Expression of hypoxia-inducible factor 1α, hypoxia-inducible factor 2α, and von Hippel–Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1α is an independent prognosti

SummaryThe hypoxia-inducible factor (HIF) is a transcriptional factor with important roles in tumor biology. To clarify the possible involvement of the HIF-α subunit and von Hippel–Lindau (VHL) protein in the development and progression of ovarian carcinoma, we analyzed the immunohistochemical expressions of HIF-1α, HIF-2α, and VHL in 107 cases of epithelial ovarian tumors. In addition, we examined loss of heterozygosity (LOH) at VHL gene loci. The frequency of the cytoplasmic expression of HIF-2α in carcinomas was higher than that in benign and borderline tumors (P < .0001). Furthermore, the nuclear expression of HIF-1α and the cytoplasmic expression of HIF-2α were significantly higher in tumors of FIGO (International Federation of Gynecology and Obstetrics) stages III and IV than in those of stages I and II. On the other hand, the cytoplasmic expression of HIF-1α did not show differences among histological malignancies. There was a positive correlation between nuclear HIF-1α expression and vascular endothelial growth factor (ρ = 0.320, P < .001). Although LOH at the VHL gene locus was frequent in ovarian carcinomas (24%), there is no significant correlation between LOH and loss of VHL expression. In 22 clear cell carcinomas, VHL expression showed a significantly negative correlation with the nuclear expression of HIF-1α (ρ = −0.529, P = .0153). The log-rank test showed that nuclear positive immunostaining for HIF-1α (P = .002) and cytoplasmic positive immunostaining for HIF-2α (P = .0112) in tumor cells are associated with poor prognosis of patients with ovarian carcinoma. Multivariate analysis also showed that the nuclear expression of HIF-1α is an independent prognostic factor. These results show that the HIF-α subunit represents an important biomarker in the evaluation of the prognosis of patients with ovarian carcinoma.