REGγ Promotes Hepatocellular Carcinoma By Regulating ATM/ATR Pathway

In recent years,the incidence of hepatocellular carcinoma has gradually increased.It has been ranked as the sixth most common neoplasm and the third leading cause of cancer death.This article focuses the effect of REGγ on the occurrence and development of hepatocellular carcinoma,and introduces the phenotypic differences of liver cancer caused by the loss of REGγ in organisms and the molecular signaling pathways that regulate it.First,for the phenotypic analysis of DEN-induced advanced hepatocellular carcinoma mouse model by visual observation,section pathology and marker protein staining,we can found that in the REGγ-deficient mice,the incidence and malignancy of liver cancer were both decreased.Then based on the phenotypic differences,we explored the molecular signaling pathway.It was found that when the REGγ was knocked out,there was a significant increase in CHK1 protein level in cells and tissues.Subsequently,using co-immunoprecipitation experiments,it was demonstrated that REGγ directly interacts with CHK1 protein,which indicates that REGγ causes the above phenotypic differences by regulating the CHK1 protein in the ATM/ATR signaling pathway.Next,we discovered that REGγ directly participates in the degradation of CHK1 protein in cells by acting on the 345 th amino acid of CHK1.Finally,we induced early hepatocellular carcinoma model in mice by intraperitoneal injection of DEN and analyzed the level of γH2AX,p-CHK1,and downstream protein p-p53 in liver tissues by immunohistochemistry.Significantly,it was found that DENinduced REGγ knockout mice developed a strong DNA damage repair response.As a result,the incidence of hepatocellular carcinoma is reduced,which also provides a basis for our previous discovery.Through the analysis of the results of this study,we may be able to reduce the development of hepatocellular carcinoma in vivo by interfering with the expression of intracellular REGγ,which has a promising clinical prospect.