Chen Xuan, Han Lihui, Xu Wenzhe
Department of Radiation Oncology, Qilu Hospital of Shandong University, West Wenhua Rd. 107, Jinan 250012, China.
Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, West Wenhua Rd. 107, Jinan 250012, China.
J Cancer. 2025 Jan 1;16(2):680-688. doi: 10.7150/jca.98035. eCollection 2025.
Glioblastoma multiforme (GBM) is one of the most common brain malignancies characterized by an inflammatory microenvironment and metabolic reprogramming. This study aims to investigate the causal relationship between inflammatory factors (IFs) and GBM, as well as the potential mediating effects of specific plasma metabolites. We used a bidirectional two-sample Mendelian randomization (MR) approach to investigate the causal associations between 91 IFs and GBM. We employed a two-step MR technique to identify significant mediators in this relationship, followed by a mediation analysis to explore and quantify the mediating effects of specific metabolites on the causal relationship between IFs and GBM. experiments were conducted to verify the effects of specific IF and metabolite on GBM cells. The response of cells to treatment was examined using a series of assays, including colony formation, cell proliferation, and migration assays. Three IFs showed significant associations with GBM. Among them, fibroblast growth factor 21 (FGF21) had a protective effect against GBM [odds ratio (OR): 0.42; 95% confidence interval (CI): 0.25, 0.71; p=1.00×10]. There was no strong evidence that genetically predicted GBM had an effect on FGF21 (OR: 1.04; 95% CI: 0.83, 1.31; p = 0.692). Mediation analysis identified 3-methoxytyrosine (3-MTyr) level (mediation effect of 11.50%) as a significant intermediary. The study demonstrated that FGF21 inhibited proliferation and migration in GBM cells, whereas 3-MTyr exerted the opposite effects. FGF21 was causally associated with a reduced risk of GBM, and this relationship is partially mediated by 3-MTyr. This identified regulatory network offers a novel avenue for further research into the pathogenic mechanisms of GBM and provides a theoretical foundation for the development of relevant therapeutic regimens.
多形性胶质母细胞瘤（GBM）是最常见的脑恶性肿瘤之一，其特征为炎症微环境和代谢重编程。本研究旨在探讨炎症因子（IFs）与GBM之间的因果关系，以及特定血浆代谢物的潜在中介作用。我们采用双向双样本孟德尔随机化（MR）方法来研究91种IFs与GBM之间的因果关联。我们运用两步MR技术来确定这种关系中的显著中介物，随后进行中介分析，以探索和量化特定代谢物对IFs与GBM之间因果关系的中介作用。进行实验以验证特定IF和代谢物对GBM细胞的影响。使用一系列检测方法，包括集落形成、细胞增殖和迁移检测，来检查细胞对治疗的反应。三种IFs与GBM显示出显著关联。其中，成纤维细胞生长因子21（FGF21）对GBM具有保护作用[比值比（OR）：0.42；95%置信区间（CI）：0.25，0.71；p = 1.00×10]。没有强有力的证据表明基因预测的GBM对FGF21有影响（OR：1.04；95%CI：0.83，1.31；p = 0.692）。中介分析确定3-甲氧基酪氨酸（3-MTyr）水平（中介效应为11.50%）为显著中介物。该研究表明，FGF21抑制GBM细胞的增殖和迁移，而3-MTyr则发挥相反作用。FGF21与GBM风险降低存在因果关联，且这种关系部分由3-MTyr介导。这一确定的调控网络为进一步研究GBM的致病机制提供了新途径，并为相关治疗方案的开发提供了理论基础。
