Abstract
Characterized with a high recurrence rate and low detection rate, prevention is the best approach to reduce mortality in hepatocellular carcinoma (HCC). The overexpression of Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is observed in various tumors, including HCC; and the frequent PREX2 mutations in melanoma are associated with invasiveness. We sought to identify somatic mutations and the functional changes in mutational signatures of PREX2. Genomic DNA sequencing was performed in 68 HCC samples with three types of hepatitis viral infection status: HBs Ag-positive, anti-HCV Ab-positive, and negative for any hepatitis B or C markers. Stabilities and interactions of proteins as well as cell proliferation and migration were evaluated. Fourteen non-silent point mutations in PREX2 were detected, with 16 of 68 HCC patients harboring at least one non-silent mutation. All mutant forms of PREX2, except for K400f, had an extended half-life compared with wild-type PREX2. Moreover, only the half-life of S1113R was twice that of the wild-type. PREX2 mutant-S1113R also promoted migration and activated the AKT pathway as well as impaired HectH9-mediated ubiquitination. Our study identified a gain-of-function mutation of PREX2 – S1113R in HCC. Such mutation enhanced PREX2 protein stability, promoted cell proliferation, and was associated with aggressiveness of HCC.
Highlights
Characterized with a high recurrence rate and low detection rate, prevention is the best approach to reduce mortality in hepatocellular carcinoma (HCC)
Berger has reported that PREX2 somatic mutations render melanoma cells susceptible to oncogenic activities, which may perturb or inactivate one or more of its cellular functions[6]
To investigate whether the PREX2 gene harbors somatic mutations in HCC, the PREX2 genome was analyzed in 68 pairs of hepatocellular carcinomas and peripheral blood mononuclear cells from HCC patients using HaloPlex target enrichment sequencing
Summary
Characterized with a high recurrence rate and low detection rate, prevention is the best approach to reduce mortality in hepatocellular carcinoma (HCC). The overexpression of Phosphatidylinositol-3,4,5Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is observed in various tumors, including HCC; and the frequent PREX2 mutations in melanoma are associated with invasiveness. Our study identified a gain-of-function mutation of PREX2 – S1113R in HCC Such mutation enhanced PREX2 protein stability, promoted cell proliferation, and was associated with aggressiveness of HCC. Rational results were found when PREX2 was overexpressed causing the migration and invasion capabilities to increase; while knocking down the gene resulted in decreased migration and invasion[5,6]. Both PREX1 and PREX2 play important roles in tumor growth, the incidence of somatic mutation in PREX2 was much higher than that of PREX14.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call