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

Colorectal cancer (CRC) 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 non-invasive 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 microRNAs (miRs) 23a and 27a. miRs-23a and 27a levels are upregulated in mouse intestinal adenocarcinomas, primary tumors from stage I/II CRC patients, as well as in human CRC cell lines and cancer stem cells. Functionally, miR-23a promotes CRC cells and stem cells migration and invasion, while 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 CRC patient microarray datasets are consistent with a role for miR-23a, but not miR-27a, specifically in invasive CRC.