线粒体磷酸酶PTPMT1调节小细胞肺癌干细胞代谢及生物学特性研究

The cancer stem cells are located in hypoxic microenvironment and with abnormal energy metabolism. These characteristics are very important for developing novel target therapeutics. Ferroptosis is a recently recognized form of regulated cell death which closely related to energy metabolism and chemo-sensitivity. Our previous works indicated that PTPMT1 is a specific mitochondrial phosphatase closely related to energy metabolism and regulated by hypoxia signaling. However, its expression and roles in regulation of lung cancer stem cells including energy metabolism, ferroptosis and chemo-sensitivity have not been explored. In this study, by analyzing of PTPMT1 in clinical samples of patients with SCLC and PDX models, we will systematically elucidate the roles of PTPMT1 in regulation of lung cancer stem cell characteristics. By using the PTPMT1 silence strategies, we will clarify the roles of PTPMT1 in invasion, proliferation, apoptosis regulation and their mechanisms. We will establish of the assays for ferroptosis and clarify its roles in regulation of ferroptosis and chemo-resistance. The correlation of PTPMT1 expression and SCLC cell chemo-resistance will be explored. In conclusion, this project will elucidate a novel pathophysiological mechanism for SCLS development and provide novel diagnosis and therapeutic targets.

低氧微环境和能量代谢异常是肿瘤干细胞的重要特征，也是肿瘤靶向治疗的重要领域。细胞铁死亡是新近发现的一种细胞死亡方式。我们前期工作发现PTPMT1是线粒体特异并与细胞能量代谢密切相关的磷酸酶，并受低氧信号调控。但其在肺癌干细胞的表达调控及在细胞铁死亡及化疗敏感性的作用和机制并不清楚。本课题通过临床SCLC病人的标本分析和PDX动物模型，系统阐明低氧调控SCLC干细胞调控PTPMT1表达作用的机制；通过基因干涉策略，系统阐明其在SCLC细胞侵袭、增殖、凋亡、恶性转化过程中的作用；建立肺癌细胞铁死亡的检测技术，阐明其对细胞铁死亡的调控作用和机制；阐明PTPMT1和SCLC细胞耐药形成的相关性。本课题将阐明为SCLC病理生理的新机制并为其诊断及治疗提供新的靶点。