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Regulation of the Adenomatous Polyposis Coli Gene by the miR-135 Family in Colorectal Cancer

¹ The Netherlands Cancer Institute, Division of Tumor Biology and ² VU University Medical Center, Department of Pathology, Amsterdam, the Netherlands

Requests for reprints: Reuven Agami, Netherland Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, the Netherlands. Phone: 31-0-20-512-2079; Fax: 31-0-20-512-2029; E-mail: r.agami{at}nki.nl.

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]

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