MicroRNA 483-3p overexpression unleashes invasive growth of metastatic colorectal cancer via NDRG1 downregulation and ensuing activation of the ERBB3/AKT axis.

ABSTRACT

In colorectal cancer, the mechanisms underlying tumor aggressiveness require further elucidation. Taking advantage of a large panel of human metastatic colorectal cancer xenografts and matched stem-like cell cultures (m-colospheres), here we show that the overexpression of microRNA 483-3p (miRNA-483-3p; also known as MIR-483-3p), encoded by a frequently amplified gene locus, confers an aggressive phenotype. In m-colospheres, endogenous or ectopic miRNA-483-3p overexpression increased proliferative response, invasiveness, stem cell frequency, and resistance to differentiation. Transcriptomic analyses and functional validation found that miRNA-483-3p directly targets NDRG1, known as a metastasis suppressor involved in EGFR family downregulation. Mechanistically, miRNA-483-3p overexpression induced the signaling pathway triggered by ERBB3, including AKT and GSK3ß, and led to the activation of transcription factors regulating epithelial-mesenchymal transition (EMT). Consistently, treatment with selective anti-ERBB3 antibodies counteracted the invasive growth of miRNA-483-3p-overexpressing m-colospheres. In human colorectal tumors, miRNA-483-3p expression inversely correlated with NDRG1 and directly correlated with EMT transcription factor expression and poor prognosis. These results unveil a previously unrecognized link between miRNA-483-3p, NDRG1, and ERBB3-AKT signaling that can directly support colorectal cancer invasion and is amenable to therapeutic targeting.