Cell Biology – Immunology – Pathology
Kidney International (2003) 64, 1671–1674; doi:10.1046/j.1523-1755.2003.00257.x
VHL down-regulation and differential localization as mechanisms in tumorigenesis
Yih-Horng Shiao, Asta Forsti, Lars Egevad, Lucy M Anderson, Per Lindblad and Kari Hemminki
Laboratory of Comparative Carcinogenesis, NCI-Frederick, National Institutes of Health, Frederick, Maryland; Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden; German Cancer Research Center, Heidelberg, Germany; Department of Pathology and Cytology, Karolinska Hospital, Stockholm, Sweden; and Department of Urology, Sundsvall Hospital, Sundsvall, Sweden
Correspondence: Yih-Horng Shiao, Ph.D., Building 538, Room 205, NCI-Frederick, NIH, Frederick, Maryland 21702. E-mail: shiao@mail.ncifcrf.gov
Received 30 April 2003; Revised 21 May 2003; Accepted 17 June 2003.
Abstract
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).
Conclusion
This study provides the first evidence of the role of VHL protein level and intracellular localization in tumorigenesis in humans.
Keywords:
von Hippel-Lindau, immunohistochemistry, down-regulation, localization, membrane, renal tumor
