Methylation-induced loss of miR-484 in microsatellite-unstable colorectal cancer promotes both viability and IL-8 production via CD137L

Abstract

Colorectal cancer (CRC) exhibiting MSI (microsatellite instability) represents a well-defined subtype characterized by a deficient mismatch repair pathway and typical clinico-pathological features. Our objective was to identify the entire miRNome and its molecular pathological roles in MSI CRCs. We profiled miRNA expression in MSI CRCs and compared it with MSS counterparts. Microarray and qRT-PCR analysis identified eight miRNAs that could distinguish the MSI status of CRCs. MiR-484 was the most significantly decreased miRNA in MSI CRCs, primarily mediated by the CpG island methylator phenotype. MiR-484 functions as a tumour suppressor to inhibit MSI CRC cell viability in vitro and in vivo. Moreover, miR-484 repressed CD137L expression and thereby attenuated IL-8 production by MSI CRC cells. Our results contribute to a better understanding of the roles of dysregulated miRNAs in the distinct phenotypic features of MSI CRCs and indicate an option for early diagnosis and gene therapy for these patients.

Keywords: CD137L; cell viability; colorectal cancer (CRC); cytokine production; miR-484; microRNA; microsatellite instability (MSI).