Microglial Exosome miR-7239-3p Promotes Glioma Progression by Regulating Circadian Genes
Xuepei Li1,2 • Junwen Guan3 • Zhou Jiang1 • Shuting Cheng1 • Wang Hou4 • Junjie Yao5 • Zhengrong Wang1
1 Ministry of Health Key Laboratory of Chronobiology, College of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu 610041, China
2 Medical Simulation Center, Chengdu First People’s Hospital, Chengdu 610041, China
3 Neurosurgery Department, West China Hospital, Sichuan University, Chengdu 610041, China
4 Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
5 Department of Anesthesiology, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 410000, China
Abstract
Glioma-associated microglial cells, a key component of the tumor microenvironment, play an important role in glioma progression. In this study, the mouse glioma cell line GL261 and the mouse microglia cell line BV2 were chosen. First, circadian gene expression in glioma cells co-cultured with either M1 or M2 microglia was assessed and the exosomes of M2-polarized and unpolarized BV-2 microglia were extracted. Subsequently, we labeled the exosomes with PKH67 and treated GL261 cells with them to investigate the exosome distribution. GL261 cell phenotypes and related protein expression were used to explore the role of M2 microglial exosomes in gliomas. Then a specific miR-7239-3p inhibitor was added to verify miR-7239-3p functions. Finally, the mouse subcutaneous tumorigenic model was used to verify the tumorigenic effect of M2 microglial exosomes in vivo. Our results showed that in gliomas co-cultured with M2 microglia, the expression of the BMAL1 protein was decreased (P < 0.01), while the expression of the CLOCK protein was increased (P < 0.05); opposite results were obtained in gliomas co-cultured with M1 microglia. After treatment with M2 microglial exosomes, the apoptosis of GL261 cells decreased (P < 0.001), while the viability, proliferation, and migration of GL261 cells increased. Increased expression of N-cadherin and Vimentin, and decreased E-cadherin expression occurred upon treatment with M2 microglial exosomes. Addition of an miR-7239-3p inhibitor to M2 microglial exosomes reversed these results. In summary, we found that miR-7239-3p in the glioma microenvironment is recruited to glioma cells by exosomes and inhibits Bmal1 expression. M2 microglial exosomes promote the proliferation and migration of gliomas by regulating tumor-related protein expression and reducing apoptosis.
Keywords
Glioma; Microglia; Bmal1; Exosome; miR7239-3p
