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[Cancer Research 62, 2957-2961, May 15, 2002]
© 2002 American Association for Cancer Research

Tumor Biology

Expression of Hypoxia-inducible Factors in Human Renal Cancer

Relationship to Angiogenesis and to the von Hippel-Lindau Gene Mutation1

Kevin J. Turner, John W. Moore, Adam Jones, Claire F. Taylor, Darren Cuthbert-Heavens, Cheng Han, Russell D. Leek, Kevin C. Gatter, Patrick H. Maxwell, Peter J. Ratcliffe, David Cranston and Adrian L. Harris2

Imperial Cancer Research Fund Molecular Oncology Laboratory and Angiogenesis Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU [K. J. T., J. W. M., A. J., C. H., A. L. H.]; Imperial Cancer Research Fund Mutation Detection Facility, Ashley Wing, St. James’s University Hospital, Leeds LS9 7TF [C. F. T., D. C-H.]; Nuffield Department of Cellular Science and Clinical Biochemistry, John Radcliffe Hospital, Oxford OX3 9DU [R. D. L., K. C. G.]; Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN [P. H. M., P. J. R.]; and Department of Urology, Churchill Hospital, Oxford OX3 7LJ [D. C.], United Kingdom

The von Hippel-Lindau tumor suppressor protein acts as the substrate recognition componentof 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-2{alpha} 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.




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