Microglial Exosome miR-7239-3p Promotes Glioma Progression by Regulating Circadian Genes

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.

Microglia and Brain Macrophages as Drivers of Glioma Progression

“…In line with these results, a more recent study has shown that microglia derived OLFML3 acts as a paracrine factor that facilitates glioma invasion [ 42 ]. Moreover, this idea is further supported by the recent finding that microglial exosomes and miRNA have been found to induce glioma progression by regulating circadian genes [ 41 ]. In turn, Dong et al have proposed to target GSCs through disruption of their circadian clock [ 174 ].…”

Exosome‐Derived Circ_0094343 Promotes Chemosensitivity of Colorectal Cancer Cells by Regulating Glycolysis via the miR‐766‐5p/TRIM67 Axis

“…Then, transmission electron microscopy (TEM) was utilized to identify exosome morphology. Besides, bicinchoninic acid (BCA) protein assay (Solarbio, China) was applied for the measurement of the protein content; Western blot for the detection of the expression of exosome-specific markers CD63 and HSP70; and Nanoparticle Tracker (NTA) system for determination of the size of vesicles [ 18 ].…”

Current Understanding of Exosomal MicroRNAs in Glioma Immune Regulation and Therapeutic Responses

“…Figueroa et al found that miR-1587 could be transferred by glioma related-mesenchymal stem cells (GA-hMSCs) to glioma stem-like cells (GSCs) via exosomes and increased GSC proliferation and clonogenicity to maintain a GSC-supportive niche via directly targeting the expression of nuclear receptor co-repressor-1 (NCOR1) (25). Li et al also revealed that miR-7239-3p, released by M2 microglial exosomes, could enter glioma cells via endocytosis, resulting in the repression of brain and muscle ARNT-like protein-1 (Bmal1) expression and facilitating glioma cells proliferation and migration (26). In addition, the molecule mechanisms of exosomal miRNA in medulloblastoma (MB), another subtype of glioma, have been recently investigated.…”