High ELK3 expression is associated with the wild type IDH1 in glioma and enhances infiltration of M2 macrophages

Abstract

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.

Keywords: Diagnosis; Diffuse glioma; ELK3; Microenvironment; Prognosis; Tumor-infiltrating immune cells.