Hypoxia-Induced Neuronal Activity in Glioma Patients Polarizes Microglia by Potentiating RNA m6A Demethylation

小胶质细胞 胶质瘤 运动前神经元活动 MAPK/ERK通路 生物 神经元 下调和上调 癌症研究 基因敲除 神经科学 细胞生物学 化学 信号转导 炎症 免疫学 细胞培养 生物化学 遗传学 基因
作者
Xiaofan Guo,Wei Qiu,Boyan Li,Yanhua Qi,Shaobo Wang,Rongrong Zhao,Bo Cheng,Xiao Han,Hao Du,Ziwen Pan,Shulin Zhao,Jiawei Qiu,Gang Li,Hao Xue
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:30 (6): 1160-1174 被引量:8
标识
DOI:10.1158/1078-0432.ccr-23-0430
摘要

Abstract Purpose: Neuronal activity in the brain has been reported to promote the malignant progression of glioma cells via nonsynaptic paracrine and electrical synaptic integration mechanisms. However, the interaction between neuronal activity and the immune microenvironment in glioblastoma (GBM) remains largely unclear. Experimental Design: By applying chemogenetic techniques, we enhanced and inhibited neuronal activity in vitro and in a mouse model to study how neuronal activity regulates microglial polarization and affects GBM progression. Results: We demonstrate that hypoxia drove glioma stem cells (GSC) to produce higher levels of glutamate, which activated local neurons. Neuronal activity promoted GBM progression by facilitating microglial M2 polarization through enriching miR-200c-3p in neuron-derived exosomes, which decreased the expression of the m6A writer zinc finger CCCH-type containing 13 (ZC3H13) in microglia, impairing methylation of dual specificity phosphatase 9 (DUSP9) mRNA. Downregulation of DUSP9 promoted ERK pathway activation, which subsequently induced microglial M2 polarization. In the mouse model, cortical neuronal activation promoted microglial M2 polarization whereas cortical neuronal inhibition decreased microglial M2 polarization in GBM xenografts. miR-200c-3p knockdown in cortical neurons impaired microglial M2 polarization and GBM xenograft growth, even when cortical neurons were activated. Treatment with the anti-seizure medication levetiracetam impaired neuronal activation and subsequently reduced neuron-mediated microglial M2 polarization. Conclusions: These findings indicated that hypoxic GSC-induced neuron activation promotes GBM progression by polarizing microglia via the exosomal miR-200c-3p/ZC3H13/DUSP9/p-ERK pathway. Levetiracetam, an antiepileptic drug, blocks the abnormal activation of neurons in GBM and impairs activity-dependent GBM progression. See related commentary by Cui et al., p. 1073
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