微小RNA 483-3p 过量表达引发转移性结直肠癌的浸润性生长，通过 NDRG1 下调和随之而来的 ERBB3/AKT 轴的激活。
MicroRNA 483-3p overexpression unleashes invasive growth of metastatic colorectal cancer via NDRG1 downregulation and ensuing activation of the ERBB3/AKT axis.
发表日期：2023 Mar 02
作者：
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
来源：
Stem Cell Research & Therapy
摘要：
在结肠直肠癌中，肿瘤侵袭机制需要进一步解明。本研究充分利用人类转移性结肠直肠癌移植瘤和匹配的干细胞培养（m-球体）大面积试验，发现由经常放大的基因位置编码的microRNA 483-3p（miRNA-483-3p；也称为 MIR-483-3p）过度表达，赋予一种侵袭性表型。在m-球体中，内源性或外源性miRNA-483-3p过度表达增加了增殖反应、侵袭性、干细胞频率及分化抵抗性。 转录组分析和功能验证发现，miRNA-483-3p直接靶向NDRG1，NDRG1是一个参与EGFR家族下调的转移抑制因子。在机制上，miRNA-483-3p过度表达诱导了由ERBB3引发的信号通路，包括AKT和GSK3β，并导致活化转录因子调控上皮间质转化（EMT）。一致地，选择性抗ERBB3抗体的治疗抵消了miRNA-483-3p过度表达m-球体的侵袭性增长。在人类结肠直肠肿瘤中，miRNA-483-3p表达与NDRG1呈负相关，与EMT转录因子表达和预后差直接相关。这些结果揭示了miRNA-483-3p、NDRG1和ERBB3-AKT信号这三者之间以前未认识的联系，该联系直接支持结肠癌侵袭，并有利于治疗靶向化。本文受版权保护。保留所有权利。
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 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 leading to activation of transcription factors regulating epithelial-mesenchymal transition (EMT). Consistently, treatment with selective anti-ERBB3 antibodies counteracted 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.This article is protected by copyright. All rights reserved.