VHL down-regulation and differential localization as mechanisms in tumorigenesis.
BACKGROUND
The von Hippel-Lindau (VHL) gene has been widely analyzed in many tumors. Early studies in animal tumors suggest that changes in VHL protein level and localization may be also important in tumorigenesis. In this study, we determined the role of VHL protein in human renal cell carcinomas.


METHODS
Seventy-five human renal cell carcinomas, predominantly of clear cell type (60 of 75), were examined for VHL protein by immunohistochemistry. The level and pattern of protein expression were then compared to VHL mutations and tumor characteristics.


RESULTS
An apparent decline of VHL level (positive in <50% of tumor cells) was observed in 49 (65%) tumors, a change more frequent than VHL mutations (28 of 75) (37%). In tumors, VHL was localized to the cytoplasm and/or the cell membrane. The occurrence of a predominantly membranous signal was significantly associated with missense mutations (9 of 14 tumors with missense mutations versus 14 of 61 tumors with no or nonmissense mutations, P = 0.0025) and tumor stage (23 of 60 tumors with stage TI versus 0 of 15 tumors with TII and TIII, P = 0.0034).


CONCLUSIONS
This study provides the first evidence of the role of VHL protein level and intracellular localization in tumorigenesis in humans.
Shiao
Yih-Horng
YH
Laboratory of Comparative Carcinogenesis, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA. shiao@mail.ncifcrf.gov
Forsti
Asta
A
Egevad
Lars
L
Anderson
Lucy M
LM
Lindblad
Per
P
Hemminki
Kari
K
D000906:Antibodies; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005838:Genotype; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D009367:Neoplasm Staging; D010641:Phenotype; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D000906:Antibodies; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human