<p>Exosomal Transfer of Macrophage-Derived miR-223 Confers Doxorubicin Resistance in Gastric Cancer</p>

Abstract

Purpose: Macrophages are a major component of the tumour microenvironment and play an important role in chemoresistance of cancer. However, how exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of doxorubicin resistance in gastric cancer (GC) are not clearly defined. The aim of this study was to investigate whether macrophage-derived exosomes mediate doxorubicin resistance in GC. Methods: Exosomes isolated from macrophage culture medium were characterized and cocultured with GC cells and the miR-223 level was detected using real-time quantitative PCR (RT-qPCR). The internalization of exosomes and transfer of miR-223 were observed via immunofluorescence. Macrophages were transfected with an miR-223 inhibitor or negative control. Cell Counting Kit-8 and flow cytometry were employed to explore the effect of macrophage-derived exosomes on the doxorubicin resistance of GC cells. Western blot and RT-qPCR assay were also performed to explore the regulation of GC chemotherapy resistance by exosomal miR-223. Results: Here, the macrophages and macrophage-derived exosomes promoted doxorubicin resistance in GC cells. MiR-223 was enriched in macrophage-derived exosomes and they could be transferred to co-cultivated GC cells. The miR-223 knockdown in macrophages could reduce the effects of exosomes on GC cells. Functional studies revealed that exosomal miR-223 derived from macrophages promoted doxorubicin resistance in GC cells by inhibiting F-box and WD repeat domain-containing 7 (FBXW7). Clinically, the expression of miR-223 significantly increased in GC tissues and high expression of plasma exosomal miR-223 was highly linked with doxorubicin resistance in GC patients. Conclusion: The exosomal transfer of macrophage-derived miR-223 conferred doxorubicin resistance in GC and targeting exosome communication may be a promising new therapeutic strategy for GC patients.

The role and application of small extracellular vesicles in gastric cancer

“… [ 107 ] miR-223 miRNA Promote doxorubicin resistance in GC cells by inhibiting FBXW7. [ 108 ] Vincristine CLIC1 protein Induce the development of resistance to vincristine in vitro, which might relate to up-regulated P-gp and Bcl-2. [ 109 ] Paclitaxel miR-155-5p miRNA Induce EMT and chemo-resistant phenotypes from paclitaxel-resistant GC cells to the sensitive cells, which may be mediated by GATA3 and TP53INP1 suppression.…”

“…Additionally, sEVs may be involved in resistance to doxorubicin [ 107 , 108 ], vincristine [ 109 ] and paclitaxel [ 110 ]. However, some data seem to be from cell research and it is speculated that they may be found in sEVs as they belong to a group of molecules which are frequently found in sEVs.…”

Role of Exosomal Non-coding RNAs in Gastric Cancer: Biological Functions and Potential Clinical Applications

“…Zheng et al found that M2-polarized macrophage-derived exosome microRNA-21 can transfer to GC cells to inhibit cell apoptosis by downregulating PTEN and enhancing the activation of the PI3K/AKT signaling pathway, thereby inducing DDP resistance in GC patients (140). In addition, Gao and colleagues reported that macrophage-derived exosomes transferred miR-223 into cocultured GC cells to activate their resistance to ADR by targeting FBXW7, a p53-dependent tumor-suppressor protein (86).…”

“…Exosomes produced by other cells in the TME, such as CAF and M2 macrophages, can also induce chemoresistance in GC cells ( 85 , 86 , 140 ). Ferroptosis is a novel mode of non-apoptotic cell death induced by the accumulation of toxic lipid peroxides (lipid-ROS) in an iron-dependent manner ( 141 ).…”

Tumor Cell-Derived Exosomal miR-770 Inhibits M2 Macrophage Polarization via Targeting MAP3K1 to Inhibit the Invasion of Non-small Cell Lung Cancer Cells

“…In addition, the macrophages of the tumor environment showing oncogenic effects are considered as tumor-associated macrophages (TAMs), which usually exhibit M2 phenotype ( Dessouki et al, 2020 ). The correlation between tumor cells and TAMs has been revealed some cancers (gastric cancer, pancreatic cancer, et al) ( Gao et al, 2020 ; Zhou et al, 2021 ). Nevertheless, the detailed association between NSCLC treatments with TAMs is unclear.…”