TRPM7参与EGF诱导的肺腺癌细胞迁移的分子机制研究

TRPM7 is a special non-selective cation channel with dual function of ion channel and serine/threonine kinase. In past eleven years since TRPM7 was cloned in 2001, many research institutes around world have been studying its function including its roles in carcinogenesis. However, few work have been reported to study the roles of TRPM7 in tumor metastasis. A search on the Pubmed only found three related research papers, including one published by us. In 2011, we published an article in Cell Calcium that described the EGF-mediated up-regulation of TRPM7, which seems underlie the EGF-induced migration of lung adenocarcinoma cells. Based on these findings, this application is designed to further investigate the molecular mechanisms involved in the EGF-mediated up-regulation of TRPM7 and to study the participation of TRPM7 in the migration of cancer cells. Especially investigate the roles of kinase of TRPM7 in the migration of cancer cells.The whole cell patch clamp, confocal microscopy and molecular biology techniques will be used to perform experiments using A549 and Flp-InTMT-REXTM293 cells. This study will increase our knowledge about mechanisms involved in the regulation of TRPM7 function and roles of TRPM7 in the tumor metastasis. It will provide new thinking and targets for treatment of tumor metastasis.

TRPM7是2001年成功克隆，有通道和激酶双重作用的特殊的非选择性阳离子通道。经过短短十一年的研究，其在肿瘤方面的作用已引起世界多家研究机构的关注。但迄今为止，关于TRPM7在肿瘤转移方面的作用研究较少，目前尚处于起步阶段。通过pubmed检索到的相关研究论文只有三篇。其中一篇为申请人2011年在Cell Calcium上发表的论文，文章描述和论证了EGF通过上调TRPM7的通道功能促进肺腺癌细胞迁移这一现象。本课题基于上述实验现象，拟采用全细胞膜片钳、激光共聚焦及分子生物学等技术手段，在A549和Flp-InTMT-REXTM293细胞，探讨此现象所涉及的EGF上调TRPM7以及TRPM7参与肺腺癌细胞迁移两方面的分子机制。其中重点阐明其激酶功能在细胞迁移中的作用。我们的研究将有利于更全面揭示TRPM7的调节机制以及其在肿瘤迁移中的作用，为肿瘤转移的防治提供新的理论及作用靶点。

TRPM7是一种兼有激酶作用的非选择性阳离子通道，通道功能与肿瘤细胞的增殖和迁移有关，但其参与肿瘤细胞迁移的分子机制尚不清楚且临床缺乏以TRPM7为靶点的抗肿瘤药物。本课题以肺腺癌A549细胞、乳腺癌MCF-7细胞、胃癌BGC823细胞及肺动脉平滑肌细胞为研究对象，探讨TRPM7参与肿瘤细胞及肺动脉平滑肌细胞迁移的分子机制并对新型苯酰脲类衍生物SUD抗肿瘤细胞迁移的分子机制进行研究。本课题工作为临床寻找抑制肿瘤转移及抑制肺动脉高压的作用靶点及以TRPM7为靶点的抗肿瘤药物提供实验依据。