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(American Journal of Pathology. 2003;163:1013-1020.)
© 2003 American Society for Investigative Pathology

Relevance of Nuclear and Cytoplasmic von Hippel Lindau Protein Expression for Renal Carcinoma Progression

Peter Schraml*, Alexander Hergovitz{dagger}, Florian Hatz*, Mahul B. Amin{ddagger}, So D. Lim{ddagger}, Wilhelm Krek{dagger}, Michael J. Mihatsch* and Holger Moch*

From the Institute of Pathology,*University of Basel, Basel, Switzerland; the Friedrich Miescher Institute,{dagger}Basel, Switzerland; and the Department of Pathology and Laboratory Medicine,{ddagger}Emory University, School of Medicine, Atlanta, Georgia

Alterations of the von Hippel-Lindau tumor-suppressor gene (VHL) on 3p25-p26 are frequent in clear-cell renal-cell carcinoma (RCC). The VHL protein (pVHL) is implicated in cell-cycle control and gene regulation, and requires transcription-dependent nuclear-cytoplasmic trafficking for its function. There are two biologically active VHL protein isoforms: pVHL30 and pVHL19. To study prevalence, subcellular expression and biological significance of pVHL in renal tumors, tissue microarrays with renal-cell carcinomas were immunohistochemically examined for pVHL expression. Antibodies against both protein isoforms (anti-pVHL30/pVHL19) and against pVHL30 (anti-pVHL30; Ig33) were used. The anti-pVHL30/pVHL19 antibody showed nuclear and cytoplasmic pVHL expression, whereas the anti-pVHL30 antibody (Ig33) detected cytoplasmic pVHL expression, suggesting that the distribution of VHL protein isoforms varies in the nuclear and cytoplasmic compartments of renal tumors. There were 175 of 398 primary clear-cell RCCs (44%) with both nuclear and cytoplasmic pVHL expression. Seventy-seven clear-cell RCCs (19%) showed only nuclear, 22 (6%) showed only cytoplasmic, and 124 tumors (31%) showed no pVHL expression. Notably, combined nuclear and cytoplasmic pVHL expression was associated with low histological grade (P < 0.0001), early tumor stage (P < 0.01), and better prognosis (P < 0.01). These results imply that alteration of subcellular pVHL trafficking is of potential relevance for the biological behavior of clear-cell RCC.




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