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 prognostic factor in ovarian carcinoma
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 prognostic factor in ovarian carcinoma
复制标题
DOI：
10.1016/j.humpath.2007.02.010
复制
发表时间：
2007-09-01
期刊：
影响因子：
3.3
通讯作者：
Konishi, Ikuo
中科院分区：
文献类型：
--
作者：
Osada, Ryosuke;Horiuchi, Akiko;Konishi, Ikuo
缺氧诱导因子（hypoxia inducible factor， HIF）是一种在肿瘤生物学中具有重要作用的转录因子。为了阐明hif - α亚基和von Hippel-Lindau （VHL）蛋白在卵巢癌发生发展中的可能参与，我们分析了107例卵巢上皮性肿瘤中HIF-1 α、HIF-2 α和VHL的免疫组织化学表达。此外，我们还检测了VHL基因位点的杂合性缺失（LOH）。癌组织中HIF-2 α的细胞质表达频率高于良性和交界性肿瘤（P < 0.0001）。FIGO (International Federation of Gynecology and Obstetrics) III期和IV期肿瘤中HIF-1 α的核表达和HIF-2a的细胞质表达明显高于I期和II期肿瘤。另一方面，HIF-1 α的细胞质表达在组织学恶性肿瘤中没有表现出差异。核HIF-1 α表达与血管内皮生长因子呈正相关（p = 0.320, p < 0.001）。虽然VHL基因位点的LOH在卵巢癌中很常见（24%），但LOH与VHL表达缺失之间没有显著相关性。在22例透明细胞癌中，VHL表达与HIF-1 α的核表达呈显著负相关（rho = -0.529, P = 0.0153）。log-rank检验显示，肿瘤细胞中HIF-1 α的核阳性免疫染色（P = 0.002）和HIF-2 α的细胞质阳性免疫染色（P = 0.0112）与卵巢癌患者预后不良相关。多因素分析也显示HIF-1 α的核表达是一个独立的预后因素。这些结果表明，hif - α亚基是评估卵巢癌患者预后的重要生物标志物。(c) 2007爱思唯尔公司版权所有。
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.