Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma.
OBJECTIVE
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1 alpha in renal cell carcinoma (RCC).


METHODS
Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival.


RESULTS
HIF-1 alpha expression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1 alpha was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1 alpha was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1 alpha expression predicted outcome in metastatic patients: patients with high HIF-1 alpha expression (>35%) had significantly worse survival than patients with low expression (< or =35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1 alpha and CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC.


CONCLUSIONS
HIF-1 alpha is an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1 alpha and CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.
Klatte
Tobias
T
Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Seligson
David B
DB
Riggs
Stephen B
SB
Leppert
John T
JT
Berkman
Maria K
MK
Kleid
Mark D
MD
Yu
Hong
H
Kabbinavar
Fairooz F
FF
Pantuck
Allan J
AJ
Belldegrun
Arie S
AS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor / Q000032:analysis*; D002256:Carbonic Anhydrases / Q000096:biosynthesis; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011494:Protein Kinases / Q000096:biosynthesis; D054367:Receptors, CXCR3 / Q000096:biosynthesis; D058570:TOR Serine-Threonine Kinases; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D014408:Biomarkers, Tumor; C515187:CXCR3 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D054367:Receptors, CXCR3; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C483903:CA13 protein, human; D002256:Carbonic Anhydrases