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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.