Effect Of Mitochondrial Transcription Factor A On Tumor Cell Proliferation And Autophagy And Its Regulatory Mechanism

In the evolution stage of tumor,the function of mitochondria are forced to change.Oncomine data show that there are many abnormal expressions of mitochondrial related genes in a variety of tumor cells,one of them is mitochondrial transcription factor A(TFAM).TFAM is encoded by nucleus and located in mitochondria,which is involved in the transcription and replication of mitochondrial genome and maintains the function of mitochondria.TFAM expression in sarcoma,liver cancer and breast cancer cells are generally higher than that in normal tissues and cells.Although TFAM is believed to promote and maintain the abnormal proliferation and metabolic characteristics of tumor cells,its potential molecular mechanism is not clear.Based on this,this paper mainly focuses on the impact of TFAM on tumor cells and its related mechanisms,including two parts:1.In view of the abnormally high expression of TFAM gene in many tumor cells,the effects of TFAM on tumor cell proliferation,apoptosis and radio-sensitivity were studied by constructing a stable low-expression cell line(sh-TFAM).The results showed that inhibition of TFAM expression could significantly reduce the proliferation rate of tumor cells and block the cell cycle from G1 to S phase.At the same time,the inhibition of TFAM expression also affected the stability and transcriptional activity of p53 protein and resulted in the low expression of its downstream target gene TIGAR.The down-expression of TIGAR could lead to ROS accumulation and DNA damage.Interestingly,the clone survival rate of the irradiated sh-TFAM groups were further reduced.These results indicated that inhibition of TFAM expression can downregulate p53-TIGAR signal transduction and increase DNA damage and the radio-sensitivity of tumor cells,which proved that TFAM can be a potential target for tumor radio-therapy.2.Tumor cells are accompanied by a high level of autophagy in the stage of deterioration and metastasis,which aims to provide material and energy supply for the proliferation and invasion of tumor cells.Considering the relationship between mitochondria and autophagy,based on the work of the first part,we continue to study the effect of TFAM on autophagy of tumor cells.The results showed that TFAM decreased the acetylation modification of p53 protein,which affected its protein stability and transcriptional activity,and then p53 regulated the expression of PISD gene by binding to PISD enhancer region;because the metabolite phosphatidylethanolamine(PE)of PISD participated in the biosynthesis of LC3-II,and LC3-? played an important role in the extension and closure of autophagic bodies.In conclusion,TFAM mainly affects the autophagy process of tumor cells through p53-PISD-LC3-? pathway,which provides a new experimental theoretical basis for understanding the relationship between mitochondria and autophagy of tumor cells.Mitochondrion are the metabolic reaction center of cells,participate in many kinds of life activities of cells,which are very important to maintain the functional state of cells.In this paper,through the study of tumor cell proliferation,cycle transformation,DNA damage repair and autophagy,we had proved that TFAM play an important role in the maintenance of tumor cell homeostasis,and the related mechanisms also have the certain significance for further understanding the relationship between mitochondria and tumor.