线粒体MTA3通过ROS促进食管鳞癌顺铂耐药的机制研究

耐药是导致食管鳞癌化疗失败和预后不良的主要原因，但相关机制不明。前期通过分析食管鳞癌顺铂耐药患者的临床标本，我们发现组蛋白修饰共调节因子MTA3在细胞浆中异常表达，其表达水平与顺铂耐药密切相关且预后更差。细胞实验表明：顺铂耐药时高表达的MTA3主要定位于线粒体，MTA3通过影响线粒体基因组诱导活性氧ROS升高。免疫共沉淀和蛋白印迹等分子实验显示：MTA3通过与线粒体基因组相关转录因子TFAM竞争结合轻链启动子LSP，降低TFAM转录活性，从而抑制电子传递链复合物I主成分MT-ND6的转录，导致ROS升高，最终诱发细胞耐药。基于此，本项目拟从分子、细胞、动物及临床标本等多个层面，系统阐释MTA3通过调控MT-ND6/ROS信号促进食管鳞癌顺铂耐药的机理，为食管鳞癌个体化治疗提供新的思路。

Drug resistance is the main factor leading to the failure of chemotherapy for esophageal squamous cell carcinoma, but the mechanism remains unclear. Using clinical samples, we found that histone modified co-regulator MTA3 was aberrant expressed in in cytoplasm. Cytoplasm MTA3 expression was closely related to cisplatin resistance and poorer survival. Cellular experiments were performed to demonstrate that MTA3 was mainly expressed in mitochondria and promoted ROS production when tumor cells were resistant to cisplatin. Molecular experiments, such as immunoprecipitation and immunoblotting, were performed to show that MTA3 inhibited the transcription function of TFAM, a transcription factor associated with mitochondrial genome, by competitively binding to LSP and thus prevents the transcription of electron transport chain complex I principal component MT-ND6, leading to ROS elevation and drug-resistance. This project intends to systematically study the mechanism of MTA3 promoting cisplatin resistance in esophageal squamous cell carcinoma by regulating MT-ND6 /ROS signals from molecular and cellular level using mouse and clinical samples.