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Constitutive Activation of Hypoxia-inducible Genes Related to Overexpression of Hypoxia-inducible Factor-1 in Clear Cell Renal Carcinomas¹

Departments of Nephrology and Medical Intensive Care [M. S. W., P. M. M., A. S., J. S. J., G. G., U. F., K-U. E.] and Urology [J. R., S. A. L.], Charité, Humboldt University, 13353 Berlin, Germany; German Cancer Research Center, 69120 Heidelberg, Germany [I. B., H-J. G.]; Department of Paediatrics, Section of Medical and Molecular Genetics, University of Birmingham B15 2TT, United Kingdom [N. V. M., E. R. M.]; Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom [P. H. M.]

The transcription factor hypoxia-inducible factor (HIF)-1 is an important mediator of hypoxic adaptation of tumor cells and controls several genes that have been implicated in tumor growth. Oxygen-dependent degradation of HIF-1, the regulatory subunit, requires binding to the von Hippel Lindau (VHL) protein. Because functional inactivation of the VHL tumor suppressor gene occurs in up to 70% of clear cell renal carcinomas, we investigated whether this results in overexpression of HIF-1 and its target genes. Immunoblotting revealed increased expression of HIF-1 in 24 of 32 (75%) clear cell renal carcinomas but only 3 of 8 non-clear cell renal tumors. Somatic mutations of the VHL gene were detected only in clear cell renal carcinomas that overexpressed HIF-1. None of the HIF-1-negative tumors displayed a VHL mutation. The level of HIF-1 mRNA was not different between tumors and adjacent kidney tissue. Immunohistochemistry revealed distinct patterns of nuclear staining for HIF-1, depending on histological type and overall abundance of HIF-1. In those clear cell renal carcinomas that showed increased expression on immunoblots, HIF-1 was expressed in almost all cells. In the remaining clear cell and in non-clear cell tumors, staining was focal; these different patterns thus were compatible with genetic stabilization in contrast to microenvironmental stimulation of HIF-1 as the primary mechanism. The mRNA expression of two known target genes of HIF-1, vascular endothelial growth factor and glucose transporter 1, increased progressively with increasing amounts of HIF-1 in tumor extracts. In addition, glucose transporter 1 protein levels correlated with HIF-1 abundance. In conclusion, the data provide in vivo evidence for a constitutive up-regulation of HIF-1 in the majority of clear cell renal carcinomas, which leads to more widespread accumulation of this transcription factor than hypoxic stimulation. These observations are most likely linked to functional inactivation of the VHL gene product. Increased expression of HIF-1 is associated with alterations in gene expression patterns that are likely to contribute to tumor phenotype and progression.

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