PT  - JOURNAL ARTICLE
AU  - Nagel, Remco
AU  - le Sage, Carlos
AU  - Diosdado, Begoña
AU  - van der Waal, Maike
AU  - Oude Vrielink, Joachim A.F.
AU  - Bolijn, Anne
AU  - Meijer, Gerrit A.
AU  - Agami, Reuven
TI  - Regulation of the Adenomatous Polyposis Coli Gene by the miR-135 Family in Colorectal Cancer
AID  - 10.1158/0008-5472.CAN-08-0951
DP  - 2008 Jul 15
TA  - Cancer Research
PG  - 5795--5802
VI  - 68
IP  - 14
4099  - http://cancerres.aacrjournals.org/content/68/14/5795.short
4100  - http://cancerres.aacrjournals.org/content/68/14/5795.full
SO  - Cancer Res2008 Jul 15; 68
AB  - 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 β-catenin binding sites. APC-free β-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. [Cancer Res 2008;68(14):5795–802] ©2008 American Association for Cancer Research.