MCU上调线粒体钙信号促进结直肠癌生长的作用机制研究

Mitochondrial calcium signaling is critical for mitochondrial function and cellular function. Mitochondrial calcium signaling abnormalities causes many diseases, but the roles of mitochondrial calcium signaling abnormalities in the development and progression of colorectal cancer remains unknown. Our previous study showed that the expression of mitochondrial calcium uniporter （MCU）was significantly increased in colorectal carcinoma tissues, and the upregulated MCU promoted the growth of colorectal carcinoma cells, which was associated to mitochondrial calcium signaling-mediated mitochondrial biogenesis and ROS. Based on the previous study, we hypothesized that upregulated MCU enhanced induces mitochondrial calcium signal, and ultimately promotes growth of colorectal carcinoma cells through regulating mitochondrial biogenesis and ROS production and activating its downstream signaling pathways. Based on the previous study on the mitochondrial function and the occurrence development of colorectal cancer, this project aims to explore the biological effects of mitochondrial calcium signal abnormality on the progression of colorectal carcinoma cells. This project will be beneficial to update the understanding on the molecular pathology of CRC and provide novel potential targets for the prevention, diagnosis and treatment of CRC.

线粒体钙信号对于线粒体及细胞功能的发挥至关重要。线粒体钙信号异常是多种疾病发生的重要原因，但这一改变是否在结直肠癌发生及进展中发挥关键作用尚无明确报道。我们前期获得重要发现：结直肠癌组织中线粒体钙离子单向转运体MCU表达异常升高，显著促进结直肠癌细胞增殖能力，而这一变化与线粒体钙信号介导的线粒体发生增强及ROS增加密切相关。基于此，我们提出假设：MCU上调引发线粒体钙信号增强，通过调控线粒体生物发生及ROS生成并影响其下游信号通路活化，最终促进结直肠癌细胞恶性增殖。本项目拟在以往研究线粒体功能与结直肠癌的工作基础上，以线粒体钙离子转运蛋白MCU为切入点，从动物-组织-细胞-分子等四个层次深入探索线粒体钙信号异常对结直肠癌生长的生物学作用，探讨关键信号通路改变，进而系统阐明线粒体钙信号异常参与结直肠癌细胞恶性进展的分子机制，为结直肠癌病因学研究及发现具潜在应用前景的肿瘤防治策略奠定理论基础。

线粒体钙信号对于线粒体及细胞功能的发挥至关重要。线粒体钙信号异常是多种疾病发生的重要原因。但线粒体钙信号改变是否在结直肠癌发生及进展中发挥关键作用尚无明确报道。钙离子“进”线粒体主要由线粒体钙离子单向转运体（mitochondrial calcium uniporter, MCU）复合体完成，MCU是该复合体的核心成员，在线粒体钙摄取过程中发挥核心作用。我们的研究发现：MCU在结直肠腺癌中呈显著高表达，且高表达MCU与结直肠癌患者不良预后有关。在结直肠癌细胞中，再次证实MCU表达水平与静息线粒体钙离子水平及线粒体钙离子摄取紧密相关。MCU诱导的线粒体钙离子摄取促进结直肠癌细胞线粒体生物发生。在细胞表型方面发现，MCU诱导的线粒体钙摄取促进结直肠癌细胞生长。体内实验证实，MCU诱导的线粒体摄取促进裸鼠皮下瘤恶性生长。机制研究表明，线粒体钙离子通过促进TFAM去磷酸化增强线粒体生物发生，线粒体钙离子介导的线粒体生物发生通过ROS/NFκB信号促进结直肠癌细胞恶性生长。以上研究结果不仅有助于深入理解MCU的功能，为结直肠癌的治疗提供新的理论基础，同时为全面理解线粒体钙信号调控线粒体生物发生促肿瘤恶性生长的作用机制提供新的依据和线索。