Functional Study Of DNASE1L3 In Human Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is a malignan type of cancer with a second mortality rate worldwide.HCC is difficulty in early detection,poor prognosis and high mortality in later stage.According to statistics,there are 800,800 people who die of liver cancer around the world each year.In the past three decades,the incidence of HCC has tripled in developed regions,and it has become the fastest growing cancer cause in the developed countries.In China,where the majority of liver cancer occurs,the incidence and mortality of HCC are higher than the average level in the world.At present,diagnosis and treatment methods for HCC are limited and the recurrence rate remains high.Therefore,it is increasingly important to study the molecular mechanism of HCC development and to screen out the corresponding HCC prognosis and progression biomarkers to provide effective targets for clinical HCC treatment.Deoxyribonuclease 1 Like 3(DNASE1L3)belongs a member of the deoxyribonuclease I family.It catalizes DNA hydrolization.DNASE1L3 is capable of cleaving single and double stranded DNA,and have the ability to process chromatin into nucleosome units and to cleave nucleosomes and liposome-coated DNA.At present,the most important research on DNASE1L3 is its correlation with systemic lupus erythematosus and it plays a important role in autoimmune diseases.Using bioinformatics analysis and HCC patient samples,we found that the expression level of DNASE1L3 in HCC was downregulated compared to their matched adjacent tissues or normal tissues.Furthermore,the expression level of DNASE1L3 was positively correlated with the survival rate of clinical HCC patients,indicating that DNASE1L3 may play an important role in the development of HCC as a potential tumor suppressor.Next,we stably overexpressed DNASE1L3 in Huh7,HCCLM9 and HepG2 hepatoma cells and measure the proliferation and migration of these cells by CCK-8,Transwell and RTCA methods.We found that DNASE1L3 has an inhibitory function on the proliferation and migration of Huh7 and HCCLM9 cells.The ability of DNASE1L3 to inhibit the migration of HCCLM9 cells required its DNase activity.DNASE1L3 with poin mutation R206 C or with C terminal deletion showed significantly reduced ability to suppress migration.Subsequently,DNASE1L3 suppressed the ability of HCCLM9 cell to form tumors subcutaneously in nude mice.In addition,the dual luciferase reporter assay showed that DNASE1L3 may be associated with the most classical cGAS-STING pathway in innate immunity.Taken together,this study reveals the inhibitory effect of DNASE1L3 on the proliferation and migration HCC cells,and this inhibition is related to the DNase activity of DNASE1L3.In addition,the function of DNASE1L3 may be related to the innate immune cGAS-STING pathway.This experiment provides new insights for the study of DNASE1L3 function.Overall,our research contributes to an in-depth understanding of the molecular mechanisms underlying the development of hepatocellular carcinoma and provides potential biomarkers or therapeutic targets for HCC.