Extracellular vesicle-encapsulated microRNA-425-derived from drug-resistant cells promotes non-small-cell lung cancer progression through DAPK1-medicated PI3K/AKT pathway.

Investigations in the area of tumor-derived extracellular vesicles (EVs) open a new horizon in developing cancer biology and its potential as cancer biomarkers. Following this prospect, we aimed to identify that the role of successfully isolated EVs from drug-resistance cells in the progression of non-small-cell lung cancer (NSCLC). P-EVs and R-EVs secreted by A549 cells and drug-resistant A549-R cells respectively were extracted and characterized. The targeting relationship between miR-425 and MED1 was verified. Cell proliferation, invasion, migration and apoptosis after treatment of P-EVs, R-EVs, miR-425 inhibitor, miR-425 mimic, pcDNA-MED1, or phosphatidylinositol-3-kinase (PI3K)/AKT inhibitor LY294002 were detected. Furthermore, xenograft tumor in nude mice was established for further confirming our in vitro findings. P-EVs and R-EVs were successfully extracted and could be internalized by A549 cells. A549-R cells and R-EVs showed higher miR-425 expression compared with A549 cells and P-EVs, respectively. miR-425 delivered by R-EVs could promote the proliferation, migration, and invasion, while inhibit apoptosis of NSCLC cells. MED1 was the target gene of miR-425. EVs-encapsulated miR-425-derived from A549-R cells could promote the progression of NSCLC in vivo through regulating DAPK1-medicated PI3K/AKT pathway. Moreover, miR-425 delivered by R-EVs promoted tumorigenesis in vivo. Taken together, the result suggested that EVs-delivered miR-425-derived from A549-R cells promoted the progression of NSCLC through regulating DAPK1-medicated PI3K/AKT signaling pathway.