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Glioblastoma-associated microglia-derived exosomal circKIF18A promotes angiogenesis by targeting FOXC2

Oncogene volume 41, pages 3461–3473 (2022)Cite this article

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Abstract

Glioblastoma multiforme (GBM) is the most lethal primary tumor with active neovascularization in the central nervous system. Studying the novel molecular mechanisms of GBM angiogenesis is very important. The glioblastoma-associated microglia (GAM) M2 polarization was constructed, and microglia-derived exosomes (MDEs) were isolated to co-culture with human brain microvessel endothelial cells (hBMECs). CircRNA sequence and molecular biological experiments were used to detect the expression levels and regulation functions among circKIF18A, FOXC2, ITGB3, CXCR4, DLL4 and the PI3K/AKT signaling. The functional effects of silencing or overexpression of these molecules were evaluated in hBMECs viability, invasion, and tube formation in vitro and tumorigenicity in vivo. M2 microglia polarization is positively correlated with microvessels’ density in GBM patients. M2 GAM can promote the angiogenesis of GBM via transporting exosomal circKIF18A into hBMECs. Mechanistically, circKIF18A can bind to, maintain the stability and nuclear translocation of FOXC2 in hBMECs. Furtherly, as a transcription factor, FOXC2 can directly bind to the promoter of ITGB3, CXCR4, and DLL4 and upregulate their expressions. Besides, FOXC2 can also activate the PI3K/AKT signaling and promote the angiogenesis of GBM. Our study identified a novel molecular mechanism for M2 GAM-derived exosomal circKIF18A participating in GBM angiogenesis via targeting FOXC2. This may provide a novel treatment target to improve the outcomes for anti-angiogenic therapies in GBM.

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Fig. 1: M2 microglia correlated with the density of microvessels in GBM patients.
Fig. 2: M2 microglia-derived exosomes promote angiogenesis in vitro and in vivo.
Fig. 3: M2-MDEs transported circKIF18A into hBMECs.
Fig. 4: M2 microglial exosomal circKIF18A can directly bind to FOXC2.
Fig. 5: M2 microglial exosomal circKIF18A promotes angiogenesis via FOXC2 in vitro.
Fig. 6: M2 microglial exosomal circKIF18A can promote the transcriptional regulation ability of FOXC2 on ITGB3, CXCR4, and DLL4 and PI3K/AKT signaling.
Fig. 7: M2 microglial exosomal circKIF18A promotes the growth and angiogenesis of tumors in vivo.

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Data availability

The datasets obtained and analyzed during the current study were made available from the corresponding authors through request.

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Acknowledgements

We would like to acknowledge our lab colleagues for their support in the development of this article.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82072794, 82004423), the Major Disease Prevention and Control Technology Action Plan of China (2018ZX-07S-006), the Natural Science Foundation of Liaoning province (2021-MS-207), the Social Development Program from Shenyang Science and Technology Bureau, China (20-205-4-075), Shanghai Sailing Program (No. 21YF1449900), Shanghai Post-doctoral Excellence Program (No. 2021336) and China Postdoctoral Science Foundation (No. 267285).

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Author notes

  1. These authors contributed equally: Yang Jiang, Junshuang Zhao, Jinkun Xu.

Authors and Affiliations

  1. Department of Neurosurgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China

    Yang Jiang

  2. Department of Neurosurgery, The First Hospital of China Medical University, NO. 155 North Nanjing Street, Shenyang, 110001, China

    Junshuang Zhao, Jinkun Xu, Jinpeng Zhou, Hao Li, Guoqing Zhang, Kai Xu & Zhitao Jing

  3. International Education College, Liaoning University of Traditional Chinese Medicine, NO. 79 Chongshan East Road, Shenyang, 110042, China

    Haiying Zhang

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Contributions

ZTJ conceived and designed the study; YJ and JSZ performed the experiments and wrote the manuscript; JKX, HYZ, JPZ, HL, GQZ, and KX collected and analyzed the data. YJ, JSZ, and JKX contributed equally to this work. All authors read and approved the final version of the manuscript.

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Correspondence to Zhitao Jing.

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Patients and controls were acquired with informed consent, under the protocol approved by the First Hospital of China Medical University research ethics committee (AF-SOP-07-1.1-01). No blinding was done.

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Jiang, Y., Zhao, J., Xu, J. et al. Glioblastoma-associated microglia-derived exosomal circKIF18A promotes angiogenesis by targeting FOXC2. Oncogene 41, 3461–3473 (2022). https://doi.org/10.1038/s41388-022-02360-4

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