MiR-23a Promotes the Transition from Indolent to Invasive Colorectal Cancer

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.