FOXP3 Contributes to TMZ Resistance, Prognosis, and Immune Infiltration in GBM from a Novel Pyroptosis-Associated Risk Signature.

Abstract

Background Pyroptosis is a form of programmed cell death, playing a significant role in cancer. Glioblastoma multiforme (GBM) is the most common malignant brain tumor. The poor prognosis in GBM due to temozolomide (TMZ) resistance has been widely discussed. Such being the case, the correlation between TMZ resistance and pyroptosis is seldom investigated. On this basis, this paper aims to explore the potential prognostic value of genes related to TMZ resistance and pyroptosis as well as their relationship to the immune microenvironment in GBM. Methods A total of 103 patients from TCGA were assigned to a training cohort; 190 from CGGA were assigned to a validation cohort. The prognostic risk model reflecting pyroptosis and TMZ resistance was built from the training cohort using multivariate Cox regression and performed validation. RT-qPCR was used to examine the expression of 4 genes from the risk signature. FOXP3 was selected for overexpression and verified using the western blot. The TMZ IC50 of FOXP3-overexpressed cell lines was determined by CCK8. Results A four genes-based risk signature was established and validated, separating GBM patients into high- and low-risk groups. Compared with the low-risk group, the high-risk group presented worse clinical survival outcomes. Its differential expressed genes were enriched in immune-related pathways and closely related to the immune microenvironment. Moreover, RT-qPCR results suggested that FOXP3, IRF3, and CD274 were significantly upregulated in TMZ-resistant strains, while TP63 was downregulated. FOXP3-overexpressed GBM cell lines had higher TMZ IC50, implying an increased resistance of TMZ. Conclusion A novel gene signature relevant to pyroptosis and TMZ resistance was constructed and could be used for the prognosis of GBM. The four genes from the risk model might play a potential role in antitumor immunity and serve as therapeutic targets for GBM.