c-Met是治疗胃癌的一个重要靶点，然而现有证据表明抗c-Met治疗仅在部分胃癌患者中有效，如何选择潜在有效患者进行靶向c-Met治疗是目前亟需解决的科学问题。研究显示多个靶点基因的转录变异体与患者选择及耐药密切相关。在前期研究工作中，申请者通过生物信息学成功克隆了一个新的c-Met转录变异体，并在转录水平验证了该变异体的存在。该变异体缺少C端的酪氨酸激酶结构域，提示其在胃癌中的作用与野生c-Met不同，在靶向c-Met治疗筛选患者中可能起“假阳性”作用。本研究拟在蛋白质水平验证该转录变异体在胃癌中的表达，通过受体-配体相互结合、生物学行为、信号传导等阐述c-Met新转录变异体与野生型c-Met的功能关系及其作用机制，并进一步明确其在靶向c-Met治疗晚期胃癌中的患者选择作用。该项目在阐明c-Met转录变异体作用机制的基础上，将为临床靶向c-Met精准治疗胃癌患者提供新的理论和应用基础。

c-Met is an important target in treatment of gastric cancer, which has been proved in several clinical trials. However, how to choose suitable patients for targeted therapy is still needed to be resolved. It was reported that transcript variants are close related to the tumorigenesis and progression, as well as drug resistance of targeted therapy. In the preliminary study, we cloned a novel c-Met transcript variant through bioinformatics and validated it in transcriptional level. The novel c-Met transcript variant only contain the N terminal of wild c-Met and shortage of C terminal of wild c-Met, which indicates the transcript variant might have different role compared with wild c-Met. It indicates that c-Met transcript variant may play “false positive” in patient selection for targeting c-Met treatment. This study will validate the novel c-Met transcript variant protein expression in gastric cell lines and tissues. Receptor-ligand interaction, biological behavior and signaling transduction were used to illustrate the role and molecular mechanism between novel c-Met transcript variant and wild c-Met. We will further investigate the role of c-Met transcript variant in patient selection for targeting therapy of c-Met in gastric cancer. This study is on target to reveal the functional mechanism of novel c-Met transcript variant in gastric cancer. It will also provide important foundations of theory and application for individual therapy of targeting c-Met in gastric cancer.