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

Oncogene volume 39, pages 428–442 (2020)Cite this article

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Abstract

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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Acknowledgements

We thank the surgeons, physicians, and patients who participated in these studies.

Funding

This work was supported by grants from the National Natural Science Foundation of China (grant No.30872645, 81372719, 81172403, 81571284, 91542115, 81874083, 81702468), Natural Science Foundation of Shandong Province of China (grant No.2017CXGC1203, 2013GGE27006, 2017G006012) and the Taishan Scholars of Shandong Province of China (grant No.ts201511093).

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  1. These authors contributed equally: Mingyu Qian, Shaobo Wang

Authors and Affiliations

  1. Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong, China

    Mingyu Qian, Shaobo Wang, Xiaofan Guo, Jian Wang, Zongpu Zhang, Wei Qiu, Xiao Gao, Zihang Chen, Jianye Xu, Rongrong Zhao, Hao Xue & Gang Li

  2. Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China

    Mingyu Qian, Shaobo Wang, Xiaofan Guo, Jian Wang, Zongpu Zhang, Wei Qiu, Xiao Gao, Zihang Chen, Jianye Xu, Rongrong Zhao, Hao Xue & Gang Li

  3. Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway

    Jian Wang

  4. Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Rongrong Zhao, Hao Xue & Gang Li

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Correspondence to Hao Xue or Gang Li.

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Qian, M., Wang, S., Guo, X. et al. Hypoxic glioma-derived exosomes deliver microRNA-1246 to induce M2 macrophage polarization by targeting TERF2IP via the STAT3 and NF-κB pathways. Oncogene 39, 428–442 (2020). https://doi.org/10.1038/s41388-019-0996-y

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