肥大细胞通过内质网应激抑制胶质母细胞瘤的进展

Abstract

Aims Mast cells (MCs) are the major infiltrating immune cells in glioblastoma (GBM) and have been implicated in tumor development; however, their role and underlying mechanisms in GBM progression remain unclear. This study aimed to characterize the distribution of MCs infiltration in GBM, the functional role of MCs in GBM progression, and the associated regulatory mechanisms. Methods First, we used the CIBERSORT algorithm to determine the distribution of MCs in GBM based on TCGA data, followed by validation using clinical GBM tissue samples. R language packages were used to assess the prognostic impact of MCs on patients with GBM. Subsequently, in vitro and in vivo experiments were performed to determine the effects of MCs on the GBM phenotype. Next, high-throughput RNA sequencing was performed on GBM cells treated with or without MCs to screen for differentially expressed genes. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were performed to identify key signaling pathways involved in MCs-mediated GBM regulation. Finally, we validated the critical regulatory role of this pathway in MC-mediated GBM apoptosis using transmission electron microscopy for ultrastructure, CCK-8 assay for viability, Western blotting and immunofluorescence for gene expression and regulatory relationships, and flow cytometry for apoptosis. Results We observed that the distribution of activated and resting MCs differed markedly in GBM. Moreover, pharmacological activation of MCs with C48/80 limited the growth and induced apoptosis of GBM cells in vitro and suppressed tumor growth in vivo . GO and KEGG enrichment analyses revealed that many of the top-ranked pathways were associated with immune responses, among which the classical osteoclast differentiation pathway was among the most prominent. Further pathway analysis and biological validation demonstrated that endoplasmic reticulum stress (ERS) is a key apoptotic pathway through which MCs supp