Expression of HIF-2alpha/EPAS1 in hepatocellular carcinoma

Abstract

Aim: To investigate the expression of hypoxia-inducible factor (HIF)-2alpha/endothelial PAS domain protein1 (EPAS1) in hepatocellular carcinoma (HCC).

Methods: Expression of HIF-2alpha/EPAS1 was investigated immunohistochemically on paraffin-embedded sections from 97 patients with HCC. To further confirm that HIF-2alpha/EPAS1 in HCC tissues also correlated with angiogenesis, a parallel immunohistchemistry study of vascular endothelial growth factor (VEGF) was performed on these 97 cases.

Results: HIF-2alpha/EPAS1 could be detected in 50 of 97 cases (51.6%), including 19 weakly positive (19.8%), and 31 strongly positive (31.1%), the other 47 cases were negative (48.4%). The expression of HIF-2alpha/EPAS1was significantly correlated with tumor size, capsule infiltration, portal vein invasion, and necrosis. A parallel immunohistochemical analysis of VEGF demonstrated its positive correlation with capsule infiltration, portal vein invasion, and HIF-2alpha/EPAS1 overexpression, which supported the correlation of HIF-2alpha/EPAS1up-regulation with tumor angiogenesis. No apparent correlation was observed between HIF-2alpha/EPAS1 and capsular formation, presence of cirrhosis, and histological grade.

Conclusion: HIF-2alpha/EPAS1 is expressed in most of HCC with capsular infiltration and portal vein invasion, which indicates a possible role of HIF-2alpha/EPAS1 in HCC metastasis.

Figure 1

Characterization of HIF-2α/EPAS1 expression in human hepatocellular carcinoma tissues by IHC technique. A: Weak expression of HIF-2α/EPAS1 in membranes and cytoplasms of HCC cells (× 400). B: Strong cytoplasmic immunoreactivity of HIF-2α/EPAS1 in HCC cells (× 400). C: HIF-2α/EPAS1 positive staining (arrows) in perinecrotic region near tumor in a HCC sample (with capsular infiltration and portal vein invasion) (× 400). D: Strong HIF-2α/EPAS1 expression in HCC tissues whereas no staining in adjacent stroma cells (× 400). E: Strong staining in the cytoplasm of macrophages compared with cancer cells, showing weak staining for HIF-2α/EPAS1 (× 400). F: Moderate to strong positive staining of HIF-2α/EPAS1 in tumor clusters infiltrating to the tissue (× 400).

Figure 2

Parallel study of VEGF protein expression in HCC samples. A mAb against VEGF was used for immunostainig of slides from HCC patients. A: HCC with capsular infiltration and portal vein invasion showing strong staining (++) in the cytoplasm of tumor cells. B: HCC without capsular infiltration and portal vein invasion showing weak staining (+) (× 200).