线粒体DNA 10398位点突变异质性对非小细胞肺癌放射敏感性的影响

项目名称： 线粒体DNA 10398位点突变异质性对非小细胞肺癌放射敏感性的影响

项目编号： No.81472798

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： 周福祥

作者单位： 武汉大学

项目金额： 72万元

中文摘要： 我们前期研究发现临床接受综合治疗（含放疗）的肺癌患者组织标本mtDNA含量低并伴有mtDNA 10398A的患者预后差，提示10398位点突变可能与放射敏感性有关。然而多项该位点突变影响肿瘤治疗敏感性和预后的研究结论并不一致，分析其原因可能与突变异质性有关。本研究拟检测接受放疗的非小细胞肺癌患者组织标本mtDNA 10398G/A突变比例，估计该位点突变异质性范围；在此基础上建立体外和体内非小细胞肺癌mtDNA 10398G/A突变异质性模型，研究其对放射敏感性的影响，并从呼吸链复合酶I的活性和含量变化、线粒体形态和功能代谢改变（ROS、ATP、乳酸代谢、凋亡等）及线粒体对细胞核逆向调控（HIF-1α通路、核DNA损伤修复等）等方面探讨其可能机制，为非小细胞肺癌放射敏感性的预测及预后评估提供有效手段，也为肺癌放疗增敏提供潜在的分子靶标，并进一步丰富放射敏感性的理论研究。

中文关键词： 放射敏感性；突变异质性；非小细胞肺癌；线粒体DNA

英文摘要： In our previous study, in patients with lung cancer who received comprehensive treatments (including radiotherapy), we found that those who carried mtDNA 10398A and lower mtDNA content have poor prognosis. This finding indicated that missense mutation in mtDNA 10398 locus may be associated with the radiosensitivity. However, the relationship between prognosis and mtDNA 10398G/A mutation had been reported in several studies with controversial conclusions. The reason why there were controversial may be related to heteroplasmic mutation. Herein, in our further study, the mtDNA 10398G/A heteroplasmic mutation in tumor tissue of non-small lung cancer(NSCLC) who have received radiotherapy will be detected to estimate the range of this heteroplasmic mutation. And then, the model of heteroplasmic mutation in NSCLC cells will be constructed in vivo and in vitro for studying the influence of these cells on radiosensitivity and determine the ratio of the heteroplasmic mutation. After that, the content and activity of respiratory chain complex I , the changes of morphology and metabolism in mitochondrial (ROS, lactate, apoptosis)，and the mitochondrial retrograde signaling(HIF-1α signal pathway, nuclear DNA damage and repair) will be detected to investigate the mechanism that how these changes affects the radiosenstivity of NSCLC cells. The results of this research will provide an effective approach for a prediction of radiosensitivity , a evaluation of prognosis, and a potential molecular target of radiosensitization. This work will help for developing the theory that mitochondrial regulates radiosensitivity.

英文关键词： radiosensitivity;heteroplasmic mutation;non-small cell lung cancer;mitochangdrial DNA