Abstract
Exosomal microRNAs (miRNAs) have been implicated in the development and progression of a variety of tumors; however, whether they contribute to medulloblastoma (MB) tumorigenesis remains to be elucidated. To address this, we first characterized the miRNA profiles of circulating exosomes by miRNA sequencing to identify miRNAs differentially expressed between children with MB and healthy controls. Then, we conducted in vitro and in vivo functional assays with the identified miRNAs and their predicted targets. We found that, compared with healthy controls, 35 miRNAs were upregulated and 5 downregulated in exosomes isolated from the plasma of MB patients. We further found that the expression of miR-101-3p and miR-423-5p was significantly higher in plasma exosomes from MB patients than in healthy controls in an expanded cohort and these exosomal miRNAs could be delivered to tumor cells via exosomes. An in vitro functional analysis of miR-101-3p and miR-423-5p showed that treating MB cells with the corresponding mimics significantly inhibited the proliferation, colony-forming ability, migratory ability, and invasive capacity of tumor cells, and promoted cell apoptosis. Additionally, miR-101-3p and miR-423-5p were found to act as tumor suppressors by directly targeting a common gene, FOXP4, which encodes a transcription factor with a vital role in embryonic development and tumorigenesis. Moreover, miR-101-3p also targeted EZH2, a histone methyltransferase, to reinforce its tumor inhibitory effects. Using a xenograft nude mouse model of MB, we further identified that the overexpression of miR-101-3p and miR-423-5p inhibited tumorigenesis in vivo. Our findings provide novel insights into the functions of exosomal miRNAs in mediating MB progression and suggest a potential therapeutic approach for the treatment of children with MB.
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Data availability
The sequencing data have been deposited in the Gene Expression Omnibus (GEO) under accession numbers GSE123376.
Change history
04 September 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41418-024-01345-y
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Acknowledgements
We acknowledge and appreciate the colleagues from our lab for their valuable efforts and comments on this paper.
Funding
This work was supported by grants from the National Key R&D Program of China (2016YFC1305102 to YZ), National Natural Science Foundation of China (81671561, 81974248 to YZ, 81900751 to XH), International Joint Laboratory Program of the National Children’s Medical Center (EK1125180109 to YZ), Program for Outstanding Medical Academic Leader (2019LJ19 to YZ), and Shanghai Committee of Science and Technology (21140902400 to YZ, 21ZR1410000 and 19ZR1406400 to JF).
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These authors contributed equally: PX, SH, and XH. PX, SH, and XH designed and performed experiments and analyzed data. CZ and LY generated mice model together with PX and SH. JF and WX designed experiments and analyzed data. PX and SH analyzed data, prepared figures, and wrote the manuscript. HL recruited the human participants. YZ planned, designed, supervised, and coordinated the overall research efforts.
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The study protocol was approved by the Ethics Committee of Children’s Hospital of Fudan University. Informed consent was obtained from all participants.
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The original online version of this article was revised: In this article fig. 5 has been corrected.
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Xue, P., Huang, S., Han, X. et al. Exosomal miR-101-3p and miR-423-5p inhibit medulloblastoma tumorigenesis through targeting FOXP4 and EZH2. Cell Death Differ 29, 82–95 (2022). https://doi.org/10.1038/s41418-021-00838-4
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DOI: https://doi.org/10.1038/s41418-021-00838-4
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