Skóra Klaudia, Strojny Damian, Sobański Dawid, Staszkiewicz Rafał, Gogol Paweł, Miller Mateusz, Grabarek Beniamin Oskar
Department of Neurological Rehabilitation, District Hospital of St. Padre Pio in Sędziszów Małopolski, 39-120 Sędziszów Małopolski, Poland.
Collegium Medicum, WSB University, 41-300 Dąbrowa Górnicza, Poland.
Int J Mol Sci. 2025 Jun 19;26(12):5892. doi: 10.3390/ijms26125892.
Chronic inflammation is increasingly recognized as a driver of glioma progression, with tumor necrosis factor-alpha (TNF-α) playing a central role in modulating the tumor microenvironment. This study aimed to investigate the expression profiles and regulatory mechanisms of TNF-α and its downstream mediators-including interleukin-1 beta (IL-1β), Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8), and Mitogen-activated protein kinase kinase (MAP2K7)-in astrocytic tumors of varying malignancy. We conducted an integrative molecular analysis of 60 human astrocytic tumor samples (20 G2, 12 G3, 28 G4) using transcriptomic microarrays, Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR), Enzyme-Linked Immunosorbent Assay (ELISA), Western blotting, immunohistochemistry, methylation-specific PCR, and miRNA profiling. Prognostic associations were evaluated using Kaplan-Meier survival and Cox regression analyses. TNF-α, IL-1β, and MAP3K8 were significantly upregulated in high-grade tumors, with log fold changes ranging from 5.56 to 8.76 ( < 0.001). High expression of TNF-α (HR = 2.10, 95% CI: 1.27-3.46, = 0.004), IL-1β (HR = 2.35, 95% CI: 1.45-3.82, = 0.001), and MAP3K8 (Hazard Ratio; HR = 1.88, 95% confidence interval; 95% CI: 1.12-3.16, = 0.015) was associated with poorer overall survival. miR-34a-3p and miR-30 family members, predicted to target TNF-α and IL-1β, were markedly downregulated in G3/G4 tumors (e.g., miR-30e-3p fold change: -3.78, < 0.01). Promoter hypomethylation was observed in G3/G4 tumors, supporting epigenetic activation. Our findings establish a multi-layered regulatory mechanism of TNF-α signaling in astrocytic tumors. These data highlight the TNF-α/IL-1β/MAP3K8 axis as a critical driver of glioma aggressiveness and a potential therapeutic target.
慢性炎症越来越被认为是胶质瘤进展的驱动因素，肿瘤坏死因子-α（TNF-α）在调节肿瘤微环境中起核心作用。本研究旨在调查TNF-α及其下游介质（包括白细胞介素-1β（IL-1β）、丝裂原活化蛋白激酶激酶激酶8（MAP3K8）和丝裂原活化蛋白激酶激酶（MAP2K7））在不同恶性程度的星形细胞瘤中的表达谱和调控机制。我们使用转录组微阵列、逆转录定量聚合酶链反应（RT-qPCR）、酶联免疫吸附测定（ELISA）、蛋白质印迹、免疫组织化学、甲基化特异性PCR和miRNA谱分析，对60个人类星形细胞瘤样本（20个G2级、12个G3级、28个G4级）进行了综合分子分析。使用Kaplan-Meier生存分析和Cox回归分析评估预后相关性。TNF-α、IL-1β和MAP3K8在高级别肿瘤中显著上调，对数倍变化范围为5.56至8.76（<0.001）。TNF-α高表达（HR = 2.10，95%CI：1.27 - 3.46，P = 0.004）、IL-1β高表达（HR = 2.35，95%CI：1.45 - 3.82，P = 0.001）和MAP3K8高表达（风险比；HR = 1.88，95%置信区间；95%CI：1.12 - 3.16，P = 0.015）与较差的总生存期相关。预测靶向TNF-α和IL-1β的miR-34a-3p和miR-30家族成员在G3/G4级肿瘤中显著下调（例如，miR-30e-3p倍变化：-3.78，P < 0.01）。在G3/G4级肿瘤中观察到启动子低甲基化，支持表观遗传激活。我们的研究结果建立了星形细胞瘤中TNF-α信号传导的多层调控机制。这些数据突出了TNF-α/IL-1β/MAP3K8轴作为胶质瘤侵袭性的关键驱动因素和潜在治疗靶点。
