p66Shc在肝纤维化发病中的作用及lncRNA-Mical2/miR-203a-3p对其调控研究

氧化应激是肝纤维化损伤的关键环节。我们研究首次发现：p66Shc介导氧化应激参与肝上皮间质转化，动物及人肝纤维化病变与p66Shc表达正相关。进一步发现：1）干扰p66Shc可显著抑制细胞内ROS产生及肝星状细胞激活，抑制纤维化；2）miR-203a-3p可靶向抑制p66Shc，且在肝纤维化表达显著降低；信息学预测lncRNA-Mical2和miR-203a-3p具有ceRNA关系，其与miR-203a-3p在纤维化表达负相关。据此提出科学假说，p66Shc在肝纤维化中发挥重要作用，通过lncRNA-Mical2与miR-203a-3p的ceRNA网络抑制p66Shc的表达及活性，可有效防治肝纤维化。本研究利用基因敲减及过表达体内外模型，采用多种分子生物学技术阐明p66Shc及lncRNA-Mical2/miR-203a-3p调控在肝纤维化发病中的机制，为肝纤维化防治及药物研发提供新靶标。

Oxidative stress is critical to liver fibrosis. Our studies have demonstrated that the p66Shc-mediated oxidative stress participates in the hepatic epithelial-to-mesenchymal transition，and the liver fibrosis in animals and humans are positively correlated with the p66Shc expression. We further found that 1) Depletion of p66Shc by RNA interference significantly inhibits reactive oxygen species (ROS) generation and hepatic stellate cell activation; 2) p66Shc can be inhibited by miR-203a-3p, which is significantly reduced in liver fibrosis; Bioinformatics further predicate that lncRNA-Mical2 has the ceRNA interaction with miR-203a-3p, and is negatively correlated with miR-203a-3p expression. Accordingly, we put forward the hypothesis that p66Shc plays a vital role in liver fibrosis, and inhibition of p66Shc by lncRNA-Mical2/ miR-203a-3p protects against liver fibrosis. In this study, by utilizing gene model animal and RNA intervention, we investigate the significant role of lncRNA-Mical2/miR-203a-3p-p66Shc pathway in liver fibrosis and intend to provide a novel pharmacological target for the treatment of liver fibrosis.