Extracellular vesicles derived from lung cancer cells exposed to intermittent hypoxia promote M2 macrophage polarization through miR-20a-5p/PTEN/Akt pathway

Objective: Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea. Herein, we investigated the effects of extracellular vesicles derived from intermittent hypoxic lung cancer cells on macrophage polarization. Methods: A549 cells were exposed to normoxia or IH (48 cycles, 5 min of 1% O₂ hypoxia, followed by 5 min of normoxia). Cancer cell–derived EVs were isolated and cocultured with macrophages differentiated from THP-1. Results: EVs derived from IH group highly expressed miR-20a-5p. Macrophages treated with EVs from IH group or miR-20a-5p-rich EVs showed M2 phenotype. Luciferase reporter analysis confirmed that PTEN was a target gene of miR-20a-5p. Transfection of miR-20a-5p mimics down-regulated PTEN expression, upregulated M2 polarization markers expressions and promoted Akt phosphorylation in macrophages, whereas the miR-20a-5p inhibitor had the opposite influence. Conclusions: EVs derived from intermittent hypoxic lung cancer cells promote M2 macrophage polarization through miR-20a-5p/PTEN/Akt pathway.