HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron.
Mutations in the von Hippel-Lindau (VHL) gene are associated with hereditary and sporadic clear cell renal carcinoma. VHL acts in a ubiquitin ligase complex regulating hypoxia-inducible factor-1 (HIF-1), but the link between this function and cancer development is unclear. Here we show that in the kidneys of patients with VHL disease, HIF activation is an early event occurring in morphologically normal single cells within the renal tubules. In comparison, dysplastic lesions, cystic lesions, and tumors showed evidence of additional mechanisms that amplify HIF activation. Detection of cells with constitutive HIF activation identified a large number of previously unrecognized foci of VHL inactivation. In proximal tubules these were almost entirely unicellular, whereas multicellular foci were almost exclusively seen in the distal nephron.
Mandriota
Stefano J
SJ
Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom.
Turner
Kevin J
KJ
Davies
David R
DR
Murray
Paul G
PG
Morgan
Neil V
NV
Sowter
Heidi M
HM
Wykoff
Charles C
CC
Maher
Eamonn R
ER
Harris
Adrian L
AL
Ratcliffe
Peter J
PJ
Maxwell
Patrick H
PH
D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000502:physiology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D051272:Glucose Transporter Type 1; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009392:Nephrectomy; D009399:Nephrons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D015347:RNA Probes; D014157:Transcription Factors; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015347:RNA Probes; C495677:SLC2A1 protein, human; D014157:Transcription Factors; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases