c-MET信号通路与肝癌耐药机制的研究

项目名称： c-MET信号通路与肝癌耐药机制的研究

项目编号： No.81472321

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 孙学英

作者单位： 哈尔滨医科大学

项目金额： 80万元

中文摘要： 肝癌是我国高发恶性肿瘤，在癌症致死原因中居第二位。在国家自然基金资助的项目研究中，课题组发现索拉菲尼耐药肝癌细胞高表达c-MET和磷酸化c-MET，组织芯片发现索拉菲尼治疗后的肝癌组织表达c-MET的水平和阳性率明显上升；另外与肿瘤耐药机制密切相关的缺氧状态显著提高了肝癌细胞c-MET的活化。这些初期研究结果提示c-MET介导的信号通路在肝癌耐药机制起着重要作用。本项目中，课题组利用在肝癌索拉非尼耐药机制和治疗研究方面建立的技术平台和方法，进一步研究索拉非尼影响c-MET表达和活化的分子机制、缺氧影响c-MET活化的分子通路、索拉非尼作用通路、缺氧信号和c-MET信号通路间的相互调节作用以及信号网络的关键分子靶点。对于这些问题的研究将有助于阐明肝癌细胞索拉非尼耐药机制，寻找影响肝癌对索拉菲尼耐药机制的关键分子靶点，为研发新的分子靶向药物提供有力的证据。

中文关键词： C09_肝和肝内胆管肿瘤；c-MET；索拉菲尼；细胞信号通路；耐药

英文摘要： Hepatocellular carcinoma (HCC) ranks the second place of cancer-related deaths in China. In the last project supported by National Natural Scientific Foundation of China, our team has revealed that sorafenib-resistant HCC cells expressed higher levels of c-MET and phosphoralted c-MET. The results of tissue arrays showed that tissues of human HCC that had been treated with sorafenib had significantly higher positive rates and expression levels of c-MET compared with untreated HCC tissues. Hypoxia, which is closely related to drug resistance in HCC, induced the activation of c-MET in HCC cells. These preliminary results indicate that the c-MET signal pathway may participate in the sorafenib resistance in HCC.However, there are several key questions on the regulatory mechanisms and cross-talks among these pathways remain unclear. The current project aims to explore further the mechanisms accounting for the resistance to sorafenib based on our recent discovery on this area in HCC, our recent preliminary data of studies on c-MET, hypoxia-inducible signaling pathway and already established techniques and methods in therapeutic strategies in HCC. The project will investigate how sorafenib affect the expression and activation of c-MET, the signaling pathways involved in the activation of c-MET by hypoxia, the cross-talks among sorafenib-targetted molecular pathways, c-MET pathway and hypoxia-inducible pathway, and whether blocking c-MET pathway could overcome the resistance of HCC to sorafenib. The answers to these questions will better our understanding of the molecular mechniams involved in the sorafenib resistance in HCC, and help seeking appropriate molecular targets and therapeutic strategies.

英文关键词： Hepatocellular carcinoma;c-MET;sorafenib;cellular signalling;drug resistance