Glioblastoma (GBM), as the most common primary brain tumor, usually results in an extremely poor prognosis, in which glioma stem cells (GSCs) and their immunosuppressive microenvironment prominently intervene in the resistance to radiotherapy and chemotherapy that directly leads to tumor recurrence and shortened survival time. The specific mechanism through which exosomes generated from GSCs support the creation of an immunosuppressive microenvironment remains unknown, while it is acknowledged to be engaged in intercellular communication and the regulation of the glioma immunosuppressive microenvironment. The elevated expression of LncRNA-NEAT1 was found in glioma cells after radiotherapy, chemotherapy, and DNA damage stimulation, and NEAT1 could promote the malignant biological activities of GSCs. Emerging evidence suggests that lncRNAs may reply to external stimuli or DNA damage by playing a role in modulating different aspects of tumor biology. Our study demonstrated a promotive role of the carried NEAT1 by GSC-derived exosomes in the polarization of M2-like macrophages. Further experiments demonstrated the mediative role of miR-125a and its target gene STAT3 in NEAT1-induced polarization of M2-like macrophages that promote glioma progression. Our findings elucidate the mechanism by which GSCs influence the polarization of M2-like macrophages through exosomes, which may contribute to the formation of immunosuppressive microenvironments. Taken together, our study reveals the miR-125a-STAT3 pathway through which exosomal NEAT1 from treatment-resistant GSCs contributes to M2-like macrophage polarization, indicating the potential of exosomal NEAT1 for treating glioma.
胶质母细胞瘤作为最常见的原发性脑肿瘤，通常预后极差，其中胶质瘤干细胞及其免疫抑制微环境显著干预放化疗抵抗，直接导致肿瘤复发和生存期缩短。胶质瘤干细胞来源的外泌体支持免疫抑制微环境形成的具体机制尚不明确，但已知其参与细胞间通讯并调控胶质瘤免疫抑制微环境。研究发现经放疗、化疗及DNA损伤刺激后，胶质瘤细胞中LncRNA-NEAT1表达升高，且NEAT1能促进胶质瘤干细胞的恶性生物学活性。新近证据表明lncRNAs可能通过调控肿瘤生物学的不同方面来应对外部刺激或DNA损伤。本研究证实胶质瘤干细胞来源外泌体携带的NEAT1可促进M2样巨噬细胞极化。进一步实验证明miR-125a及其靶基因STAT3在NEAT1诱导的M2样巨噬细胞极化中起中介作用，该过程促进胶质瘤进展。我们的发现阐明了胶质瘤干细胞通过外泌体影响M2样巨噬细胞极化的机制，这可能有助于免疫抑制微环境的形成。综上所述，本研究揭示了治疗抵抗性胶质瘤干细胞来源的外泌体NEAT1通过miR-125a-STAT3通路促进M2样巨噬细胞极化，表明外泌体NEAT1具有治疗胶质瘤的潜力。
肿瘤(癌症)患者之家