Correlation study showing no concordance between EPAS-1/HIF-2α mRNA and protein expression in transitional cellcancer of the bladder

Abstract

Objectives Endothelial Per-ARNT-Sim (PAS) domain protein-1 (EPAS-1)/hypoxia-inducible factor (HIF)-2α is a recently identified, endothelial-specific, hypoxia-induced transcription factor and is reputed to have an important role in tumor angiogenesis and tumor progression. Only a few studies have reported on the clinical correlation with grade, stage, necrosis, and microvessel density in transitional cell carcinoma of the bladder. In vitro studies have reported no concordance of EPAS-1/HIF-2α mRNA and protein expression. We sought to elucidate these two issues. Methods Surgical specimens from 110 patients with transitional cell carcinoma comprised the study, including 51 from radical cystectomy and 59 from transurethral resection of bladder tumor. Immunohistochemistry and in situ hybridization were performed with antibodies against EPAS-1/HIF-2α, CD31, and a human EPAS-1/HIF-2α cDNA subclone probe. Results EPAS-1/HIF-2α protein expression was found almost exclusively in high-grade and high-stage tumors ( P <0.0001). EPAS-1/HIF-2α mRNA expression was detectable only in high-grade (grade 3) and high-stage (pT3a or greater) cases with positive EPAS-1/HIF-2α protein expression ( P = 0.0017). The presence of necrosis correlated with EPAS-1/HIF-2α expression, tumor grade, and tumor stage ( P <0.0001). Microvessel density was much lower in invasive, larger tumor nodules in EPAS-1/HIF-2α-positive cases than in the negative cases ( P <0.0001). Conclusions EPAS-1/HIF-2α protein and mRNA levels correlate with higher grade and advanced bladder transitional cell carcinoma. In lower stage cases, no concordance was found between transcription and translation of EPAS-1/HIF-2α gene expression. Because EPAS-1/HIF-2α mRNA is only detectable in highly invasive cancer cases, it may serve as a therapeutic target (eg, by an antisense mRNA approach) for bladder cancer.