Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis

Purpose: Characterization of colorectal cancer (CRC) transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed involving previously unreported microRNAs abnormalities. Here, we followed a systematic approach on a global scale to identify microRNAs as clinical outcome predictors, and further validated them in the clinical and experimental setting. Experimental Design: Genome-wide microRNA sequencing data of 228 CRC patients from the cancer genome atlas (TCGA) dataset were analyzed as a screening cohort to identify microRNAs significantly associated with survival according to stringent pre-specified criteria. A panel of six microRNAs was further validated for their prognostic utility in a large independent validation cohort (n=332). In situ hybridization and functional experiments in a panel of CRC cell lines and xenografts further clarified the role of clinical relevant miRNAs. Results: Six microRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR-188-3p expression proves to be an independent prognostic factor (screening cohort: hazard ratio = 4.137, 95%CI=1.568-10.917, p=0.004; validation cohort: hazard ratio HR=1.538, 95%CI=1.107-2.137, p=0.010, respectively). Forced miR-188-3p expression increased migratory behavior of CRC cells in vitro and metastases formation in vivo (p<0.05). The pro-migratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in CRC cell migration. Conclusions: MiR-188-3p is a novel independent prognostic factor in CRC patients which can be partly explained by its effect on MLLT4 expression and migration of cancer cells.