Transcriptional activation of the beta-catenin gene at the invasion front of colorectal liver metastases.

beta-Catenin is a pivotal molecule of the Wnt-signalling pathway, involved in regulation of developmental and oncogenic processes as well as in intercellular adhesion. So far, beta-catenin has been thought to be regulated mainly at the protein level. Here, we provide evidence for a transcriptional mechanism of beta-catenin regulation at the invasion front of colorectal liver metastases. In a nude mouse/LS174T cell xenograft model of colorectal liver metastases, we observed beta-catenin up-regulation at the mRNA and protein levels and a 13.7-fold increase of beta-catenin promoter activity in the cancer cells of the invasion front. In addition, the promoter activity was five-fold higher in the interior of the tumour than in cells growing in cell culture. In vitro studies revealed binding of TCF-4 to the beta-catenin promoter and reduced promoter activity by over-expression of dominant negative TCF-4, or beta-catenin knock-down and increased activity by beta-catenin over-expression, indicating that beta-catenin acts as co-transcription factor of its own promoter. In 55% (7/13) of clinical specimens, beta-catenin mRNA was markedly elevated in the cancer cells of the invasion front. Elevation of mRNA was paralleled by increased nuclear and cytoplasmic beta-catenin protein concentrations. These data indicate that transcriptional regulation contributes to the dynamic changes of beta-catenin levels upon the confrontation of tumour cells with the host microenvironment. 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.