Xin Zhaoqi, Guo Youwei, Zhou Quanwei, Wang Lei, Liu Weidong, Jiang Xingjun, Ren Caiping
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China, Cancer Research Institute, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan Province 410078, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China, Cancer Research Institute, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan Province 410078, China; The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan Province 410078, China.
Int Immunopharmacol. 2025 Aug 28;161:115064. doi: 10.1016/j.intimp.2025.115064. Epub 2025 Jun 12.
BACKGROUND: The ETS transcription factor ELK3 has been identified as a novel oncogene that plays a significant role in the pathological processes and progression of various human cancers. Recent research indicates that ELK3 may serve as a potential prognostic molecular marker for glioma; however, its mechanistic role in glioma remains insufficiently explored. PURPOSE: This study aimed to investigate the impact of ELK3 on glioma prognosis, examine the regulatory influence of IDH1 on ELK3, and assess the role of ELK3 in tumor immune infiltration. METHODS: Bioinformatics techniques were employed to identify the gene ELK3, which exhibited significant differential expression and was associated with grading and prognosis in the public database. This finding was validated through immunohistochemistry and RT-qPCR, while the association between ELK3 expression and IDH1 status was confirmed using Western blotting and IHC. Furthermore, ELK3 expression demonstrated a positive correlation with the infiltration of M2 macrophages, as evidenced by immune co-culture studies. RESULTS: The study identified ELK3 as significantly differentially expressed and associated with tumor grading and prognosis through analyses of public databases. Univariate and multivariate Cox proportional hazards regression analyses established ELK3 as an independent negative prognostic factor. Within The TCGA cohort, a prognostic nomogram was developed by integrating ELK3 with other clinical indicators, and its efficacy was evaluated using ROC curves and calibration curves. The nomogram demonstrated robust performance, with an AUC of no less than 0.9, and showed strong concordance in both internal and external validation cohorts. Furthermore, ELK3 expression was linked to the DNA methylation and mutation status of IDH1. Gene profiling related to ELK3 was constructed, revealing its potential biological functions in immunoregulatory processes through functional enrichment analysis. ELK3 expression exhibited a positive correlation with macrophage and neutrophil infiltration, consistent with findings from the TIMER and spatial transcriptomics. Additionally, ELK3 expression showed a moderate correlation with CD163 expression, suggesting its role in promoting immune infiltration involving M2 macrophages. CONCLUSIONS: ELK3 is a potential prognostic marker for poor outcomes in diffuse glioma and may play a regulatory role in immune infiltration, particularly by enhancing M2 macrophage-mediated immune infiltration.
背景：ETS转录因子ELK3已被鉴定为一种新型癌基因，在多种人类癌症的病理过程和进展中发挥重要作用。最近的研究表明，ELK3可能作为胶质瘤的潜在预后分子标志物；然而，其在胶质瘤中的作用机制仍未得到充分探索。 目的：本研究旨在探讨ELK3对胶质瘤预后的影响，研究异柠檬酸脱氢酶1（IDH1）对ELK3的调控作用，并评估ELK3在肿瘤免疫浸润中的作用。 方法：利用生物信息学技术在公共数据库中鉴定出差异表达显著且与分级和预后相关的ELK3基因。通过免疫组织化学和逆转录定量聚合酶链反应（RT-qPCR）验证这一发现，同时使用蛋白质免疫印迹法和免疫组织化学法确认ELK3表达与IDH1状态之间的关联。此外，免疫共培养研究表明，ELK3表达与M2巨噬细胞浸润呈正相关。 结果：通过对公共数据库的分析，本研究确定ELK3差异表达显著，且与肿瘤分级和预后相关。单因素和多因素Cox比例风险回归分析确定ELK3为独立的不良预后因素。在癌症基因组图谱（TCGA）队列中，通过将ELK3与其他临床指标整合，构建了预后列线图，并使用受试者工作特征（ROC）曲线和校准曲线评估其效能。该列线图表现出强大的性能，曲线下面积（AUC）不低于0.9，并且在内部和外部验证队列中均显示出高度一致性。此外，ELK3表达与IDH1的DNA甲基化和突变状态相关。构建了与ELK3相关的基因图谱，通过功能富集分析揭示了其在免疫调节过程中的潜在生物学功能。ELK3表达与巨噬细胞和中性粒细胞浸润呈正相关，这与肿瘤免疫估计资源（TIMER）和空间转录组学的研究结果一致。此外，ELK3表达与CD163表达呈中度相关，表明其在促进涉及M2巨噬细胞的免疫浸润中的作用。 结论：ELK3是弥漫性胶质瘤预后不良的潜在标志物，可能在免疫浸润中起调节作用，特别是通过增强M2巨噬细胞介导的免疫浸润。
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