title: Increased expression of hypoxia-inducible factor 1alpha in type I and type II endometrial carcinomas.
abstract: Hypoxia-inducible factor 1alpha (HIF-1alpha) is a nuclear protein that is upregulated in many tumors and triggers biologic events intimately associated with aggressive tumor behavior. The aim of this study was to analyze the expression of HIF-1alpha, vascular endothelial growth factor (VEGF), Ki-67 and p53 in type I and type II endometrial adenocarcinoma. In total, 149 patients diagnosed with endometrial adenocarcinoma in our institute from 1995 to 2001 were included in this study, of which 108 were type I and 41 were type II endometrial adenocarcinoma. Patient demographics, clinical and pathological data were reviewed. Tissue microarrays were prepared from the paraffin blocks and immunohistochemistry was performed for antibodies against HIF-1alpha, VEGF, Ki-67 and p53. High expression of HIF-1alpha, VEGF, Ki-67 and p53 were significantly more frequent in type II than type I endometrial adenocarcinoma (P<0.001). HIF-1alpha expression was highly correlated with VEGF expression in the tumor cells (P=0.001). In type I endometrial adenocarcinoma, high expression of HIF-1alpha showed a significant correlation with higher grade of the tumor, depth of myometrial invasion, adnexal invasion and clinical stage. A similar correlation was not observed in type II endometrial adenocarcinoma. Surgical stage was the only independent prognostic marker for survival. In conclusion, high expression of HIF-1alpha is more frequent in type II than in type I endometrial adenocarcinoma. In type I endometrial adenocarcinoma, HIF-1alpha expression correlates with morphologic features of aggressiveness. In type II endometrial adenocarcinoma, there is no correlation between HIF-1alpha expression and these features. Thus, HIF-1alpha may play an important role in endometrial adenocarcinoma progression, particularly in type I endometrial adenocarcinoma. Additional investigations of HIF-1alpha as a biomarker of aggressive potential and as a novel target for therapeutics in endometrial adenocarcinoma are warranted.
authors.affiliation: Department Pathology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Pansare
authors.forename: Adnan R
authors.initials: AR
authors.lastname: Munkarah
authors.forename: Veronica
authors.initials: V
authors.lastname: Schimp
authors.forename: M
authors.initials: M
authors.lastname: Haitham Arabi
authors.forename: Ghassan M
authors.initials: GM
authors.lastname: Saed
authors.forename: Robert T
authors.initials: RT
authors.lastname: Morris
authors.forename: Rouba
authors.initials: R
authors.lastname: Ali-Fehmi
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D015331:Cohort Studies; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013997:Time Factors; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A