Effect of plasminogen activator inhibitor-1 transcriptionally upregulated by C-terminal truncated hepatitis B virus X on the development of hepatocellular carcinoma

BACKGROUND: C-terminal carboxy-truncated hepatitis B virus X (Ct-HBx) exerts its hepatocarcinogenic effects, at least in part, through the upregulation of plasminogen activator inhibitor-1 (PAI-1). This study aimed to explore the mechanisms by which Ct-HBx upregulates PAI-1 and determine the effects of PAI-1 functional polymorphisms and expression on the development of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). METHOD: Transposase-accessible chromatin sequencing was performed to identify chromatin accessibility induced by wild-type HBx (WT-HBx) and Ct-HBx. Functional polymorphisms of PAI-1 and their association with HBV mutations and HCC risk were evaluated in 3472 participants. PAI-1 in the HBV-infected cohort was measured using enzyme-linked immunosorbent assay. Associations between functional polymorphisms, serum PAI-1 levels, and postoperative prognosis in HBV-HCC were assessed in two cohort studies. RESULTS: Compared with WT-HBx, Ct-HBx upregulated the expression of histone acetyltransferases and chromatin-remodeling factors, thereby increasing the chromatin accessibility of the -1kb promoter and the 3'-untranslated region (3'UTR) of PAI-1 and promoting PAI-1 expression. rs2227631-G at the promoter and the rs11178-T and 1050955-A at the 3'UTR of PAI-1 were significantly associated with an increased risk of HCC. The polymorphic genotypes predisposing to higher PAI-1 expression were often associated with higher frequencies of HCC-risk HBV mutations. The interaction between these polymorphic genotypes and the HBV mutations greatly increased HBV-HCC risk. Serum concentration of PAI-1 increased progressively during HBV-induced hepatocarcinogenesis. rs2227631-GG and rs11178-TT genotypes, along with higher PAI-1 expression, were risk factors for poor postoperative prognosis in HBV-HCC. CONCLUSIONS: Ct-HBx upregulates PAI-1 expression by increasing chromatin accessibility. Functional polymorphic genotypes that facilitate PAI-1 expression and their interactions with HCC-risk HBV mutations promote HBV-HCC. PAI-1 is a novel prognostic and predictive factor for HBV-HCC.