Effects Of Mitochondrial Genomic Variation On The Progression And Prognosis Of Colorectal Cancer

The mtDNA variations consist of mt DNA copy number variation,mtDNA germline mutations and mitochondrial somatic mtDNA mutations,which has been linked to the evolution of tumor.So far,the mtDNA mutations has been detected in almost all types of tumors.These mutations can cause cellular mitochondrial oxidative stress,leading to a vicious cycle.Our previous work showed a significant positive correlation between increased mtDNA copy number and the risk of colorectal cancer(CRC).In addtion,we also found that mtDNA copy number is closely related to clinical stage and pathologic stage of CRC.The present study intends to systematically analyze the relationship between mtDNA mutation and the progression and prognosis of CRC,and to further explore its underline mechanisms.Our study can be divided into three parts:In the first part,we examined mtDNA copy number and the expression of TFAM in 120 cases of colorectal cancer tissues.Then,we constructed the cell model without mtDNA and with abnormal mtDNA copy number.After that,cell cycle,proliferation,apoptosis and migration were analyzed.The effect of mtDNA copy number on mitochondrial respiratory function was also detected on the basis of the changes of tumorigenic ability of mtDNA abnormalities in nude mice by subcutaneous tumorigenesis.Our results showed that:(1)The mtDNA copy number in microsatellite stable cancer tissue was clearly increased comparaed with in microsatellite unstable tussue,the expression level of TFAM showed a similar pattern.(2)There was a significant positive correlation between the mtDNA copy number and the expression levels of TFAM,and both of mtDNA copy number and the expression levels of TFAM have a consistent trend with the prognosis of patients with colorectal cancer.(3)The abnormal of mtDNA copy number can significantly promotes the proliferation invasion and migration of CRC cells,,while inhibits the cell apoptosis.(4)The overexpression of TFAM increased mtDNA copy number a tumorigenicability of CRC cells.(5)The increased mtDNA copy number can induce metastasis and proliferation ability of CRC cells.(6)The abnormal increase of mtDNA copy number can significantly promote the oxygen consumption rate,ROS and ATP production,and inhibitcell membrane potential of CRC cells.In the second part,we analyzed the number,distribution,function and prognosis of SNP shift in 116 colorectal cancer tissues and the datas from the public CRC databases.Our results showed that:(1)172 SNP shift mutations were found in colorectal cancer and paracancerous tissue and 75 SNP shift mutations were found in normal tissues and blood.(2)The SNP shift was mainly positive in cancer.The SNP shift mutation in cancer tissue was mainly G> A,T> C conversion.In the third part,we analyzed the number,distribution,function and prognosis of mtDNA mutations in colorectal cancer tissues by analyzing the mtDNA depth of 116 colorectal cancer tissues and the datas from the public CRC databases.Our results showed that:(1)110 mt DNA mutations were found in colorectal cancer tissues,and an average of 0.95 mutations in one CRC patient.(2)According to the location of mtDNA mutations in colorectal cancer tissue,mtDNA mutations map of colorectal cancer was drawn.(3)The percentage of mutations in the complex 1 region of the cancer tissue was significantly higher than that of the normal tissue,while the percentage of mutation in the D-loop region was significantly higher than that in the normal tissue.(4)The conversion of G> A,T> C in cancer tissue was the main.Our present study analysised the influence of mitochondrial genomic variation on the progression and prognosis of colorectal cancer.We clarified both the effect and its underline meachnisms of abnormal mtDNA copy number on the progression and prognosis of colorectal cancer.It will not only provides the experimental basis for systematic study of the mitochondrial genomic variation.,but alos provides a useful thought to construct typing system to promote colorectal cancer molecular precision.