Constitutive expression of HIF-? plays a major role in generation of clear-cell phenotype in human primary and metastatic renal carcinoma.

ABSTRACT: The extensive lipid accumulation occurring in clear-cell renal cell carcinoma (ccRCC) results in a clear-cell cytoplasm. Hypoxia-inducible factor ? (HIF-?) is constitutively expressed in many ccRCC and transcriptionally regulates >100 genes. In a recent breakthrough study, HIF-1? induced ccRCC in transgenic mice. On the basis of these findings, we developed a hypothesis that accounted for HIF-? 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-? 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-? 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-? (HIF-1? and/or HIF-2?). In contrast, HIF-? was expressed in only 1 of the 23 (4%) non-ccRCCs. These data supported the hypothesis that in the majority of the tumors HIF-? expression overlapped with the clear-cell phenotype and was indicative of an HIF-?-mediated lipid accumulation. In a smaller percentage of ccRCC cases (16%), HIF-? was not detected in the tumor cells and suggested that lipid accumulation by HIF-?-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-? expression in ccRCC.

SUBMITTER: Toth K 

PROVIDER: S-EPMC4184929 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature