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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 research

Publication Date

05/2002

Volume

62

Pages

2957 - 2961

Addresses

Imperial Cancer Research Fund Molecular Oncology Laboratory and Angiogenesis Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK.

Keywords

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