Development and validation of a pyroptosis-related genes signature for risk stratification in gliomas

Penggang Sun; Xinyu Wang; Junzhe Zhong; Daohan Yu; Hanwen Xuan; Tianye Xu; Dan Song; Changxiao Yang; Pandeng Wang; Yuxiang Liu; Xiangqi Meng; Jinquan Cai

doi:10.3389/fgene.2023.1087563

Development and validation of a pyroptosis-related genes signature for risk stratification in gliomas

Front Genet. 2023 Feb 13:14:1087563. doi: 10.3389/fgene.2023.1087563. eCollection 2023.

Authors

Affiliation

¹ Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

Abstract

Background: Glioma is a highly heterogeneous disease, causing the prognostic prediction a challenge. Pyroptosis, a programmed cell death mediated by gasdermin (GSDM), is characterized by cell swelling and the release of inflammatory factors. Pyroptosis occurs in several types of tumor cells, including gliomas. However, the value of pyroptosis-related genes (PRGs) in the prognosis of glioma remains to be further clarified. Methods: In this study, mRNA expression profiles and clinical data of glioma patients were acquired from TCGA and CGGA databases, and one hundred and eighteen PRGs were obtained from the Molecular Signatures Database and GeneCards. Then, consensus clustering analysis was performed to cluster glioma patients. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to establish a polygenic signature. Functional verification of the pyroptosis-related gene GSDMD was achieved by gene knockdown and western blotting. Moreover, the immune infiltration status between two different risk groups were analyzed through the "gsva" R package. Results: Our results demonstrated that the majority of PRGs (82.2%) were differentially expressed between lower-grade gliomas (LGG) and glioblastoma (GBM) in the TCGA cohort. In univariate Cox regression analysis, eighty-three PRGs were shown to be associated with overall survival (OS). A five-gene signature was constructed to divide patients into two risk groups. Compared with patients in the low-risk group, patients in the high-risk group had obviously shorter OS (p < 0.001). Also, we found that the high-risk group showed a higher infiltrating score of immune cells and immune-related functions. Risk score was an independent predictor of OS (HR > 1, p < 0.001). Furthermore, knockdown of GSDMD decreased the expression of IL-1β and cleaved caspase-1. Conclusion: Our study constructed a new PRGs signature, which can be used to predict the prognosis of glioma patients. Targeting pyroptosis might serve as a potential therapeutic strategy for glioma.

Keywords: gene signature; glioma; immune status; overall survival; pyroptosis.

Grants and funding

This work was supported by 1. National Natural Science Foundation of China (No. 82073298, No. 82003022); 2. Heilongjiang Provincial Key R&D Project (GA21C002); 3. Central Government Supporting Local University Reform and Development Fund for Excellent Youth Talents (0202-300011190006); 4. China Postdoctoral Science Foundation (2022T150173, 2020T130157, 2019M660074); 5. Heilongjiang Postdoctoral Science Foundation (LBH-TZ2113, LBH-Z19029); 6. The Research Project of the Health and Family Planning Commission of Heilongjiang Province (2019-102).