Liang Lu, Fu Jijun, Wang Siran, Cen Huiyu, Zhang Lingmin, Mandukhail Safur Rehman, Du Lingran, Wu Qianni, Zhang Peiquan, Yu Xiyong
Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.
Department of Prosthodontics, the Second Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Acta Pharm Sin B. 2020 Jun;10(6):1036-1046. doi: 10.1016/j.apsb.2019.11.009. Epub 2019 Nov 16.
MiR-142-3p has been reported to act as a tumor suppressor in breast cancer. However, the regulatory effect of miR-142-3p on drug resistance of breast cancer cells and its underlying mechanism remain unknown. Here, we found that miR-142-3p was significantly downregulated in the doxorubicin (DOX)-resistant MCF-7 cell line (MCF-7/DOX). MiR-142-3p overexpression increased DOX sensitivity and enhanced DOX-induced apoptosis in breast cancer cells. High-mobility group box 1 (HMGB1) is a direct functional target of miR-142-3p in breast cancer cells and miR-142-3p negatively regulated HMGB1 expression. Moreover, overexpression of HMGB1 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by miR-142-3p up-regulation. In conclusion, miR-142-3p overexpression may inhibit autophagy and promote the drug sensitivity of breast cancer cells to DOX by targeting HMGB1. The miR-142-3p/HMGB1 axis might be a novel target to regulate the drug resistance of breast cancer patients.
据报道，miR-142-3p在乳腺癌中发挥肿瘤抑制作用。然而，miR-142-3p对乳腺癌细胞耐药性的调控作用及其潜在机制仍不清楚。在此，我们发现miR-142-3p在阿霉素（DOX）耐药的MCF-7细胞系（MCF-7/DOX）中显著下调。miR-142-3p过表达增加了乳腺癌细胞对DOX的敏感性，并增强了DOX诱导的细胞凋亡。高迁移率族蛋白B1（HMGB1）是miR-142-3p在乳腺癌细胞中的直接功能靶点，miR-142-3p负向调节HMGB1的表达。此外，HMGB1的过表达显著逆转了miR-142-3p上调介导的细胞凋亡促进和自噬抑制。总之，miR-142-3p过表达可能通过靶向HMGB1抑制自噬并促进乳腺癌细胞对DOX的药物敏感性。miR-142-3p/HMGB1轴可能是调节乳腺癌患者耐药性的新靶点。
