Constitutive Expression of HIF-α Plays a Major Role in Generation of Clear-cell Phenotype in Human Primary and Metastatic Renal Carcinoma

The extensive lipid accumulation occurring in clear-cell renal cell carcinoma (ccRCC) results in a clear-cell cytoplasm. Hypoxia-inducible factor α (HIF-α) is constitutively expressed in many ccRCC and transcriptionally regulates >100 genes. In a recent breakthrough study, HIF-1α induced ccRCC in transgenic mice. On the basis of these findings, we developed a hypothesis that accounted for HIF-α generation of the clear-cell phenotype. The aim of the present study was to use immunohistochemical staining methods in tissue microarray to determine the extent to which the clear-cell phenotype coincided with HIF-α expression in primary and metastatic ccRCC. In addition, we studied whether the prolyl-hydroxylases (PHD2,3) play a role in promoting the elevated expression of HIF-α in tumor cells. The clear-cell phenotype was observed in all primary and metastatic cases of ccRCC examined. A total of 168 renal cell carcinomas were evaluated by immunohistochemical methods; 141 of the 168 (84%) tumors expressed HIF-α (HIF-1α and/or HIF-2α). In contrast, HIF-α was expressed in only 1 of the 23 (4%) non-ccRCCs. These data supported the hypothesis that in the majority of the tumors HIF-α expression overlapped with the clear-cell phenotype and was indicative of an HIF-α-mediated lipid accumulation. In a smaller percentage of ccRCC cases (16%), HIF-α was not detected in the tumor cells and suggested that lipid accumulation by HIF-α-lipid-independent process. PHD3 was undetectable in both primary and metastatic ccRCC cases. We concluded that the undetectable PHD3 could contribute to the higher HIF-α expression in ccRCC.