Radiated glioblastoma cell-derived exosomal circ_0012381 induce M2 polarization of microglia to promote the growth of glioblastoma by CCL2/CCR2 axis

Abstract

Background Radiotherapy is the primary therapeutic option for glioblastoma. Some studies proved that radiotherapy increased the release of exosomes from cells. The mechanism by which these exosomes modify the phenotype of microglia in the tumor microenvironment to further determine the fate of irradiated glioblastoma cells remains to be elucidated. Methods We erected the co-culture system of glioblastoma cells and microglia. After radiation, we analyzing the immunophenotype of microglia and the proliferation of radiated glioblastoma cells. By whole transcriptome sequencing, we analyzed of circRNAs in exosomes from glioblastoma cells and microglia. We used some methods, which included RT-PCR, dual-luciferase reporter, et al., to identify how circ_0012381 from radiated glioblastoma cell-derived exosomes regulated the immunophenotype of microglia to further affect the proliferation of radiated glioblastoma cells. Results Radiated glioblastoma cell-derived exosomes markedly induced M2 microglia polarization. These M2-polarized microglia promoted the proliferation of irradiated glioblastoma cells. Circ_0012381 expression was increased in the irradiated glioblastoma cells, and circ_0012381 entered the microglia via exosomes. Circ_0012381 induced M2 microglia polarization by sponging with miR-340-5p to increase ARG1 expression. M2-polarized microglia suppressed phagocytosis and promoted the growth of the irradiated glioblastoma cells by CCL2/CCR2 axis. Compared with the effects of radiotherapy alone, the inhibition of exosomes significantly inhibited the growth of irradiated glioblastoma cells in a zebrafish model. Conclusions Our data suggested that the inhibition of exosome secretion might represent a potential therapeutic strategy to increase the efficacy of radiotherapy in patients with glioblastoma.

Exosomal circRNAs as promising liquid biopsy biomarkers for glioma

“…Exosomal circRNAs also play an important role in the development of glioma, including proliferation, immunosuppression, angiogenesis, invasion, migration, and therapeutic resistance. Recent studies have shown that exosomeassociated circRNAs such as circ_104948, circ_0001445, circHIPK3, circWDR62, circMMP1, circ_0012381 play roles in the glioma proliferation process through miRNAs (30,(96)(97)(98)(99)(100). CircNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3 (101).…”

“…The role of exosomal circRNAs in the development of glioma. Exosomal circRNAs affect the progression of glioma by regulating its proliferation, invasion, migration, angiogenesis, and therapeutic resistance (30,(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109).…”

Cancer‐derived non‐coding RNAs endow tumor microenvironment with immunosuppressive properties

“…It was highly expressed in the irradiated GBM‐derived exosomes compared with that secreted by non‐irradiated GBM. Exosomal circ_0012381 increased Arg‐1 expression via sponging miR‐340‐5p, which induced the polarization of M2 microglia (C. Zhang, Zhou, et al, 2022). However, the processes of macrophage polarization are complicated and not just related to a single protein (D. Zhou, Huang, et al, 2014).…”

Immunomodulatory role of EV-derived non-coding RNA in lung cancer

“…For instance, in colorectal cancer, this polarization occurs via the down-modulation of histone deacetylase 11 mediated by miR-145 within colorectal cancer cell-derived EVs [55] . In addition, miR-138-5p, which has been observed in breast cancer-derived EVs, induces an M2-like phenotype in macrophages and promotes tumour growth by inhibiting the H3K27 histone demethylase KDM6B [56] . On the other hand, in brain malignancies, the uptake by microglia of EV-sorted Circular RNAs (circRNA) circ_0012381, which sponges with miR-340-5p, increases ARG1 expression, resulting in CCL2 secretion, which in turn promotes the growth of glioblastoma cells [57] .…”