Authors: Jahid S; Sun J; Edwards RA; Dizon D; Panarelli NC; Milsom JW; Sikandar SS; Gümüs ZH; Lipkin SM
Abstract: Colorectal cancer is a classic example of a tumor that progresses through multiple distinct stages in its evolution. To understand the mechanisms regulating the transition from indolent to invasive disease, we profiled somatic copy number alterations in noninvasive adenomas and invasive adenocarcinomas from Apc and DNA mismatch repair (MMR) mutant mouse models. We identified a recurrent amplicon on mouse chromosome 8 that encodes microRNA (miRNA) 23a and -27a (miR). miR-23a and -27a levels are upregulated in mouse intestinal adenocarcinomas, primary tumors from patients with stage I/II colorectal cancers, as well as in human colorectal cancer cell lines and cancer stem cells. Functionally, miR-23a promotes the migration and invasion of colorectal cancer cells and stem cells, whereas miR-27a primarily promotes proliferation. We computationally and experimentally validated that metastasis suppressor 1 (MTSS1) is a direct miR-23a target and similarly validated that the ubiquitin ligase FBXW7 is a direct miR-27a target. Analyses of computationally predicted target genes in microarray data sets of patients with colorectal cancers are consistent with a role for miR-23a, but not miR-27a, specifically in invasive colorectal cancers.
Keywords: Adenocarcinoma/*genetics/metabolism/pathology; Adenoma/*genetics/metabolism/pathology; Animals; Colorectal Neoplasms/*genetics/metabolism/pathology; DNA Copy Number Variations; F-Box Proteins/genetics/metabolism; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs/*genetics; Neoplasm Invasiveness/genetics; Proto-Oncogene Proteins c-jun/metabolism; Proto-Oncogene Proteins c-myc/metabolism; Ubiquitin-Protein Ligases/genetics/metabolism|
Journal: Cancer discovery Volume: 2 Issue: 6 Pages: 540-53 Date: May 26, 2012 PMID: 22628407 |
Jahid S, Sun J, Edwards RA, Dizon D, Panarelli NC, Milsom JW, Sikandar SS, Gümüs ZH, Lipkin SM (2012) miR-23a promotes the transition from indolent to invasive colorectal cancer. Cancer discovery 2: 540-53.
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