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

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.