Exosomes derived from hypoxic glioma deliver miR-1246 and miR-10b-5p to normoxic glioma cells to promote migration and invasion

Laboratory Investigation (2021)Cite this article

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Abstract

Hypoxia is an important feature of the tumor microenvironment and is associated with glioma progression and patient outcome. Exosomes have been implicated in the intercellular communication in the tumor microenvironment. However, the effects of hypoxic glioma exosomes on glioma migration and invasion and the underlying mechanisms remain poorly understood. In this study, we found that exosomes derived from hypoxic glioma cells (H-GDEs) promoted normoxic glioma migration and invasion in vitro and in vivo. Given that exosomes can regulate recipient cell functions by delivering microRNAs, we further revealed miR-1246 and miR-10b-5p were upregulated significantly in H-GDEs and delivered to normoxic glioma cells by H-GDEs. Moreover, we determined the clinical relevance of miR-1246 and miR-10b-5p in glioma patients. Subsequent investigations indicated that miR-1246 and miR-10b-5p markedly induced glioma migration and invasion in vitro and in vivo. Finally, we demonstrated that miR-1246 and miR-10b-5p induced glioma migration and invasion by directly targeting FRK and TFAP2A respectively. In conclusion, our findings suggest that the hypoxic microenvironment stimulates glioma to generate miR-1246- and miR-10b-5p-rich exosomes that are delivered to normoxic glioma cells to promote their migration and invasion; treatment targeting miR-1246 and miR-10b-5p may impair the motility of gliomas, providing a novel direction for the development of antitumor therapy.

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Fig. 1: Identification of GDEs and internalization of H-GDEs by normoxic glioma cells.
Fig. 2: H-GDEs promote normoxic glioma cell migration and invasion in vitro and in vivo.
Fig. 3: MiR-1246 and miR-10b-5p are increased in H-GDEs, delivered by H-GDEs and their clinical relevance.
Fig. 4: MiR-1246 and miR-10b-5p promote glioma cell migration and invasion in vitro and in vivo.
Fig. 5: MiR-1246 and miR-10b-5p promote glioma cell migration and invasion by directly targeting FRK and TFAP2A.
Fig. 6: Schematic model of effect of hypoxic exosomal miR-1246 and miR-10b-5p on glioma migration and invasion.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81874083; 82072776; 82072775; 81702468; 81802966; 81902540), Natural Science Foundation of Shandong Province of China (No. ZR2019BH057), Key clinical Research project of Clinical Research Center of Shandong University (2020SDUCRCA011) and Taishan Scholars of Shandong Province of China (No. ts201511093).

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  1. These authors contributed equally: Mingyu Qian, Zihang Chen

Affiliations

  1. Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China

    Mingyu Qian, Zihang Chen, Xiaofan Guo, Shaobo Wang, Zongpu Zhang, Wei Qiu, Yanhua Qi, Shouji Zhang, Jianye Xu, Rongrong Zhao, Hao Xue & Gang Li

  2. Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250012, Shandong, China

    Mingyu Qian, Zihang Chen, Xiaofan Guo, Shaobo Wang, Zongpu Zhang, Wei Qiu, Yanhua Qi, Shouji Zhang, Jianye Xu, Rongrong Zhao, Hao Xue & Gang Li

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  1. Mingyu Qian
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Qian, M., Chen, Z., Guo, X. et al. Exosomes derived from hypoxic glioma deliver miR-1246 and miR-10b-5p to normoxic glioma cells to promote migration and invasion. Lab Invest (2021). https://doi.org/10.1038/s41374-020-00522-0

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