Hypoxic glioma-derived exosomes deliver microRNA-1246 to induce M2 macrophage polarization by targeting TERF2IP via the STAT3 and NF-κB pathways

Exosomes are emerging as important elements that participate in intercellular communication and tumor microenvironment modulation, but the exact mechanisms by which tumor exosomes facilitate the generation of the immunosuppressive microenvironment remain unclear. Here we investigated the effects of...

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Bibliographic Details
Published in:Oncogene Vol. 39; no. 2; pp. 428 - 442
Main Authors: Qian, Mingyu, Wang, Shaobo, Guo, Xiaofan, Wang, Jian, Zhang, Zongpu, Qiu, Wei, Gao, Xiao, Chen, Zihang, Xu, Jianye, Zhao, Rongrong, Xue, Hao, Li, Gang
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01.01.2020
Subjects:
Cell Line, Tumor
Cell signaling
Exosomes
Exosomes - metabolism
Glioma
Glioma - pathology
Humans
Hypoxia
Immunotherapy
Intracellular signalling
Investigations
Leukocyte migration
Macrophages
Macrophages - cytology
Macrophages - immunology
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA
NF-kappa B - metabolism
NF-κB protein
Phagocytosis - genetics
Polarization
Sequence analysis
Shelterin Complex
Signal Transduction
Stat3 protein
STAT3 Transcription Factor - metabolism
Telomere-Binding Proteins - genetics
Tumor Hypoxia
ISSN:0950-9232, 1476-5594, 1476-5594
Online Access:Get full text
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Summary:Exosomes are emerging as important elements that participate in intercellular communication and tumor microenvironment modulation, but the exact mechanisms by which tumor exosomes facilitate the generation of the immunosuppressive microenvironment remain unclear. Here we investigated the effects of glioma-derived exosomes (GDEs) on macrophage polarization and glioma progression. We also performed microRNA sequencing analysis of GDEs to identify the microRNA that mediated macrophage polarization. The microRNA-associated intracellular signaling pathway in macrophages was further investigated. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly induced M2 macrophage polarization, which subsequently promoted glioma proliferation, migration and invasion in vitro and in vivo. MicroRNA sequencing analysis identified miR-1246 as the most enriched microRNA in H-GDEs. Moreover, miR-1246 was enriched in the CSF of GBM patients and decreased after tumor resection. Further investigation determined that miR-1246 mediated H-GDE-induced M2 macrophage polarization by targeting TERF2IP to activate the STAT3 signaling pathway and inhibit the NF-κB signaling pathway. Our study elucidated a mechanism by which hypoxia and glioma influence M2 macrophage polarization via exosomes, which could facilitate the formation of the immunosuppressive microenvironment. Moreover, our results suggested that miR-1246 in the CSF of GBM patients may be a novel biomarker for GBM diagnosis and that treatment targeting microRNA-1246 may contribute to antitumor immunotherapy.
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ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-019-0996-y