索拉非尼上调FoxM1的分子机制及该机制在肝癌治疗抵抗中的意义研究

项目名称： 索拉非尼上调FoxM1的分子机制及该机制在肝癌治疗抵抗中的意义研究

项目编号： No.81460558

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 颜冬菁

作者单位： 海南医学院

项目金额： 43万元

中文摘要： 索拉非尼是目前晚期肝癌患者的临床一线标准治疗药物，但治疗抵抗越来越成为阻碍其疗效的主要因素，相关机制亟待深入阐明。本课题组研究发现，索拉非尼可在肝癌细胞中诱导FoxM1在转录水平上调，下调FoxM1能显著促进索拉非尼对肝癌细胞的杀伤作用。索拉非尼上调FoxM1的机制可能与PI3K-Akt信号通路代偿性激活，并导致转录因子AP1活化有关。为证明这一假说，本课题拟首先通过特异性抑制剂与RNAi技术明确PI3K-Akt-AP1通路在索拉非尼上调FoxM1中的作用；然后通过报告基因、EMSA、ChIP实验证实AP1对FoxM1的转录调控作用，明确PI3K-Akt-AP1-FoxM1通路的存在；最后借助细胞与动物模型，观察PI3K-Akt-AP1-FoxM1通路在索拉非尼治疗抵抗中的意义，从而为阐明肝癌细胞对索拉非尼治疗抵抗的分子机理、设计针对性治疗策略提供理论依据。

中文关键词： 抗肿瘤药物；肝细胞癌；信号通路；多药耐药

英文摘要： Sorafenib is the first line drug currently approved to treat advanced hepatocellular carcinoma (HCC). However, acquired drug resistance have been raised and associated molecular mechanisms are not well known. Our data show that sorafenib-induced FoxM1 upregulation plays an important role in therapy resistance. Downregulation of FoxM1 significantly enhances the cytotoxity of sorafenib in HCC cells. We hypothesize that PI3K-Akt pathway is activiated after sorafenib treatment, subsequently AP1 is activiated and enhances the transcription of FoxM1. To validate this hypothesis and it's significance in HCC therapy resistance, we design this project. To investigate the role of PI3K-Akt-AP1 pathway in sorafenib-induced FoxM1 upregulation, we first inhibit this pathway by specific inhibtor and siRNA before sorafenib treatment. Then AP1-mediated FoxM1 upregulation directly at transcriptional level is tested by report gene assay, EMSA and ChIP techniques, respectively. HCC cell model and tumor-bearing mice model are used to evaluate the effect of sorafenib on HCC after suppressing or activating PI3K-Akt-AP1-FoxM1 pathway. Our project may provide evidence for elucidating the molecular mechanism of HCC cells resisting to sorafenib, and also give clues to design a new strategy for HCC therapy.

英文关键词： Sorafenib;HCC;Signal pathway;Resistance