Background: Pyroptosis is a programmed cell death mediated by the gasdermin superfamily, accompanied by inflammatory and immune responses. Exogenously activated pyroptosis is still not well characterized in the tumor microenvironment. Furthermore, whether pyroptosis-related genes (PRGs) in lower-grade glioma (LGG) may be used as a biomarker remains unknown.
Methods: The RNA-Sequencing and clinical data of LGG patients were downloaded from publicly available databases. Bioinformatics approaches were used to analyze the relationship between PRGs and LGG patients' prognosis, clinicopathological features, and immune status. The NMF algorithm was used to differentiate phenotypes, the LASSO regression model was used to construct prognostic signature, and GSEA was used to analyze biological functions and pathways. The expression of the signature genes was verified using qRT-PCR. In addition, the L1000FWD and CMap tools were utilized to screen potential therapeutic drugs or small molecule compounds and validate their effects in glioma cell lines using CCK-8 and colony formation assays.
Results: Based on PRGs, we defined two phenotypes with different prognoses. Stepwise regression analysis was carried out to identify the 3 signature genes to construct a pyroptosis-related signature. After that, samples from the training and test cohorts were incorporated into the signature and divided by the median RiskScore value (namely, Risk-H and Risk-L). The signature shows excellent predictive LGG prognostic power in the training and validation cohorts. The prognostic signature accurately stratifies patients according to prognostic differences and has predictive value for immune cell infiltration and immune checkpoint expression. Finally, the inhibitory effect of the small molecule inhibitor fedratinib on the viability and proliferation of various glioma cells was verified using cell biology-related experiments.
Conclusion: This study developed and validated a novel pyroptosis-related signature, which may assist instruct clinicians to predict the prognosis and immunological status of LGG patients more precisely. Fedratinib was found to be a small molecule inhibitor that significantly inhibits glioma cell viability and proliferation, which provides a new therapeutic strategy for gliomas.
Keywords: Drug screening; Fedratinib; Lower-grade glioma; Prognostic signature; Pyroptosis; Tumor immune microenvironment.
© 2022. The Author(s).