1. ¹Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
2. ²Department of Pathology, University Health Network, Toronto, ON, Canada
3. ³Division of Cancer Informatics, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
4. ⁴Departments of Surgery/Urology, University Health Network, Princess Margaret Hospital, University of Toronto and Surgical Oncology, Toronto, ON, Canada
5. ⁵Department of Medical Biophysics, Ontario Cancer Institute, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada

Correspondence: Dr M Ohh, PhD, Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, Canada M5S 1A8. E-mail: michael.ohh@utoronto.ca

Received 16 July 2007; Revised 29 August 2007; Accepted 4 September 2007; Published online 1 October 2007.

Abstract

The loss of functional von Hippel–Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC.