DNA Damage Repair Gene EXO1 Promotes The Proliferation And Invasion Of Hepatocellular Carcinoma And Its Upstream Transcriptional Regulation Mechanisms

Substantial evidence suggests that DNA damage repair genes play an extremely important role in cancer.Our previous gene chip results showed that exonuclease 1(EXO1)is highly expressed in hepatocellular carcinoma(HCC).However,the function and mechanism of EXO1 in HCC are currently unknown.Through clinical tissue samples,we found that the expression of EXO1 in tumor tissues were significantly higher than adjacent non-tumor tissues.Its high expression is associated with liver cirrhosis and indicates poor long-term outcomes of HCC patients.Further studies have found that EXO1 knockdown can attenuate the proliferation,colony formation,migration and invasion ability of HCC cells in vitro,and the tumorigenic ability of HCC cells in vivo,while the above capabilities of HCC cells are significantly enhanced by EXO1 overexpression.In addition,transient silencing and overexpression of EXO1 show that EXO1 can regulate the expression levels of p21,p53 and BAX.We also constructed the promoter region and truncated fragments upstream of the EXO1 transcription start site(TSS),and screened out the transcription factor FOXP3 that can regulate EXO1 gene expression.Through luciferase reporter assays we found that FOXP3 could bind to the EXO1 promoter region to promote EXO1 transcription,and the location of the FOXP3 binding site in the EXO1 promoter region was explored.Next,we verified that FOXP3 can regulate the m RNA and protein expression of EXO1.Through clinical samples and GEO database,we found that the expression of FOXP3 and EXO1 is positively correlated in HCC.In conclusion,our research revealed that EXO1 is overexpressed in HCC,which can enhance the proliferation,migration and invasion ability of HCC cells in vitro and the tumorigenic ability in vivo.The transcription factor FOXP3 can regulate the transcription of EXO1.Therefore,EXO1 and FOXP3 may become effective therapeutic targets for HCC,which will open up new paths for the diagnosis and molecular therapy of HCC.