Increased TRIM59 Expression Promotes Tumor Growth And Metastasis In Hepatocellular Carcinoma

Background and objective:Hepatocellular carcinoma(HCC)is listed as the fifth-most common cancer in male worldwide.Although the treatments for HCC have been greatly improved,the long-term survival of HCC still remains generally poor.The overall 5-year survival rate is an approximately 30%after liver resection,due to the high recurrence and metastasis rates.Tripartite motif 59(TRIM59)is a member of Tripartite motif protein family,which is frequently increased in many human cancers.However,the function of TRIM59 in hepatocellular carcinoma(HCC)has not been fully elucidated.In this study,we aimed to find the potential role and molecular mechanism of TRIM59 in growth and metastasis of HCC.Methods:TRIM59 expression in human HCC tissues was evaluated by qPCR,Western blot-ting and immunohistochemical analyses.The clinicopathological significance and prognostic value of TRIM59 were investigated in a cohort containing 103 patients with HCC.The role of TRIM59 in hepatocellular carcinoma cell proliferation and metastasis capacities was evaluated by using cell counting kit-8(CCK8),clone formation and Transwell in vitro and tumor formation assay in nude mice.Immunohistochemistry,Immunofluorescence,Western blot analysis,qPCR assay,Co-IP and Mass spectrometry were performed to assess TRIM59 interacting with PPM1B/IKK?/NF-?B.Results:We find that TRIM59 plays an essential role in growth and metastasis of HCC.TRIM59 expression is up-regulated in HCC tissues.A high level of TRIM59 expression was correlated with poor overall and disease-free survival of HCC patients.Knockdown of TRIM59 attenuated proliferation and migration in a HCC cell line,and reduced tu-mor growth in the mouse xenograft model.Ectopic expression of TRIM59 had the op-posite results.Mechanistically,TRIM59 promoted growth and metastasis through acti-vating NF-?B signal pathway.Further studies indicated that TRIM59 might interacted physically with PPM1B,which has been reported to negatively regulate NF-?B signal pathway.We also discovered that TRIM59 increased ubiquitination and degradation of PPM1B.Increased level of TRIM59 in HCC patients correlated with reduced expression of PPM1B and increased expression of NF-?B target genes.Conclusion:TRIM59 promotes growth and metastasis by PPM1B/IKK?/NF-?B signaling pathway,indicating a new prognostic biomarker candidate and a potential antitumor target for HCC.