INCREASED EXPRESSION OF THE INSULIN-LIKE GROWTH FACTOR-I RECEPTOR GENE, IGF1R, IN WILMS-TUMOR IS CORRELATED WITH MODULATION OF IGF1R PROMOTER ACTIVITY BY THE WT1 WILMS-TUMOR GENE-PRODUCT

Wilms tumor is a pediatric neoplasm that arises from the metanephric b lastema. The expression of the gene encoding insulin-like growth facto r II (IGF-II) is often elevated in these tumors. Since many of the act ions of IGF-II are mediated through activation of the IGF-I receptor ( IGF-IR), we have measured the levels of IGF-IR mRNA in normal kidney a nd in Wilms tumor samples using solution hybridization/RNase protectio n assays. IGF-IR mRNA levels in the tumors were 5.8-fold higher than i n adjacent normal kidney tissue. Among the tumors themselves, the leve ls of IGF-IR mRNA in those containing heterologous stromal elements we re 2-fold higher (P < 0.01) than in tumors without these elements. IGF -IR gene (designated IGF1R) expression in the tumors was inversely cor related with the expression of the Wilms tumor suppressor gene WT1, wh ose inactivation appears to be a key step in the etiology of Wilms tum or. Cotransfection of Chinese hamster ovary cells with rat and human I GF-IR gene promoter constructs driving luciferase reporter genes and w ith WT1 expression vectors showed that the active WT1 gene product rep resses IGF-IR promoter activity in a dose-dependent manner. These resu lts suggest that underexpression, deletion, or mutation of WT1 may res ult in increased expression of the IGF-IR, whose activation by IGF-II may be an important aspect of the biology of Wilms tumor.