Hypoxia-Inducible Factor 1α in Clear Cell Renal Cell Carcinoma

Purpose: Hypoxia-inducible factor-1α (HIF-1α) 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-1α 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-1α expression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1α 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-1α was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1α expression predicted outcome in metastatic patients: patients with high HIF-1α 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-1α and CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC. Conclusions: HIF-1α is an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1α and CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.