TGF-β/CASC15/TAZ/Ihh信号轴介导的肝细胞与HSC交叉对话促进肝纤维化进展的机制研究

TGF-β是肝纤维化重要的始动因子，可介导肝细胞与肝星状细胞（HSC）交叉对话并促进肝纤维化进展，但具体机制尚不完全清楚。我们前期研究发现TGF-β可上调肝细胞中lncRNA CASC15表达；临床样本中CASC15表达水平与肝纤维化程度呈正相关；CASC15基因敲除可减缓小鼠肝纤维化进程；CASC15通过增强肝细胞中TAZ表达及Ihh分泌促进肝纤维化。进而提出假说：肝纤维化微环境中，TGF-β转录激活肝细胞中的CASC15分子，使之与Hippo通路转录效应因子TAZ的转录本结合增强其蛋白翻译效率，TAZ促进下游Ihh的表达和分泌，最终进一步活化HSC。本课题拟在此基础上，深入研究TGF-β/CASC15/TAZ/Ihh信号轴介导的肝细胞-HSC交叉对话促进肝纤维化的新机制。这些研究可以拓展对TGF-β调控肝纤维化进程具体机制的认识，还可为肝纤维化的诊断治疗提供新的分子靶标，具有重要意义。

TGF-β is an important initiating factor of liver fibrosis, which has been shown to contribute to the fibrogenic process by mediating crosstalk between hepatocytes and hepatic stellate cells (HSCs). However, the underlying mechanism is still far from being fully understood. Our previous study has demonstrated that TGF-β could induce lncRNA-CASC15 upregulation in hepatocytes. Further analysis showed that the expression levels of CASC15 in clinical samples were positively correlated with the degree of liver fibrosis. Moreover, CASC15 knockout mice showed milder CCl4-induced liver fibrosis than wild-type mice. Mechanistic study revealed that CASC15 promotes liver fibrosis by enhancing TAZ expression and Ihh secretion in hepatocytes. Thus, we hypothesized that CASC15 was transcriptionally activated by TGF-β in hepatocytes and bound to the transcript of TAZ, which is a transcriptional effector of the Hippo signaling cascade, to enhance TAZ protein translation. Then TAZ promoted the expression and secretion of Ihh in hepatocytes, further enhancing HSC activation. On this basis, we aim to delve deeper into the mechanism by which TGF-β/CASC15/TAZ/Ihh signal axis promotes liver fibrosis. Taken together, this study could expand our understanding of TGF-β-controlled fibrogenic process in the liver and provide novel molecular targets for diagnosis and treatment of liver fibrosis. Therefore, this research project is significant to the theoretical research and practical applications.