Inhibition of tumor progression and M2 microglial polarization by extracellular vesicle-mediated microRNA- 124 in a 3D microfluidic glioblastoma microenvironment
- Inhibition of tumor progression and M2 microglial polarization by extracellular vesicle-mediated microRNA- 124 in a 3D microfluidic glioblastoma microenvironment
- 최낙원; 홍수현; 유재영; 백규림; 박주빈; 강수진; 한은희; 정석; 이원종; 김정아
- Issue Date
- VOL 11, NO 19-9704
- Background: Glioblastoma (GBM) is one of the most aggressive types of brain cancer. GBM progression is closely associated with microglia activation; therefore, understanding the regulation of the crosstalk between human GBM and microglia may help develop effective therapeutic strategies. Elucidation of efficient delivery of microRNA (miRNA) via extracellular vesicles (EVs) and their intracellular communications is required for therapeutic applications in GBM treatment.
Methods: We used human GBM cells (U373MG) and human microglia. MiRNA-124 was loaded into HEK293T-derived EVs (miR-124 EVs). Various anti-tumor effects (proliferation, metastasis, chemosensitivity, M1/M2 microglial polarization, and cytokine profile) were investigated in U373MG and microglia. Anti-tumor effect of miR-124 EVs was also investigated in five different patient-derived GBM cell lines (SNU-201, SNU-466, SNU-489, SNU-626, and SNU-1105). A three-dimensional (3D) microfluidic device was used to investigate the interactive microenvironment of the tumor and microglia.
Results: MiR-124 EVs showed highly efficient anti-tumor effects both in GBM cells and microglia. The mRNA expression levels of tumor progression and M2 microglial polarization markers were decreased in response to miR-124 EVs. The events were closely related to signal transducer and activator of transcription (STAT) 3 signaling in both GBM and microglia. In 3D microfluidic experiments, both U373MG and microglia migrated to a lesser extent and showed less-elongated morphology in the presence of miR-124 EVs compared to the control. Analyses of changes in cytokine levels in the microfluidic GBM-microglia environment showed that the treatment with miR-124 EVs led to tumor suppression and anti-cancer immunity, thereby recruiting natural killer (NK) cells into the tumor.
Conclusions: In this study, we demonstrated that EV-mediated miR-124 delivery exerted synergistic anti-tumor effects by s
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