CNTN-1介导的PINK1/Parkin途径线粒体自噬在顺铂促人肺腺癌向小细胞肺癌转化中的作用机制研究

The transformation of lung adenocarcinoma into small cell lung cancer is an important mechanism of drug resistance in patients with lung adenocarcinoma, and cisplatin may be one of the inducement of this transformation process. Previous studies have suggested that contactin-1 (CNTN-1) and mitophagy can mediate the transformation of some epithelial tumors to mesenchymal phenotype, and that CNTN-1 can promote the malignant progression of tumor cells through the upstream signal pathway of mitophagy. Our previous study found that cisplatin could mediate the transformation of lung adenocarcinoma cells from epithelial phenotype to mesenchymal phenotype by up-regulating CNTN-1 expression, and that cisplatin-stimulated lung adenocarcinoma cells showed neuroendocrine function and enhanced mitophagy through the PINK1/Parkin pathway. Given the neuroendocrine function and epithelial to mesenchymal transition-like phenotype of small-cell lung cancer, we speculated that cisplatin could activate mitophagy though the PINK1/Parkin pathway by up-regulating CNTN-1 expression, and then promote the transformation of lung adenocarcinoma into small cell lung cancer. This project will use the clinical cancer tissue samples, lung adenocarcinoma cells and nude mouse xenograft models, to investigate the role and signal transduction mechanism of the CNTN-1-mediated mitophagy through the PINK1/Parkin pathway in promoting the transformation of human lung adenocarcinoma to small cell lung cancer caused by cisplatin treatment. This study will provide theoretical basis for clinical treatment strategies for patients with this type of lung cancer.

肺腺癌向小细胞肺癌转化是肺腺癌患者耐药的重要机制，顺铂可能是该转化过程的诱因之一。既往研究提示接触蛋白-1(CNTN-1)和线粒体自噬可介导上皮源性肿瘤向间质表型转化，且CNTN-1能通过线粒体自噬上游信号通路促进肿瘤细胞的恶性进展。我们前期研究发现顺铂可通过上调CNTN-1表达介导肺腺癌细胞由上皮表型向间质表型转化，且顺铂刺激的肺腺癌细胞出现神经内分泌功能和PINK1/Parkin途径线粒体自噬增强。鉴于小细胞肺癌具有神经内分泌功能和上皮向间质转化样表型特点，我们推测：顺铂可通过上调CNTN-1表达激活PINK1/Parkin途径线粒体自噬，继而促使肺腺癌组织向小细胞肺癌组织转化。本项目拟在临床癌组织样本、肺腺癌细胞和裸鼠移植瘤模型中，探讨CNTN-1介导的PINK1/Parkin途径线粒体自噬在顺铂促肺腺癌向小细胞肺癌转化中的作用及信号传导机制，为肺腺癌患者的临床治疗策略提供理论依据。

肿瘤细胞转移和侵袭是导致晚期肺腺癌患者治疗失败，造成预后欠佳的主要因素。既往研究显示化疗药物在杀灭癌细胞的同时还具有促进肿瘤细胞恶性进展的作用。本研究摸索出了适合A549细胞生存的顺铂浓度，并探究在此浓度的顺铂作用下A549细胞恶性进展情况及潜在作用机制，为明确无基因靶向治疗机会的晚期肺腺癌患者在化疗过程中出现恶性进展甚至耐药的机制提供坚实的理论依据。本研究显示在合适剂量的顺铂作用下A549细胞发生上皮向间质样表型转化并伴随着肿瘤细胞迁移和侵袭能力增加及接触蛋白-1表达水平上调。进一步体内外研究显示在A549细胞中过表达CNTN-1后细胞表现出上皮向间质样表型转化并伴随着恶性进展。因此本研究揭示了肺腺癌中CNTN-1表达水平升高使得肿瘤细胞发生表型转化进而促进其迁移侵袭等恶行生物学行为进展。本研究与以往研究报道一致，证实了化疗药物在治疗肿瘤的同时亦可促进肿瘤细胞的进展并探索其潜在机制。