Recently, Professor Li Gang and Associate Professor Xue Hao’s team from the Department of Neurosurgery at Qilu Hospital of Shandong University published a research paper titled “Hypoxia-Induced Neuronal Activity in Glioma Patients Polarizes Microglia by Potentiating RNA m6A Demethylation” in the journal Clinical Cancer Research (IF=11.5). Besides, an accompanying commentary was published, offering a highly positive evaluation of the scientific and clinical significance of the research. Professor Li Gang and Associate Professor Xue Hao are the corresponding authors of the paper. Dr. Guo Xiaofan and Dr. Qiu Wei, postdoctoral researchers in the Neurosurgery Department at Qilu Hospital share the first authorship. Qilu Hospital of Shandong University is the primary affiliation for this significant research contribution.

In the central nervous system (CNS), a reciprocal interaction exists between neurons and gliomas. Gliomas enhance neuronal activity through various mechanisms, and this heightened neuronal activity, in turn, promotes the malignant progression of glioma cells via non-synaptic paracrine signaling and electrical synapse integration mechanisms. Microglia in the CNS are highly adaptable and capable of adopting distinct phenotypes. M2-like microglia are characterized by the production of immunosuppressive cytokines and play a role in promoting the growth of glioma cells. Previous research conducted by the team has demonstrated that the hypoxic microenvironment in glioblastomas (GBM) promotes the M2 polarization of macrophages by inducing the secretion of POSTN and exosomes by glioma cells. However, it remains unclear whether neuronal activity plays a role in the hypoxia-induced M2 polarization of microglia in glioblastomas.

The research team demonstrated that hypoxia drove glioma stem cells (GSCs) 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 (NDEs), 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. Treatment with the anti-seizure medication levetiracetam impaired neuronal activation and subsequently reduced neuron-mediated microglial M2 polarization and inhibited glioma progression.

Professor Li Gang and his team have long been dedicated to studying the pathogenic mechanisms of glioblastomas, identifying precise diagnostic and therapeutic molecular targets, facilitating clinical translation, and exploring the intersection of brain tumor medicine and engineering. And they have achieved a series of high-level research outcomes. The aforementioned research has been supported by grants from the National Natural Science Foundation of China, Taishan Pandeng Scholar Program of Shandong Province, and Youth Taishan Scholar Program of Shandong Province. Additionally, support has been received from the Shandong Key Laboratory of Brain Function Remodeling and the Cheeloo College of Medicine and the Institute of Brain and Brain-Inspired Science.