Correlation study showing no concordance between EPAS-1/HIF-2alpha mRNA and protein expression in transitional cellcancer of the bladder.
OBJECTIVE
Endothelial Per-ARNT-Sim (PAS) domain protein-1 (EPAS-1)/hypoxia-inducible factor (HIF)-2alpha 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-2alpha 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-2alpha, CD31, and a human EPAS-1/HIF-2alpha cDNA subclone probe.


RESULTS
EPAS-1/HIF-2alpha protein expression was found almost exclusively in high-grade and high-stage tumors (P <0.0001). EPAS-1/HIF-2alpha mRNA expression was detectable only in high-grade (grade 3) and high-stage (pT3a or greater) cases with positive EPAS-1/HIF-2alpha protein expression (P = 0.0017). The presence of necrosis correlated with EPAS-1/HIF-2alpha expression, tumor grade, and tumor stage (P <0.0001). Microvessel density was much lower in invasive, larger tumor nodules in EPAS-1/HIF-2alpha-positive cases than in the negative cases (P <0.0001).


CONCLUSIONS
EPAS-1/HIF-2alpha 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-2alpha gene expression. Because EPAS-1/HIF-2alpha 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.
Ji
Pingguang
P
Department of Surgery, University of Western Ontario, London, Ontario, Canada.
Xuan
Jim W
JW
Onita
Toru
T
Sakai
Hideki
H
Kanetake
Hiroshi
H
Gabril
Manal Y
MY
Sun
Yunming
Y
Moussa
Madeleine
M
Chin
Joseph L
JL
D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000032:analysis; D015534:Trans-Activators / Q000032:analysis*; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D000099162:Endothelial PAS Domain-Containing Protein 1