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.
Bandapalli
Obul R
OR
Department of General Pathology, University of Heidelberg, Germany.
Dihlmann
Susanne
S
Helwa
Reham
R
Macher-Goeppinger
Stephan
S
Weitz
Jurgen
J
Schirmacher
Peter
P
Brand
Karsten
K
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D000818:Animals; D015179:Colorectal Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015398:Signal Transduction; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051176:beta Catenin