Target genes of β-catenin–T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas

Abstract

Mutations in the adenomatous polyposis coli or β-catenin gene lead to cytosolic accumulation of β-catenin and, subsequently, to increased transcriptional activity of the β-catenin–T cell-factor/lymphoid-enhancer-factor complex. This process seems to play an essential role in the development of most colorectal carcinomas. To identify genes activated by β-catenin overexpression, we used colorectal cell lines for transfection with the β-catenin gene and searched for genes differentially expressed in the transfectants. There are four genes affected by β-catenin overexpression; three overexpressed genes code for two components of the AP-1 transcription complex, c-jun and fra-1, and for the urokinase-type plasminogen activator receptor (uPAR), whose transcription is activated by AP-1. The direct interaction of the β-catenin–T cell-factor/lymphoid-enhancer-factor complex with the promoter region of c-jun and fra-1 was shown in a gel shift assay. The concomitant increase in β-catenin expression and the amount of uPAR was confirmed in primary colon carcinomas and their liver metastases at both the mRNA and the protein levels. High expression of β-catenin in transfectants, as well as in additionally analyzed colorectal cell lines, was associated with decreased expression of ZO-1, which is involved in epithelial polarization. Thus, accumulation of β-catenin indirectly affects the expression of uPAR in vitro and in vivo. Together with the other alterations, β-catenin accumulation may contribute to the development and progression of colon carcinoma both by dedifferentiation and through proteolytic activity.