Expression of hypoxia-inducible factor 1alpha, hypoxia-inducible factor 2alpha, and von Hippel-Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1alpha 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-1alpha, HIF-2alpha, 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-2alpha in carcinomas was higher than that in benign and borderline tumors (P < .0001). Furthermore, the nuclear expression of HIF-1alpha and the cytoplasmic expression of HIF-2alpha 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-1alpha did not show differences among histological malignancies. There was a positive correlation between nuclear HIF-1alpha expression and vascular endothelial growth factor (rho = 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-1alpha (rho = -0.529, P = .0153). The log-rank test showed that nuclear positive immunostaining for HIF-1alpha (P = .002) and cytoplasmic positive immunostaining for HIF-2alpha (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-1alpha 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.
Osada
Ryosuke
R
Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
Horiuchi
Akiko
A
Kikuchi
Norihiko
N
Yoshida
Junko
J
Hayashi
Akiko
A
Ota
Masao
M
Katsuyama
Yoshihiko
Y
Melillo
Giovanni
G
Mellilo
Giovanni
G
Konishi
Ikuo
I
D018262:Adenocarcinoma, Clear Cell / Q000737:chemistry / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000737:chemistry / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000737:chemistry* / Q000473:pathology*; D018269:Carcinoma, Endometrioid / Q000737:chemistry / Q000473:pathology; D002467:Cell Nucleus / Q000737:chemistry; D018284:Cystadenocarcinoma, Serous / Q000737:chemistry / Q000473:pathology; D003593:Cytoplasm / Q000737:chemistry; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis*; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000473:pathology*; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000032:analysis* / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1