The Relationship Between The Expression Of USP22,BMI-1 And EZH2 In HCC And Their Impacts On Prognosis

Objective: Current studies have shown that deubiquitination plays a key role in tumor progression,metastasis,resistance to chemotherapy drugs and prognosis.In this study,we investigated the effects of the deubiquitinating enzyme ubiquitin specific peptidase 22(USP22)on the expression of the drug resistance gene B lymphoma Mo-MLV insertion region 1 homolog(BMI1)and the methylase enhancer of zeste homolog 2(EZH2)in hepatocellular carcinomas(HCCs)and on prognosis.Methods : A total of 175 specimens of cancerous tissue and 167 specimens of para-cancerous tissue were taken from HCC patients who underwent radical surgery at the Department of Hepatobiliary and Pancreatic Surgery of Guilin Medical College from 2006 to 2008.Immuonhistochemistry was used to detect the expression of USP22,BMI-1 and EZH2 in 40 specimens of HCC and paraneoplastic liver tissue.RT-PCR,qRT-PCR and Western blot was used to detect the expression of USP22,BMI-1 and EZH2 in HCC tissues.ROC curve analysis was employed to determine a cutoff score for USP22,BMI-1 and EZH2 expression in a training set(n=40).For validation,the ROC-derived cutoff score was subjected to analysis the expression of USP22,BMI-1 and EZH2 with patient outcome and clinical characteristics in a testing set(n=40)and overall patient(n=167);analysis The correlations between USP22,BMI-1 and EZH2 and the relationships to clinical characteristics of HCC and The relationship between co-expression of USP22 and BMI-1 and prognosis in HCC patients receiving transcatheter arterial chemoembolization(TACE).Detect the expression of BMI-1 and EZH2 after RNA interference of USP22 expression in the 5-FU resistant HCC cell line Bel/Fu;observed the impact of USP22 downregulation on the growth of the xenografts in the nude mice and tumor growth was monitored.Results: Downregulation of USP22 expression with interference ribonucleic acid(RNAi)in resistant HCC cell lines with high USP22 expression resulted in decreased BMI-1 expression but had no effect on EZH2 expression.USP22,BMI-1 and EZH2 were highly expressed in HCC tissue,and the expression levels were positively correlated with tumor grade and clinical stage.Correlation analysis showed that USP22 expression was positively correlated with that of BMI-1.Kaplan-Meier analysis showed that high levels of USP22 and BMI-1 expression were associated with poor overall survival(OS)and relapse-free survival in all o f t h e c a s e s a n d i n p a t i e n t s t r e at e d w i t h t r a n s c a t h e t e r a r t e r i a l chemoembolization(TACE).Conclusions: These results suggested that high levels of USP22 expression played an important role in drug resistance to chemotherapeutic drugs in HCC patients by upregulating the expression of BMI-1;therefore,co-expression of USP22 and BMI-1 may become a new predictor for HCC prognosis and may help guide clinical treatment.