CBX4 Promote Hepatocellullar Carcinoma Progression Via Inhibiting Senescence

Background: Hepatocellular carcinoma(HCC)is one of the most common malignant tumors,although the diagnosis and treatment of HCC has improved,the prognosis is still very poor.Because most of the liver cancer is developed from cirrhosis,it is unsuitable for curative surgical treatment,and very necessary to find a new alternative treatment.Cell senescence is a stable cell cycle arrest.Therapy-induced senescence has emerged over the past few years as a novel approach to treat cancers.Cellular senescence provides one of the strongest antioncogenic mechanisms through key tumour suppressors,namely,p53 and p RB that inhibit a variety of signalling pathways which act to induce growth,proliferation and tumourigenesis.Non-genotoxic stress such as oncogenic Ras signalling or tissue culture stress induce senescence through the p16/p RB pathway by inhibiting CDK4/6 activity through p16INK4 A activation.The potential role of cellular senescence in anti-cancer therapy may be particularly attractive in advanced age.It is possible to provide theoretical basis for searching potential molecular therapeutic targets by studying the molecular mechanism of inhibiting senescence of HCC.Objective: PcG protein is a kind of protein associated with senescence,and it has been found that they are closely related to the occurrence of many kinds of tumors.CBX4 is exclusive among CBX proteins in that it exerts a SUMO E3-ligase activity on transcriptional repressors.CBX4 can promote cell growth through cooperation with the PRb pathway,which is mainly CBX4 and Rb-E2 F complex binding inhibition of cyclin A and cdc2 expression,and for Arrest in G2.Recent studies have found that CBX4 plays an important role in maintaining the inhibition of epidermal stem cell senescence.The expression disorders of CBX4 is closely related to the occurrence of HCC,and the prognosis of HCC is affected,but whether CBX4 inhibits tumor cell senescence is still unknown.So we wonder whether CBX4 expression disorders is associated with inhibition of tumor cell senescence.This thesis aims to explore CBX4 controls the effect of inhibiting senescence in primary HCC,in view of the senescent cells as a new means of treatment of tumor eradication,and controls the protein is a protein is closely related to aging.Therefore,the controls in the tumor with senescence is very necessary.We hope that by studying the role of CBX4 in HCC and its relationship with senescence,further clarify the mechanism of CBX4 expression and HCC,and provide a new theoretical basis for the prediction,treatment and prognosis of primary liver cancer.Methods: In this study,we collected 43 cases(between35 and 81 years old)in patients with primary liver cancer postoperative paraffin tissue sections.Through immunohistochemical detection of the expression of CBX4 and P16INK4 a in tumor tissues and adjacent tissues.By si RNA knocked down CBX4 expression of human liver cancer cell line bel-7402 and then respectively by q RT-PCR and western blotting CBX4 detection m RNA and protein level changes,and applied to senescence-associated beta-galactosidase(SA-β-gal)activity staining method to detect SA-β-gal activity changes before and after transfection.Result:By knocking down CBX4 expression in HCC line bel-7402,observed under inverted fluorescence microscope with bright field,negative control group of liver cancer cells did not see clear blue,but blue compounds increased obviously in knocked-down HCC.Immunohistochemical results showed that CBX4 was significantly higher in HCC than in adjacent tissues,while P16INK4 a was lower in tumor tissue,and P16INK4 a expression was significantly increased in the adjacent tissues.Conclusion: Our experimental data show that the expression of CBX4 is positively correlated with the malignant degree of HCC.CBX4 inhibits P16INK4 a expression by inhibiting liver cancer cell senescence,CBX4 of HCC by inhibiting cell senescence to promote the development of hepatocellular carcinoma.