Hypoxia-inducible factor 1α in clear cell renal cell carcinoma

Purpose: 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). Experimental Design: 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 CL 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 (<= 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.