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Cancer Res. 2008 Jul 15;68(14):5795-802. doi: 10.1158/0008-5472.CAN-08-0951.

Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer.

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  • 1The Netherlands Cancer Institute, Division of Tumor Biology, Amsterdam, the Netherlands.

Abstract

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.

PMID:
18632633
[PubMed - indexed for MEDLINE]
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