Wei Yigong, Zhou Kun, Wang Cheng, Du Xiaolin, Wang Zhengdi, Chen Guangtang, Zhang Huan, Hui Xuhui
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
Department of Neurosurgery, Jinyang Hospital Affiliated to Guizhou Medical University (Guiyang Second People's Hospital), Guiyang, China.
J Neurochem. 2025 Jan;169(1):e16224. doi: 10.1111/jnc.16224. Epub 2024 Sep 17.
Glioblastoma (GBM) is one of the most prevalent cancerous brain tumors. Former studies have reported that exosomes derived from M1-polarized macrophages (M1 exosomes) inhibit tumor occurrence and development through delivery of tumor suppressor genes. Also, microRNA-142-3p (miR-142-3p) has been verified to function as a tumor suppressor. GBM cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8), colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) assay; cell apoptosis was determined by flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mechanism investigations were conducted for analyzing the molecular mechanism by which miR-142-3p and M1 exosomes affect GBM progression. Upregulation of miR-142-3p expression was detected in M1-polarized macrophages and M1 exosomes. M1 exosomes inhibit GBM cell proliferation and trigger cell apoptosis. Functionally, miR-142-3p silencing promotes the proliferation and inhibits the apoptosis of GBM cells treated with M1 exosomes. As for molecular mechanism, miR-142-3p inhibits GBM cell growth via targeting high-mobility group box 1 (HMGB1). In addition, miR-142-3p/HMGB1 axis affects GBM cell immune escape through modulation of programmed death-1/programmed death ligand-1 (PD-1/PD-L1) checkpoint. Our study demonstrated that exosomal miR-142-3p from M1-polarized macrophages suppresses cell growth and immune escape in GBM through regulating HMGB1-mediated PD-1/PD-L1 checkpoint.
胶质母细胞瘤（GBM）是最常见的脑癌肿瘤之一。既往研究报道，源自M1极化巨噬细胞的外泌体（M1外泌体）通过传递肿瘤抑制基因抑制肿瘤的发生和发展。此外，微小RNA-142-3p（miR-142-3p）已被证实具有肿瘤抑制功能。通过细胞计数试剂盒-8（CCK-8）、集落形成试验和5-乙炔基-2'-脱氧尿苷（EdU）试验评估GBM细胞增殖；通过流式细胞术分析和末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）试验测定细胞凋亡。进行机制研究以分析miR-142-3p和M1外泌体影响GBM进展的分子机制。在M1极化巨噬细胞和M1外泌体中检测到miR-142-3p表达上调。M1外泌体抑制GBM细胞增殖并触发细胞凋亡。在功能上，miR-142-3p沉默促进用M1外泌体处理的GBM细胞的增殖并抑制其凋亡。至于分子机制，miR-142-3p通过靶向高迁移率族蛋白B1（HMGB1）抑制GBM细胞生长。此外，miR-142-3p/HMGB1轴通过调节程序性死亡蛋白1/程序性死亡配体1（PD-1/PD-L1）检查点影响GBM细胞免疫逃逸。我们的研究表明，来自M1极化巨噬细胞的外泌体miR-142-3p通过调节HMGB1介导的PD-1/PD-L1检查点抑制GBM中的细胞生长和免疫逃逸。
