The Roles And Mechanisms Of Ubiquitin-specific Protease 4 In Hepatocellular Carcinoma Progression,Invasion And Metastasis

Ubiquitin-specific protease 4(USP4)is a member of the deubiquitinating enzymes family,which can protect target proteins from ubiquitin-proteasome pathway-induced degradation by deubiquitination process.Studies have found that USPs are closely related with human tumor diseases progression.However,the roles and mechanisms of USP4 in tumor development,especially in hepatocellular carcinoma(HCC),remain unclear.Clinically,we found that USP4 is overexpressed in human HCC tissues compared with adjacent non-tumoral tissues and is significantly correlated with malignant phenotype characteristics,including tumor size,tumor number,differentiation,serum alpha-fetoprotein(AFP)level and microvascular invasion.In addition,the expression level of USP4 is closely correlated with the overall survival and disease-free survival rate of patients with hepatocellular carcinoma,which may be an independent risk factor for predicting the poor outcome of patients with hepatocellular carcinoma.Using in vitro and in vivo assays,we demonstrated that USP4 overexpression enhanced HCC cell growth,migration and invasion.Mechanistically,we first discovered that cyclophilin A(Cyp A)is an important protein molecule in USP4 promoting HCC progression by using LC-MS/MS.We observed that USP4 interacted with Cyp A and inhibited Cyp A degradation via deubiquitination in HCC cells.We also proved USP4/Cyp A facilitates HCC development may be through the activation of ERK1/2-MAPK and Crk? signaling pathway.These data suggest that USP4 acts as a novel independent prognostic marker of patients with HCC,offering potential therapeutic opportunities for the treatment of metastasis and recurrence of HCC.