ORIGINAL RESEARCH article
Front. Oncol.
Sec. Neuro-Oncology and Neurosurgical Oncology
Identification of exosome miRNAs regulated by SPHK2 in human glioma cells
Provisionally accepted
- 1Shenzhen Second People's Hospital, Shenzhen, China
- 2Huizhou First Hospital, Huizhou, China
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Background. Glioma is the most common primary brain tumor, and the WHO 4 glioma, glioblastoma (GB), is a malignant tumor with high invasiveness and mortality. Tumor-associated macrophages (TAMs) as the main immune cells in glioma play an important role in the growth, invasiveness, immune escape and drug resistant. M2 phenotype of macrophages but not M1 phenotype promotes glioma development. Recent studies show that sphingosine kinase 2 (SPHK2) was positively associated with TAM infiltration and glioma proliferation. SPHK2 deficient tumor showed impaired growth and failed to polarize macrophages towards an M2 phenotype. Objective. To reveal whether SPHK2 effected exosome miRNAs release from glioma cells, and which miRNAs regulated by SPHK2 could mediate the polarization of macrophages around glioma cells. Methods. SPHK2 knockdown of human glioma cells U373 was performed by shRNA lentiviruses. Exosome miRNAs were isolated and evaluated by using RNA-seq. GO analysis was carried out to view the function of exosome miRNAs targeting genes. KEGG analysis was used to view the pathway of these genes. Results. We successfully isolated exosomes from U373-HK and U373-SH glioma cell lines. We found 12 exosome miRNAs differentially expressed between U373-HK and U373-SH cells. Heat Map shows that 2 miRNAs were up-regulated in glioma cells with SPHK2 knockdown, and 10 miRNAs were down-regulated in glioma cells with SPHK2 knockdown. 12 miRNAs targeting genes were assigned to 118 GO terms, including 53 biological processes, 30 cellular components and 35 molecular function terms. KEGG mapping further clustered several signaling pathways, such as ''Wnt signaling'', ''p53 signaling'', ''Proteoglycans in cancer'' and ''Cell cycle''. The ''Wnt signaling'' was identified as the most significantly enriched pathway in KEGG analysis. A total of 17 genes were enriched in this pathway. Conclusions. The present study elucidates that SPHK2 promoted 10 exosome miRNAs release, but inhibited 2 miRNAs release. KEGG data indicated these miRNAs targeted several important genes of Wnt signaling. This study not only provides genomic resources for further studies but also gives novel insights to uncover the molecular mechanism of SPHK2 regulating M2 TAM polarization.
Keywords: Glioma, macrophage, sphingosine kinase 2, exosome, miRNA
Received: 09 Jul 2025; Accepted: 27 Nov 2025.
Copyright: © 2025 Liu, Zhao, Liu, Guan, Guo, Xu and Qiu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yanwen Xu
Jinhua Qiu
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