Glioma exosomes mediate the expansion and function of myeloid-derived suppressor cells through microRNA-29a/Hbp1 and microRNA-92a/Prkar1a pathways
Glioma exosomes mediate the expansion and function of myeloid-derived suppressor cells through microRNA-29a/Hbp1 and microRNA-92a/Prkar1a pathways
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胶质瘤外泌体通过 microRNA-29a/Hbp1 和 microRNA-92a/Prkar1a 途径介导骨髓源性抑制细胞的扩张和功能。
DOI：
10.1002/ijc.32052
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发表时间：
2019-06-15
影响因子：
6.4
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Guo, Xiaofan;Qiu, Wei;Li, Gang
骨髓源性抑制细胞（MDSC）在介导免疫抑制环境的形成和协助肿瘤逃避宿主免疫应答中起着关键作用。然而，肿瘤操纵MDSC分化和功能的机制仍不清楚。在这里，我们报道了低氧诱导的胶质瘤细胞可以通过将外泌体miR-29 a和miR-92 a转移到MDSC来刺激功能性MDSC的分化。结果表明，胶质瘤源性exosomes（GEXs）在体内外均能促进MDSCs的分化，低氧诱导的GEXs（H-GEXs）比常氧诱导的GEXs（N-GEXs）具有更强的MDSCs诱导能力。随后对N-GEXs和H-GEXs进行的miRNA测序分析显示，低氧诱导的外泌体miR-29 a和miR-92 a表达诱导了MDSC的增殖。miR-29 a和miR-92 a分别通过靶向高迁移率族蛋白盒转录因子1（Hbp 1）和蛋白激酶cAMP依赖性I型调节亚基α（Prkar 1a）激活MDSC的增殖和功能。总之，我们的研究结果为胶质瘤外泌体miRNA在介导肿瘤免疫抑制微环境形成中的作用提供了新的见解，并阐明了负责调节功能性MDSC诱导的潜在外泌体miR-29 a/miR-92 a调控机制。
Myeloid-derived suppressor cells (MDSCs) play a pivotal role in mediating the formation of an immunosuppressive environment and assisting tumors in evading the host immune response. However, the mechanism through which tumors manipulate the differentiation and function of MDSCs remains unclear. Here, we report that hypoxia-induced glioma cells can stimulate the differentiation of functional MDSCs by transferring exosomal miR-29a and miR-92a to MDSCs. Our results showed that glioma-derived exosomes (GEXs) can enhance the differentiation of functional MDSCs both in vitro and in vivo, and hypoxia-induced GEXs (H-GEXs) demonstrated a stronger MDSCs induction ability than did normoxia-induced GEXs (N-GEXs). A subsequent miRNA sequencing analysis of N-GEXs and H-GEXs revealed that hypoxia-induced exosomal miR-29a and miR-92a expression induced the propagation of MDSCs. miR-29a and miR-92a activated the proliferation and function of MDSCs by targeting high-mobility group box transcription factor 1 (Hbp1) and protein kinase cAMP-dependent type I regulatory subunit alpha (Prkar1a), respectively. Altogether, the results of our study provide new insights into the role of glioma exosomal miRNAs in mediating the formation of immunosuppressive microenvironments in tumors and elucidate the underlying exosomal miR-29a/miR-92a-based regulatory mechanism responsible for the modulation of functional MDSC induction.