Hypoxic glioma‐derived extracellular vesicles harboring MicroRNA‐10b‐5p enhance M2 polarization of macrophages to promote the development of glioma

The delivery of biomolecules by tumor cell-secreted extracellular vesicles (EVs) is linked to the development of glioma. Here, the present study was implemented to explore the functional significance of hypoxic glioma cell-derived EVs carrying microRNA-10b-5 (miR-10b-5p) on glioma with the involvement of polarization of M2 macrophages.EVs were isolated from hypoxia-stimulated glioma cells, and their role in polarization of M2 macrophages was studied by co-culturing with macrophages. miR-10b-5p expression in glioma tissues, glioma-derived EVs, and macrophages co-cultured with EVs was characterized. Interaction among miR-10b-5p, NEDD4L, and PIK3CA was analyzed. The macrophages or glioma cells were transfected with overexpressing plasmid or shRNA to study the effects of miR-10b-5p/NEDD4L/PIK3CA on M2 macrophage polarization, and glioma cell proliferation, migration, and invasion in vitro and in vivo.Promotive role of hypoxia-stimulated glioma-derived EVs in macrophage M2 polarization was confirmed. Elevation of miR-10b-5p occurred in glioma tissues, glioma-derived EVs and macrophages co-cultured with EVs, and stimulated M2 polarization of macrophages. NEDD4L was a target gene of miR-10b-5p. Overexpression of NEDD4L could inhibit PI3K/AKT pathway through increase in ubiquitination and degradation of PIK3CA. Hypoxic glioma-derived EVs harboring upregulated miR-10b-5p triggered an M2 phenotype in macrophages as well as enhanced aggressive tumor biology of glioma cells via inhibition of PIK3CA/PI3K/AKT pathway by targeting NEDD4L.In summary, miR-10b-5p delivered by hypoxic glioma-derived EVs accelerated macrophages M2 polarization to promote the progression of glioma via NEDD4L/PIK3CA/PI3K/AKT axis.