Exosomal miR‑3681‑3p from M2‑polarized macrophages confers cisplatin resistance to gastric cancer cells by targeting MLH1

Cisplatin (DDP) is a key chemotherapeutic agent in the treatment of gastric cancer; however, its efficacy is often limited by chemoresistance, a notable challenge in clinical oncology. The present study aimed to investigate the influence of exosomes derived from M2-polarized macrophages, which promo...

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Published in:Molecular medicine reports Vol. 31; no. 4
Main Authors: Wei, Wujun, Li, Jiaxing, Huang, Jingjing, Jiang, Qi, Lin, Cheng, Hu, Rentong, Wei, Jiazhu, Li, Qiao, Xu, Guidan, Chang, Zhengyi
Format: Journal Article
Language:English
Published: Greece D.A. Spandidos 01.04.2025
Spandidos Publications
Spandidos Publications UK Ltd
Subjects:
Animals
Antibodies
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Biotechnology
Calnexin
Cancer cells
Cancer therapies
Care and treatment
CD163 antigen
CD9 antigen
Cell differentiation
Cell growth
Cell Line, Tumor
Chemoresistance
Chemotherapy
Cisplatin
Cisplatin - pharmacology
cisplatin resistance
Cytokines
Dosage and administration
Drug resistance
Drug Resistance, Neoplasm - genetics
Exosomes
Exosomes - genetics
Exosomes - metabolism
Gastric cancer
Gene Expression Regulation, Neoplastic - drug effects
Genetic aspects
Health aspects
Humans
Immunofluorescence
Immunotherapy
Invoices
M2 macrophages
Macrophages
Macrophages - drug effects
Macrophages - metabolism
Mice
microRNA-3681-3p
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
Microscopy
miRNA
MLH1
MLH1 protein
MutL protein
MutL Protein Homolog 1 - genetics
MutL Protein Homolog 1 - metabolism
Physiological aspects
RNA-mediated interference
siRNA
Stomach cancer
Stomach Neoplasms - drug therapy
Stomach Neoplasms - genetics
Stomach Neoplasms - metabolism
Stomach Neoplasms - pathology
Therapeutic targets
Transfection
Transmission electron microscopy
Tumor necrosis factor-TNF
China
M2 macrophages
gastric cancer
MLH1
microRNA‑3681‑3p
cisplatin resistance
ISSN:1791-2997, 1791-3004, 1791-3004
Online Access:Get full text
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Summary:Cisplatin (DDP) is a key chemotherapeutic agent in the treatment of gastric cancer; however, its efficacy is often limited by chemoresistance, a notable challenge in clinical oncology. The present study aimed to investigate the influence of exosomes derived from M2-polarized macrophages, which promote this resistance, on the response of gastric cancer cells to DDP, examining both the effects and the underlying mechanisms. M2 macrophages, differentiated from mouse bone marrow cells with interleukin (IL)-13 and IL-4, were identified using immunofluorescence staining for CD206 and CD163. Exosomes derived from these macrophages were characterized using transmission electron microscopy and protein markers, including calnexin, tumor susceptibility gene 101 and CD9. The role of exosomal microRNA (miR)-3681-3p in DDP resistance was assessed using Cell Counting Kit-8 and apoptosis assays, while a luciferase reporter assay was used to elucidate the interaction between miR-3681-3p and MutL protein homolog 1 (MLH1). Co-culturing gastric cancer cells with M2 macrophages enhanced DDP resistance, an effect amplified by exosomes from M2 macrophages enriched with miR-3681-3p. This microRNA directly targeted and reduced MLH1 protein expression. Overexpression of miR-3681-3p through mimic transfection, along with MLH1 silencing by small interfering RNA transfection, significantly increased DDP resistance, as evidenced by elevated IC50 values in AGS cells. By contrast, the overexpression of MLH1 effectively reversed the drug resistance of AGS cells to DDP caused by miR-3681-3p mimic transfection, as evidenced by a decrease in the IC50 value. In conclusion, exosomal miR-3681-3p from M2 macrophages may have a key role in conferring DDP resistance to gastric cancer by suppressing MLH1, offering a new therapeutic target for overcoming chemoresistance.
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Contributed equally
ISSN:1791-2997
1791-3004
1791-3004
DOI:10.3892/mmr.2025.13459