mtSSB分子通过调控线粒体/ROS/端粒轴抑制结直肠癌生长的机制研究

Abnormality in mitochondrial functions and regulation of telomere length play a critical role in the initiation and progression of malignancies. Our previous studies have demonstrated that mitochondrial DNA (mtDNA) content and telomere length are associated with the risk and prognosis of several types of cancers. However, the interaction between mitochondria and telomere remains unknown. Mitochondrial single-strand DNA binding protein (mtSSB) is a key regulator of mitochondrial biogenesis. Our preliminary study has shown that mtSSB expression is significantly associated with the prognosis of colorectal cancer (CRC) patients. Forced expression of mtSSB induced significant enhancement of mitochondrial biogenesis and the fluorescence staining of reactive oxygen species (ROS) and telomere attrition in CRC cells. These findings raised our hypothesis that mtSSB may exert its effects on the growth of CRC through the mitochondria/ROS/telomere axis. Based on this hypothesis, we will examine the alterations in mitochondrial biogenesis, ROS level, telomere length, apoptosis and cell cycle of CRC cells after changing the expression of mtSSB in this proposed project. We will validate the mitochondria/ROS/telomere axis hypothesis on molecular, cell, animal and human tissue levels in our project. The data generated in our project will provide novel theoretical support for the current understanding on the molecular mechanisms of CRC development.

线粒体功能改变及端粒长度调控异常在肿瘤发生及进展中发挥了极其关键的作用，我们前期研究发现线粒体DNA（mtDNA）含量及端粒长度异常改变与多种肿瘤发病风险和预后密切相关，然而二者在肿瘤中的作用关系远未阐明。线粒体单链DNA结合蛋白mtSSB是调控线粒体发生的关键分子，我们预实验结果表明mtSSB表达与结直肠癌（CRC）患者预后显著相关，进一步实验证实上调mtSSB表达可显著增强线粒体生成及活性氧族（ROS）荧光染色，同时可见端粒明显缩短。进而我们提出研究假设：mtSSB可通过调控线粒体/ROS/端粒轴影响CRC生长。基于此，本项目拟通过调控mtSSB表达，利用各种生物学定量技术，检测线粒体发生、ROS水平及端粒长度，分别从分子、细胞、动物及组织水平深入探讨mtSSB影响CRC增殖、凋亡的作用，验证线粒体/ROS/端粒轴的机制假设，本项目的完成将为深入理解CRC分子病理机制提供新的理论支持。

线粒体功能改变及端粒长度调控异常在肿瘤发生及进展中发挥了极其关键的作用，我们前期研究发现线粒体DNA（mtDNA）含量及端粒长度异常改变与多种肿瘤发病风险和预后密切相关，然而二者在肿瘤中的作用关系远未阐明。线粒体单链DNA结合蛋白mtSSB是调控线粒体发生的关键分子，本项目发现mtSSB表达与结直肠癌患者预后显著负相关。通过干预细胞模型中mtSSB表达发现，mtSSB表达升高促进结直肠癌细胞生长。同时体内裸鼠成瘤实验证实以上结论。进一步研究发现，mtSSB通过促进线粒体发生增加ROS含量，从而通过增强端粒酶活性和端粒长度促进肿瘤细胞生长。同时，本项目发现白介素6可通过调节mtSSB启动子区的转录因子FOXP1促进mtSSB表达。本项目的完成将为深入阐明结直肠癌分子病理机制，建立以mtSSB为靶点的防治策略奠定理论基础。