Journal Article

MiR-668-3p in M2 macrophage-derived exosomes activates autophagy through the ETS1/EGFR axis and promotes cisplatin resistance in gastric cancer

Zhang, Xin, Wang, Weijun, Huang, Xin, Wei, Ziran, Zheng, Zhi, Xu, Dapeng, Zhu, Zhenxin, Yan, Ronglin, Hu, Zunqi, Yang, Dejun, Fu, Hongbing

2025

Overview

Background Previous research suggests that tumor-associated macrophages (TAMs) influence the cisplatin (DDP) tolerance of gastric cancer (GC) cells via the secretion of microRNA-containing exosomes. This study aims to investigate the role of exosomal miR-668-3p from M2 macrophages in modulating DDP resistance, using both in vitro and in vivo models to provide a comprehensive analysis. Materials and methods The expression profiles of DDP-resistant GC tissues were assessed through microarray, while immunofluorescence confirmed the uptake of these exosomes by GC cells. The role of miR-668-3p in regulating DDP resistance was explored using CCK8 assays, colony formation, EDU incorporation, and Western blotting. The interaction between miR-668-3p and ETS1 was validated through RIP and RNA pull-down assays. Furthermore, the regulatory role of the miR-668-3p/ETS1/EGFR axis in autophagy and DDP resistance was examined in GC cell lines and a tumor xenograft model. Results miR-668-3p was significantly upregulated in DDP-resistant GC tissues. Exosomes originating from M2 macrophages transfer miR-668-3p to GC cells, enhancing their DDP resistance. Additionally, miR-668-3p was found to bind to ETS1 mRNA, leading to its suppression and a consequent decrease in EGFR expression. This reduction in EGFR expression was closely linked to the activation of autophagy, further augmenting DDP resistance in GC cells. Conclusion M2 macrophage-derived exosomal miR-668-3p promotes DDP resistance in GC cells by targeting the ETS1/EGFR axis, thereby activating the autophagy pathway. Future research should focus on developing targeted inhibition strategies for miR-668-3p to effectively reverse DDP resistance in GC cells, optimizing its potential for clinical application.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adjuvants / Autophagy / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Cell Biology / Cells / Chemotherapy / Cisplatin / Cisplatin resistance / EGFR / Epidermal growth factor receptors / Ets-1 protein / ETS1 / Exosomes / Gastric cancer / Gender / Homeostasis / Immunofluorescence / Immunological tolerance / Kinases / Macrophages / Medical prognosis / Metastasis / MicroRNAs / MiRNA / mRNA / Patients / Tumor cell lines / Tumors / Western blotting