Wnt signaling regulates expression of the receptor tyrosine kinase met in colorectal cancer.
Overexpression of the receptor tyrosine kinase Met is an early event in the colorectal adenoma-carcinoma sequence. This suggests a link with disruption of adenomatous polyposis coli-controlled regulation of beta-catenin/T-cell factor (TCF)-mediated transcriptional activation, which is crucial in initiating tumorigenesis. Indeed, in intestinal biopsies from patients with familial adenomatous polyposis, we find Met already overexpressed in dysplastic aberrant crypt foci, the earliest neoplastic lesions of colorectal cancer (CRC). Moreover, in CRC cells, induction of dominant-negative TCF proteins and the consequent abrogation of beta-catenin/TCF-mediated transcriptional activation lead to a strong down-regulation of Met expression. Our results indicate that Met expression is part of a genetic program controlled by the Wnt pathway and suggest a role for Met in controlling the turnover and differentiation of intestinal epithelium.
Boon
Elles M J
EM
Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
van der Neut
Ronald
R
van de Wetering
Marc
M
Clevers
Hans
H
Pals
Steven T
ST
D000236:Adenoma / Q000201:enzymology / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000201:enzymology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D019859:Proto-Oncogene Proteins c-met