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The von Hippel-Lindau tumor suppressor protein acts as the substrate recognition component of a ubiquitin E3 ligase that targets hypoxia-inducible factor (HIF)-alpha subunits for proteolysis. Stabilization of HIF-alpha subunits has been described in VHL-defective cell lines, leading to HIF activation and up-regulation of hypoxia-inducible mRNAs. Mutations of the von Hippel-Lindau tumor suppressor protein are found in most clear cell renal cell carcinomas (CC-RCCs) but not other renal tumors, raising a question about the importance of activation of the HIF pathway in CC-RCC development. To address this question, we have examined the expression of HIF-alpha subunits in 45 primary renal tumors and related this to tumor subtype, the presence of VHL mutations, and measures of angiogenesis. We show that HIF-alpha is up-regulated in the majority of CC-RCCs, and that the pattern of expression is biased toward the HIF-2alpha isoform. Expression of HIF-alpha proteins was associated significantly with up-regulation of VEGF mRNA and protein and increased microvessel density. Up-regulation of HIF-alpha in CC-RCC was found to involve increased mRNA as well as protein expression, suggesting that both VHL-dependent and VHL-independent mechanisms are involved. These results suggest that activation of the HIF pathway is functionally important in CC-RCC development and might provide a new therapeutic target.

Type

Journal article

Journal

Cancer Res

Publication Date

15/05/2002

Volume

62

Pages

2957 - 2961

Keywords

Adenocarcinoma, Clear Cell, Aged, Carcinoma, Renal Cell, Female, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Neoplasms, Ligases, Male, Middle Aged, Mutation, Neovascularization, Pathologic, RNA, Messenger, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Up-Regulation, Von Hippel-Lindau Tumor Suppressor Protein