Constitutive expression of the Wilms tumor suppressor gene (WT1) in renal cell carcinoma

The expression of the Wilms tumor suppressor gene WT1 is largely restricted to elements of the developing urogenital system. In the fetal kidney, WT1 transcripts are present at low levels in the condensing mesenchyme and at much higher levels in differentiating glomerular epithelium and are not detected in other mesenchymal-derived epithelial structures such as the proximal and distal tubules. However, WT1 expression is observed in tubule-like elements found in some Wilms tumors. As renal cell carcinoma (RCC) of the clear cell type is one of the most prevalent adult tumors of the kidney, and is thought to originate from the epithelial cells of the proximal tubules, we studied WT1 expression in RCCs. Despite the absence of WT1 in normal primary epithelial cells derived from proximal tubules, RCC tumors and tumor-derived cell lines expressed WT1 RNA. Immunocytochemical analyses of tumor cryosections showed widespread expression throughout the poorly differentiated epithelial components of the tumor. Immunoblots of RCC samples detected a normal size WT I protein and reciprocal antibody immunoprecipitations of RCC cell extracts indicated that WT I interacts with p53 as has been demonstrated for normal human fetal kidney. The aberrant expression of functional WT1 in RCC may represent a reversion to a more de-differentiated phenotype and may contribute to the tumorigenic phenotype by inappropriately activating or repressing genes involved in growth regulation.