Expression of HIF-1 and ubiquitin in conventional renal cell carcinoma: relationship to mutations of the von Hippel–Lindau tumor suppressor gene

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Conventional clear cell renal cell carcinomas (cRCC) have mutations of the von Hippel–Lindau (VHL) tumor suppressor gene at 3p25 in approximately 50% of cases. The VHL gene normally regulates ubiquitin-mediated proteolysis of hypoxia-inducible factor 1α (HIF-1α); in cell lines, VHL inactivation blocks HIF-1α proteolysis, resulting in increased HIF-1 expression. This study was undertaken to investigate the relationship between VHL mutations and the expression of ubiquitin and HIF-1α in cRCC. Eleven cRCC were studied with microsatellite analysis for 3p deletions and with sequencing for VHL mutations. Immunohistochemistry was performed for HIF-1α and ubiquitin. Deletions at 3p25 were found in 10 tumors, and VHL mutations were identified in 6 of these cases. There was staining for ubiquitin and HIF-1α in all tumors with VHL mutations. Among the five cases without VHL mutations, staining for ubiquitin or HIF-1α was not present in three cases but was present in two tumors, both of which had 3p deletions. The findings support a role for VHL mutations promoting cRCC development by an impairment of HIF-1α proteolysis. The findings also suggest that a 3p tumor suppressor gene other than VHL may also influence HIF-1α degradation and that there is an additional tumorigenic pathway for cRCC that does not involve VHL or HIF-1.