肝癌起源于肝干细胞的异常分化和增生，Wnt通路在此过程起重要作用。SPTBN1是收缩蛋白（spectrin）的βII亚基，其缺失导致小鼠发生肝癌而机制未明。我们前期发现下调肝癌细胞SPTBN1能活化Wnt促进肝癌转移。ASCL1可激活Wnt通路，促进肿瘤干细胞特征和致瘤性，而SPTBN1+/-小鼠肝脏ASCL1表达上调、肝干细胞增多。因此设想SPTBN1缺失通过诱导ASCL1表达、活化Wnt通路而调控肝干细胞的增殖及恶性转化。本课题先用SPTBN1+/-及野生小鼠建立DDC诱导的肝干细胞活化模型，体内外研究SPTBN1对肝干细胞增殖及恶性转化、ASCL1/Wnt通路的影响，并利用MEFs、肝干细胞研究其调节ASCL1/Wnt通路的机制，最后用人肝癌组织研究SPTBN1与肝癌干细胞标志物表达、临床病理特征及ASCL1/Wnt通路的相关性。本研究将为寻找新的肝癌标志物和治疗靶点提供理论依据。

Hepatocellular carcinoma (HCC) arises from the abnormal differentiation and proliferation in the liver stem cells. Wnt/β-catenin pathway plays an important role in this process. SPTBN1 is the most common nonerythrocytic member of the β-spectrin gene family. Down regulation of SPTBN1 confers susceptibility to liver cancer but the mechanism is unknown. We previously found loss of SPTBN1 in HCC cells can promote metastasis through Wnt activation. ASCL1 can promote glioblastoma cancer stem cell properties and Wnt pathway activation, and we found that the number of liver stem cell and the expression of ASCL1 increased in SPTBN1 +/- mice liver. So we hypothesize loss of SPTBN1 can promote proliferation and malignant transformation of liver stem cells by activating ASCL1-induced Wnt pathway. In this project, we firstly establish DDC -induced liver stem cell activation model with SPTBN1+/- and WT mice. Using liver tissue or sorting liver stem cells, we will study the role of SPTBN1 on proliferation and malignant transformation of liver stem cells and on activation of ASCL1/Wnt pathway. Then using liver stem cells or MEF cells, the mechanisms of SPTBN1 on Wnt pathway activation by inducing ASCL1 expression will be explored. Finally, correlation between expression of SPTBN1 and clinic pathological features, liver stem cell markers and Wnt pathway will be demonstrated by immunohistochemistry stain on HCC tissue. Our project will provide a theoretical basis for the search for new markers and therapeutic targets for liver cancer.