| Glioma is a primary malignant tumor in the central nervous system(CNS).The World Health Organization(WHO)divides gliomas into four grades,among which lowergrade gliomas(LGG)with Grade 2～3 still have a high probability of further deterioration after treatment,the median survival time of patients with Grade 4 glioblastoma(GBM)is only 14～17 months.The first-line treatment strategies for glioma include surgical resection and radiotherapy and chemotherapy.However,radiotherapy and oral alkylating agents have radiation resistance and drug resistance respectively,and no significant improvement in overall survival has been found.Glioma has obvious tumor heterogeneity and the complexity of molecular,cellular and immune microenvironment.Therefore,exploring new therapeutic targets,immune microenvironment and targeted therapy strategies has become a research hotspot.Pyroptosis,one of the most recent modes of programmed cell death(PCD)that has attracted much attention,plays a key role in cancer development and therapy,characterized by the release of pro-inflammatory mediators and a dramatic impact on tumor immunogenicity.During cancer radiotherapy and chemotherapy,researchers have discovered that there are multiple ways to induce tumor cell pyroptosis.Based on the rapid development of tumor gene expression analysis,it is very important to develop molecular markers to accurately define tumor grade and type,and to evaluate patient prognosis and efficacy.As the most relevant and prominent PCD patterns in the cancer context,such as pyroptosis and ferroptosis,have demonstrated potential for cancer prediction and prognosis assessment.However,the prognostic value of pyroptosis-related genes(PRGs)in glioma and the complex mechanisms of pyroptosis activation during therapy remain controversial.Therefore,further development,analysis,and validation of a more comprehensive independent glioma cohort are needed to provide more precise insights for clinical application.This study analyzed the transcriptional level and protein expression of PRGs and found that PRGs are generally dysregulated in glioma,especially the expression of GSDMD is positively correlated with malignant grade and poor prognosis.In view of this,the study obtained WHO 2～3 glioma RNA sequencing(RNA-seq)datasets with radiotherapy and chemotherapy records from TCGA,CGGA and Rembrandt cohorts,and constructed 3-gene signature(CASP 1/3/9).The 3-gene signature was repeatedly verified in the global multi-center glioma cohort,and it was found that it showed stable and excellent prognostic evaluation efficiency and progression risk classification ability in patients who received radiation or TMZ-based first-line chemotherapy.Multivariate logistic regression analysis showed that the progression risk score(RiskScore value)and other clinicopathological indicators were independent predictors of the prognosis of LGG patients and could be used for joint prognostic evaluation.Thus,it is suggested that the newly developed 3-gene signature has potential as a prognostic marker for LGG radiotherapy and chemotherapy.The functional enrichment of the risk population based on the 3-gene signature showed that it was related to tumor immunity,and the content of various immune cells and the expression of immune checkpoints were higher in patients with high RiskScore values(i.e.,Risk-H).It shows that immune activation is an important factor affecting the prognosis of LGG,and reveals that pyroptosis may be involved in the regulation of the glioma immune system.From this,the immune landscape characteristics of the 3-gene signature dividing the risk population were delineated.Another finding of this study is to screen potential anti-tumor drugs by matching the gene expression similarity after chemical perturbation,and identify the specific small molecule inhibitor Fedratinib targeting JAK2.In vitro,Fedratinib effectively inhibited the viability and proliferation of glioma cells,and may serve as a potential anti-tumor targeted drug.This study developed a new method for evaluating the prognosis of LGG patients receiving first-line chemoradiotherapy mainly using bioinformatics analysis techniques,which showed good predictive efficiency in terms of prognosis assessment and risk classification.Finally,combined with some cell experiments,the potential anti-tumor targeted drug Fedratinib was screened out.In summary,this study constructed the gene evaluation signature related to pyroptosis to guide the clinical accurate prediction of the prognosis of LGG radiotherapy and chemotherapy,and laid the foundation for the preclinical research on the induction of pyroptosis and immune activation in glioma. |
