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Background <p>Previous research suggests that tumor-associated macrophages (TAMs) influence the cisplatin (DDP) tolerance of gastric cancer (GC) cells <i>via</i> 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.</p> Materials and methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月25日

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

摘要

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.