Identification of cadherin-11 down-regulation as a common response of astrocytoma cells to Transforming Growth Factor-alpha

Transforming growth factor-alpha (TGF-alpha) and its receptor are frequentl y co-expressed in high-grade astrocytomas, suggesting a role for TCF-alpha autocrine/paracrine loops in the malignant progression of astrocytomas. To identify genes that may be critical in mediating TGF-alpha impact on the ma lignant progression of astrocytomas, we have used cDNA arrays to investigat e TGF-alpha effects on the gene expression profile of U-373 MG glioblastoma cells. We found that in these cells similar to 50% of the TGF-alpha regula ted genes code for cell motility/invasion-related proteins. TGF-alpha actio n on the expression of four of these proteins, alpha -catenin, IQGAP1, RhoA , and cadherin-ll, was further investigated by immunoblotting in four astro cytoma cell lines and in normal astrocytes. The results demonstrate that th e effects of TGF-alpha on IQGAP1, alpha -catenin, and RhoA expression are c ell-line dependent. On the other hand, under TGF-alpha treatment, cadherin- li expression is consistently decreased in all astrocytoma cell lines teste d but is increased in normal astrocytes. In addition, we found that cadheri n-ll is consistently down-regulated in astrocytomas versus normal brain tis sues. Altogether, these results suggest that the down-regulation of cadheri n-ll is a frequent molecular event in the neoplastic transformation of astr ocytes and that this down-regulation may be initiated and/or amplified by T GF-alpha autocrine/paracrine loops during tumor progression.