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Glioma-Stem-Cell-Derived Exosomes Remodeled Glioma-Associated Macrophage via NEAT1/miR-125a/STAT3 Pathway
by
Tong Pan
1,2,†,
Dong-Kun Xie
3,4,†,
Juan Li
1,
Yu-Jie Qiang
1,
Song-Yuan Fan
5,
Ting-Ting Wang
1,
Yuan-Yuan Han
1,
Jian Zang
6,
Yang Yang
3,
Jun-Long Zhao
4,
San-Zhong Li
1,* and
Shuang Wu
1,5,* 1
Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
2
Department of Biochemistry and Molecular Biology, Air Force Medical University, Xi’an 710032, China
3
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi’an 710069, China
4
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Air Force Medical University, Xi’an 710032, China
5
Department of Neurosurgery, The Air Force Hospital of Central Theater of PLA, Datong 037000, China
6
Department of Radiotherapy, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
*
Authors to whom correspondence should be addressed.
†
These authors have contributed equally to this work and share the first authorship.
Cancers 2024, 16(14), 2500; https://doi.org/10.3390/cancers16142500 (registering DOI)
Submission received: 27 May 2024
/
Accepted: 6 June 2024
/
Published: 9 July 2024
(This article belongs to the Special Issue Novel Transcriptional Factors Regulating Cancer Stemness)
Simple Summary
Glioblastomas (GBMs) are considered the most lethal cancer in the central nervous system (CNS), whose malignant phenotypes are majorly attributed to glioma stem cells (GSCs). Despite combined surgical radiotherapy with temozolomide chemotherapy and tumor-treating fields (TTFs), the tumor almost always recurs near the resection site. Besides the contribution of GSCs, the tumor microenvironment (TME) also plays an important role in glioma recurrence. Our work has demonstrated that GSC-derived exosomes carry lncRNA NEAT1 to promote the M2 polarization of glioma-associated macrophages (GAMs). Further mechanism exploration indicated that NEAT1 represses the expression of miR-125a in GAMs significantly. The decrease in miR-125a induces the elevation of target gene STAT3, which is required for macrophage M2 polarization. The development of M2-like GAMs contributes to the immunosuppressive microenvironment and glioma progression. Our findings elucidate the functions and mechanisms of the crosstalk between GSCs and GAMs via exosomes, providing new therapeutic targets and strategies for glioma.
Abstract
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.
