mtDNA拷贝数异常改变影响结直肠癌恶性演进的分子作用机制

Mitochondrial DNA (mtDNA) is the only genome outside nucleus and plays a crucial role in various biological functions of mammalian cells.Alterations of mtDNA copy number(increased or decreased) has been reported in various types of cancers, and several reports have showed that mtDNA copy number is significantly increased in colorectal cancer(CRC).Our recent study has revealed that the elevated mtDNA copy number is associated with higher risk of CRC. However,the molecular machanism of CRC development and progression triggered by abnormal variations of mtDNA copy number still remains to be unclear. Based on our experiences in the field of CRC and mtDNA, we aim to explore the biological functions and molecular mechanisms of CRC development and progression triggered by elevated mtDNA copy number. The major researches include: 1) To assess the association of mtDNA copy number variation and CRC progression by detecting mtDNA copy number in CRC tissues and cells. 2)To explicit the biological functions of mtDNA copy number variation on CRC progression by changing mtDNA copy number. 3) Through high-throughput screening techniques, just as gene chip, shRNA library screening, ChIP and phage-displaying polypeptides library, to investigate how the variation of mtDNA copy number promote CRC progression and explore possible mechanisms.This study will strengthen the understanding on molecular pathology of CRC and promote the establishment of the new strategy for CRC prevention and treatment based on mtDNA.

线粒体DNA（mtDNA）是细胞内唯一独立于核基因组之外的遗传物质，在人体生理及病理过程中发挥重要功能。研究表明，肿瘤细胞中的mtDNA拷贝数常呈现异常改变（增高或降低），如在结直肠癌中mtDNA拷贝数显著增高。我们前期研究证实：mtDNA拷贝数异常增高与结直肠癌的发病风险密切相关。然而，这种异常改变影响结直肠癌恶性演进的分子机制至今尚不十分清楚。本项目组基于以往在结直肠癌和mtDNA方面的研究基础和丰富经验，拟开展下列研究：①应用组织样本和细胞模型，分析mtDNA拷贝数异常改变与结直肠癌恶性演进的相关性。②通过干预细胞模型中mtDNA拷贝数，明确mtDNA异常改变在结直肠癌恶性演进中的生物学作用。③应用生物芯片等高通量技术，探讨mtDNA拷贝数异常改变影响结直肠癌恶性演进的分子机制。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mtDNA为靶点的防治策略奠定理论基础。

线粒体DNA（mtDNA）是细胞内唯一独立于核基因组之外的遗传物质，在人体生理及病理过程中发挥重要功能。研究表明，肿瘤细胞中的 mtDNA 拷贝数异常（升高和降低）呈现异常改变，如在结直肠癌中 mtDNA 拷贝数显著增高。本课题组前期研究证实： mtDNA 拷贝数异常增高与结直肠癌的发病风险密切相关。在此基础上本项目组通过组织样本研究发现，mtDNA拷贝数异常与结直肠癌患者的预后成明显的负相关。通过干预细胞模型中mtDNA拷贝数发现，mtDNA拷贝数异常显著促进结直肠癌细胞的增值和转移，并显著抑制其凋亡。应用western blot实验表明，mtDNA可通过活化AKT信号通路，增加促转移分子β-catenin和vimentin的表达，同时抑制促凋亡分子Bcl-2的表达，来促进结直肠癌的恶性进展。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 mtDNA为靶点的防治策略奠定理论基础。