Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression

作者：Ming Li, Hao Xu, Yanhua Qi, Ziwen Pan, Boyan Li, Zijie Gao, Rongrong Zhao, Hao Xue, Gang Li · 发表于：Oncogene · 年份：2022 · DOI：10.1038/s41388-022-02457-w · 被引用次数：126 · 研究领域：Extracellular vesicles in disease、MicroRNA in disease regulation、Circular RNAs in diseases

Exosomes can selectively secrete harmful metabolic substances from cells to maintain cellular homeostasis, and complex crosstalk occurs between exosomes and tumor-associated macrophages (TAMs) in the glioma immune microenvironment. However, the precise mechanisms by which these exosome-encapsulated cargos create an immunosuppressive microenvironment remain unclear. Herein, we investigated the effect of glioma-derived exosomes (GDEs) on macrophage polarization and glioma progression. We performed sequencing analysis of cerebrospinal fluid (CSF) and tumor tissues from glioma patients to identify functional microRNAs (miRNAs). High levels of miR-3591-3p were found in CSF and GDEs but not in normal brain tissue or glial cells. Functionally, GDEs and miR-3591-3p significantly induced M2 macrophage polarization and increased the secretion of IL10 and TGFβ1, which in turn promoted glioma invasion and migration. Moreover, miR-3591-3p overexpression in glioma cell lines resulted in G2/M arrest and markedly increased apoptosis. Mechanistically, miR-3591-3p can directly target CBLB and MAPK1 in macrophages and glioma cells, respectively, and further activate the JAK2/PI3K/AKT/mTOR, JAK2/STAT3, and MAPK signaling pathways. In vivo experiments confirmed that macrophages lentivirally transduced with miR-3591-3p can significantly promote glioma progression. Thus, our study demonstrates that tumor-suppressive miR-3591-3p in glioma cells can be secreted via exosomes and target TAMs to induce ...