α-catenin在肝癌发生发展中的生物学功能及分子调控机制研究

本研究从α-catenin在肿癌组织中严重下调或缺失的临床问题出发，意在借助生物学方法和分析化学技术的交叉运用，揭示α-catenin在肝癌发生发展中的生物学功能及作用机制。利用代谢组学和蛋白质组学，在过表达或shRNA敲除α-catenin的肝癌细胞中找出差异性代谢物、蛋白质和与α-catenin相互作用蛋白，揭示α-catenin在肝癌中作用机理；借助分子生物学，验证其作用机制和信号通路；利用细胞生物学和动物模型，验证最显著变化代谢物和蛋白质对肝癌细胞的增殖、侵袭性、抗凋亡等恶性生物学行为的影响，阐明α-catenin变化在肝癌发生过程中的生物学功能。最后结合临床病理特征和数据，核实α-catenin在肝癌患者中的突变和表达变化，分析肝癌中α-catenin与本研究中新发现的信号通路的相关性。综上研究，为推进α-catenin在肝癌检测、治疗和预后中的临床转化应用提供可靠的科学依据。

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death worldwide. Defining the function of tumor suppress gene has great significance for early detection, diagnosis, treatment and prognosis of HCC. As an adheren junction (AJs) connector, α-catenin (CTNNA1) is frequently mutated in HBV-related HCC patients. We will identify the tumor suppressive role of α-catenin and related new mechanisms in liver cancer development. HCC cells transduced with α-catenin-shRNAs (or ectopic expression of α-catenin) will be studied by approaches of metabolomics and proteomics, aiming to determine significantly altered metabolites and proteins, as well as protein-α-catenin.interactions. Next, molecular biology methods and animal study will be applied to verify uncovered new signaling pathways. Then, malignant behavior such as cell proliferation, migration, invasion and tumorigenicity will be inspected of HCC cells transduced with α-catenin-shRNAs (or ectopic expression of α-catenin) with significantly changed metabolites and proteins treatment. Lastly, clinical pathological data will be analyzed to verify the mutation and expression of α-catenin in human HCC and to investigate its relevance to newly-identified signaling pathways. Taken together, this proposal will provide new insights into the role of α-catenin in HCC, which could present scientific rational of utilizing α-catenin as a biomarker for detection, treatment and prognosis in HCC.