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

Autor: Ermes Candiello, Gigliola Reato, Federica Verginelli, Gennaro Gambardella, Antonio D′Ambrosio, Noemi Calandra, Francesca Orzan, Antonella Iuliano, Raffaella Albano, Francesco Sassi, Paolo Luraghi, Paolo M. Comoglio, Andrea Bertotti, Livio Trusolino, Carla Boccaccio
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Molecular Oncology, Vol 17, Iss 7, Pp 1280-1301 (2023)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.13408
Popis: 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 GSK3β, 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.
Databáze: Directory of Open Access Journals
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