Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer.
Inactivation of the adenomatous polyposis coli (APC) gene is a major initiating event in colorectal tumorigenesis. Most of the mutations in APC generate premature stop codons leading to truncated proteins that have lost beta-catenin binding sites. APC-free beta-catenin stimulates the Wnt signaling pathway, leading to active transcription of target genes. In the current study, we describe a novel mechanism for APC regulation. We show that miR-135a&b target the 3' untranslated region of APC, suppress its expression, and induce downstream Wnt pathway activity. Interestingly, we find a considerable up-regulation of miR-135a&b in colorectal adenomas and carcinomas, which significantly correlated with low APC mRNA levels. This genetic interaction is also preserved in full-blown cancer cell lines expressing miR-135a&b, regardless of the mutational status of APC. Thus, our results uncover a miRNA-mediated mechanism for the control of APC expression and Wnt pathway activity, and suggest its contribution to colorectal cancer pathogenesis.
Nagel
Remco
R
The Netherlands Cancer Institute, Division of Tumor Biology, Amsterdam, the Netherlands.
le Sage
Carlos
C
Diosdado
Begoña
B
van der Waal
Maike
M
Oude Vrielink
Joachim A F
JA
Bolijn
Anne
A
Meijer
Gerrit A
GA
Agami
Reuven
R
D020413:3' Untranslated Regions; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
D020413:3' Untranslated Regions; D025601:Adenomatous Polyposis Coli Protein; D035683:MicroRNAs; D051153:Wnt Proteins