HIF‐2α mediates hypoxia‐dependent upregulation of Serpin‐B3, a marker of early liver carcinogenesis (144.7)

Abstract

SERPINB3 (S‐B3), a cysteine‐proteases inhibitor up‐regulated in cirrhosis, dysplastic nodules and hepatocellular carcinoma (HCC), can trigger epithelial‐to‐mesenchymal transition (EMT) and increased invasiveness in hepatic cancer cells. In this study we have investigated whether hypoxia, through involvement of hypoxia inducible factors (HIFs), may affect S‐B3 expression by employing morphological, molecular and cell biology techniques in liver‐derived cancer cell lines, normal murine liver and liver specimens from HCC patients.Exposure of HepG2 and HUH7 cells to hypoxia resulted in S‐B3 up‐regulation in terms of mRNA, protein synthesis and release in the extracellular medium. The use of specific siRNAs and of ChIP assay revealed that S‐B3 up‐regulation is mediated by HIF‐2α (not HIF‐1α) binding to S‐B3 promoter and that this is a redox‐dependent event. The correlation between hypoxia, HIF‐2α and S‐B3 expression was supported by immunohistochemistry analysis on normal murine liver and on tumor specimens from HCV‐cirrhotic patients carrying HCC. Hypoxia, through HIF‐2α‐dependent and redox sensitive mechanisms, is the first ever described stimulus of pathophysiological relevance able to up‐regulate expression of S‐B3, a protein proposed as marker of early liver carcinogenesis.