β-Catenin 蛋白Tyr142位点磷酸化修饰促进肝癌发生的机制研究

Wnt/β-catenin信号通路异常激活与肝癌发生高度相关，但该通路仍缺乏安全有效的具体药物靶点。我们前期发现β-catenin蛋白Tyr142位点被磷酸化修饰后（pY142）能显著促进小鼠肝癌的发生及肝癌细胞体外增殖，提示该位点上游激酶可能作为肝癌治疗新靶点，但pY142β-catenin促癌功能的分子机制尚未明确。本项目拟首先研究pY142β-catenin在肝癌细胞系和肝癌组织中的表达水平及其与病人预后的相关性；其次明确pY142β-catenin对Wnt/β-Catenin信号活性及肝癌细胞生理活动的影响；随后从蛋白蛋白互作、蛋白核质分布及蛋白稳定性等角度阐明其促癌分子机制；最后尝试寻找Y142位点上游激酶，并在细胞及动物模型中验证其作为肝癌治疗靶点和预后分子的可能性。本项目不仅更新了β-Catenin蛋白在翻译后水平的功能调控机制，也为肝癌病人的临床治疗提供新治疗靶点和思路。

Aberrant activation of Wnt/β-catenin signaling pathway is highly associated with the oncogensis of hepatocellular carcinoma. However, therapeutic interventions of this pathway are currently very limited due to the lack of safe and efficacious drug targets. Our preliminary results showed that phosphorylation of Tyr 142 of β-catenin greatly boosted carcinogenesis of an orthotopic mouse hepatocellular carcinoma (HCC) model and the proliferation of a HCC cell line, suggesting that the upstream kinase of Tyr 142 is a potential therapeutic target for HCC. The molecular mechanism of the pro-oncogenic activity of pY142 β-Catenin remained unknown. In this proposal, we will initially examine the expression of pY142 β-Catenin in HCC cell lines and patient samples and analyze its correlation with the prognosis of patients; We will further investigate the impact of pY142 β-Catenin on the physiological activities of hepatocellular carcinoma cells as well as the activity of Wnt/β-Catenin signaling pathway; We will then aim to unravel the mechanism of the pro-oncogenic activity of pY142 β-Catenin from the angles of protein-protein interaction, protein cytoplasm/nucleus distribution and protein stability; Lastly, we will attempt to identify the upstream kinase of Tyr 142 and test its potential as a drug target or a prognostic marker of hepatocellular carcinoma using cell line, mouse xenograft models and patient samples. This project not only updates our understanding of functional regulations ofβ-Catenin at the post-translational level, but also provides new therapeutic targets and strategies for hepatocellular carcinoma patients.