Regulatory mechanisms and functional analysis of cellular senescence-associated genes GAPDH, CCND1, and HBEGF in the immune microenvironment of meningioma.

Abstract

BACKGROUND: Meningioma is a common tumor of the central nervous system, yet its pathogenesis remains incompletely understood. Cellular senescence and associated genes play crucial roles in the development of various tumors; however, their functional roles and interactions with the immune microenvironment in meningioma remain poorly characterized. OBJECTIVE: This study aims to systematically elucidate the roles of cellular senescence-related genes in meningioma pathogenesis and the tumor immune microenvironment by integrating transcriptomic and single-cell RNA sequencing data, supplemented with in vitro functional validation. METHODS: Publicly available meningioma transcriptomic datasets were analyzed to identify differentially expressed cellular senescence-associated genes (CSA-DEGs). Weighted gene co-expression network analysis (WGCNA) was employed to detect key gene modules. Subsequently, machine learning algorithms, including LASSO regression and random forest, were applied to precisely select CSA-signature genes. Immune infiltration analysis combined with single-cell RNA sequencing data was conducted to characterize macrophage subpopulations and the expression patterns of key genes within the meningioma immune microenvironment. Finally, in vitro gene knockdown experiments were performed to validate the functional roles of GAPDH, CCND1, and HBEGF in meningioma and M2 macrophage polarization. RESULTS: A total of 43 CSA-DEGs were identified, significantly enriched in pathways related to cellular senescence, the p53 signaling pathway, and inflammatory responses. WGCNA revealed 28 key immune regulatory genes. Immune infiltration analysis showed significant enrichment of M2 macrophages and regulatory T cells in meningioma tissues. Single-cell analysis demonstrated heterogeneity in M2 macrophage populations and differential expression of CSA-signature genes. In vitro knockdown of GAPDH and CCND1 markedly suppressed pro-inflammatory factor expression, whereas HBEGF knockdown reduced anti-inflammatory cytokine secretion by M2 macrophages. These three genes appear to synergistically modulate the immune microenvironment in meningioma. CONCLUSION: Cellular senescence-associated genes GAPDH, CCND1, and HBEGF show associations with M2 macrophage polarization and inflammatory cytokine secretion in meningioma. These observations suggest their potential involvement in shaping an immunosuppressive tumor microenvironment and warrant further investigation as possible therapeutic targets.