p在肿瘤发生中发挥抑制作用；在机制上， miR-199a-3p敲除增强IL-6/STAT3信号效应，进而促进肝癌发生； miR-199a-3p敲除还导致PDCD4蛋白表达水平明显上调，PDCD4蛋白表达水平的上调导致肝细胞凋亡增加，肝脏损伤加重，并最终发挥促进了肝癌的发生。研究结果为肝癌发生提出了新机制，为肝癌早期干预提供了新思路。