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

Articolo
Data di Pubblicazione:
2023
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 GSK3 beta, 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.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
ERBB3; NDRG1; cancer stem cell; colorectal cancer; metastasis; miRNA-483-3p
Elenco autori:
Candiello, Ermes; Reato, Gigliola; Verginelli, Federica; Gambardella, Gennaro; D Ambrosio, Antonio; Calandra, Noemi; Orzan, Francesca; Iuliano, Antonella; Albano, Raffaella; Sassi, Francesco; Luraghi, Paolo; Comoglio, Paolo M; Bertotti, Andrea; Trusolino, Livio; Boccaccio, Carla
Autori di Ateneo:
BERTOTTI Andrea
BOCCACCIO Carla
ORZAN FRANCESCA NOEMI
TRUSOLINO Livio
Link alla scheda completa:
https://iris.unito.it/handle/2318/1946413
Pubblicato in:
MOLECULAR ONCOLOGY
Journal
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