线粒体定位的MICAL2基因选择性剪接体调控肺癌细胞凋亡的分子机制

项目名称： 线粒体定位的MICAL2基因选择性剪接体调控肺癌细胞凋亡的分子机制

项目编号： No.81501959

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 文普帅

作者单位： 锦州医科大学

项目金额： 18万元

中文摘要： MICAL2基因是诱导活性氧产生的关键因素，其选择性剪接产物MICAL2PVs与肿瘤的发生及演进密切相关。我们的前期工作发现，肺癌组织中MICAL2PVs的表达水平降低；进一步的研究表明，MICAL2PVs定位于线粒体，能够影响线粒体内活性氧水平，并激活线粒体凋亡途径促进肺癌细胞的凋亡，但其分子机制尚不明确。本课题拟从寻找其线粒体定位信号肽、检测其对线粒体的氧化损伤与功能影响以及筛选、鉴定其线粒体内相互作用蛋白角度，阐释MICAL2PVs影响线粒体活性氧水平，促进肺癌细胞凋亡的分子机制；以裸鼠肺癌动物模型和临床肺癌样本为研究对象，进一步确证MICAL2PVs调控肺癌细胞凋亡的作用，并检测其在肺癌组织中的表达情况及与临床病理因素的关系。本课题最终将阐明MICAL2PVs调控肺癌细胞凋亡的分子机制以及与肺癌发生发展的关系，为临床寻找肺癌生物治疗新的分子靶标提供新的思路。

中文关键词： 肺癌；选择性剪接；线粒体；活性氧；凋亡

英文摘要： MICAL2 gene serves as a crucial regulator, which can induce the production of reactive oxygen species. MICAL2PVs, the alternative splicing products of MICAL2 gene, have been reported to involve in tumor development and progression. Our previous studies showed that the expression of MICAL2PVs was downregulated in lung cancer tissues; further studies discovered that MICAL2PVs can locate in mitochondria and influence the level of reactive oxygen species in mitochondria, in addition, overexpression of MICAL2PVs leads to apoptosis in lung cancer cells via mitochondrial apoptotic pathway. However, the molecular mechanisms underlying lung cancer cells apoptosis mediated by MICAL2PVs have not been clearly demonstrated. The following experiments will be carried out in the current project: to analyze MICAL2PVs’ mitochondrial signal peptide and investigate its effects on mitochondrial oxidative injuries and functional changes; to screen and identify the binding partners of MICAL2PVs in the mitochondria by tandem affinity purification and mass spectrometric analysis, and further investigate the effects of the identified binding partners on lung cancer cells apoptosis induced by MICAL2PVs; to investigate the effects of MICAL2PVs expression on lung cancer cells apoptosis using a xenograft model in nude mouse; in addition, to study the expression of MICAL2PVs in lung cancer tissues and its clinical significance. The progress from this project, is not only benificial to understand the molecular mechanisms of MICAL2PVs involvement in lung cancer apoptosis, but also the correlation between MICAL2PVs, and development and progression in lung cancer. These new progresses are expected to provide new ideas to find new targeted therapy sites for lung cancer.

英文关键词： Lung Cancer;Alternative splicing ;Mitochondrion;Reactive oxygen species;Apoptosis