Expression of hypoxia-inducible factor 1 alpha, hypoxia-inducible factor 2 alpha, and von Hippel-Lindau protein in epitheLiaL ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1 alpha is an independent prognostic factor in ovarian carcinoma

The hypoxia-inducible factor (HIF) is a transcriptional factor with important roles in tumor biology. To clarify the possible involvement of the HIF-alpha subunit and von Hippel-Lindau (VHL) protein in the development and progression of ovarian carcinoma, we analyzed the immunohistochemical expressions of HIF-1 alpha, HIF-2 alpha, 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-2 alpha in carcinomas was higher than that in benign and borderline tumors (P < .0001). Furthermore, the nuclear expression of HIF-1 alpha and the cytoplasmic expression of HIF-2a 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-1 alpha did not show differences among histological malignancies. There was a positive correlation between nuclear HIF-1 alpha expression and vascular endothelial growth factor (p = 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-1 alpha (rho = -0.529, P = .0153). The log-rank test showed that nuclear positive immunostaining for HIF-1 alpha (P = .002) and cytoplasmic positive immunostaining for HIF-2 alpha (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-1 alpha is an independent prognostic factor. These results show that the HIF-alpha subunit represents an important biomarker in the evaluation of the prognosis of patients with ovarian carcinoma. (c) 2007 Elsevier Inc. All rights reserved.

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