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.
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Authors | Károly Tóth, Sreenivasulu Chintala, Youcef M Rustum |
Journal | Applied immunohistochemistry & molecular morphology : AIMM
(Appl Immunohistochem Mol Morphol)
Vol. 22
Issue 9
Pg. 642-7
(Oct 2014)
ISSN: 1533-4058 [Electronic] United States |
PMID | 25046225
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Basic Helix-Loop-Helix Transcription Factors
- HIF1A protein, human
- Hypoxia-Inducible Factor 1, alpha Subunit
- Neoplasm Proteins
- endothelial PAS domain-containing protein 1
- EGLN1 protein, human
- EGLN3 protein, human
- Hypoxia-Inducible Factor-Proline Dioxygenases
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Topics |
- Animals
- Basic Helix-Loop-Helix Transcription Factors
(biosynthesis)
- Carcinoma, Renal Cell
(metabolism, pathology)
- Gene Expression Regulation, Neoplastic
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(biosynthesis)
- Hypoxia-Inducible Factor-Proline Dioxygenases
(biosynthesis)
- Kidney Neoplasms
(metabolism, pathology)
- Mice
- Neoplasm Metastasis
- Neoplasm Proteins
(biosynthesis)
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