title: Constitutive expression of HIF-α 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 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.
authors.affiliation: Departments of *Cancer Biology †Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY.
authors.forename: Károly
authors.initials: K
authors.lastname: Tóth
authors.forename: Sreenivasulu
authors.initials: S
authors.lastname: Chintala
authors.forename: Youcef M
authors.initials: YM
authors.lastname: Rustum
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D009363:Neoplasm Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C490190:EGLN1 protein, human; C488894:EGLN3 protein, human