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

β‐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, β‐catenin has been thought to be regulated mainly at the protein level. Here, we provide evidence for a transcriptional mechanism of β‐catenin regulation at the invasion front of colorectal liver metastases. In a nude mouse/LS174T cell xenograft model of colorectal liver metastases, we observed β‐catenin up‐regulation at the mRNA and protein levels and a 13.7‐fold increase of β‐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 β‐catenin promoter and reduced promoter activity by over‐expression of dominant negative TCF‐4, or β‐catenin knock‐down and increased activity by β‐catenin over‐expression, indicating that β‐catenin acts as co‐transcription factor of its own promoter. In 55% (7/13) of clinical specimens, β‐catenin mRNA was markedly elevated in the cancer cells of the invasion front. Elevation of mRNA was paralleled by increased nuclear and cytoplasmic β‐catenin protein concentrations. These data indicate that transcriptional regulation contributes to the dynamic changes of β‐catenin levels upon the confrontation of tumour cells with the host microenvironment. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.