Pyroptosis-related genes IRAK1, NOD2, POP1 and YWHAB impact the prognosis through immune functional pathways in hepatocellular carcinoma

Abstract Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes the prognostic prediction challenging. Pyroptosis can influence the proliferation, invasion and metastasis of tumors. However, the prognostic value of pyroptosis-related genes in HCC remains to be further elucidated.Methods: In this study, univariate Cox regression analysis and the least absolute shrinkage and selection operator Cox regression were performed to construct a four-gene signature. Kaplan-Meier curve, time-dependent receiver operating characteristic curve and univariate/multivariate Cox analysis were used to evaluate the prognostic model. Single-sample gene set enrichment analysis was performed to calculate the enrichment scores of diverse immune cell subpopulations and related functions. The correlation of the prognostic model with immune infiltrate types and drug chemosensitivity were analyzed by Analysis of variance and Pearson correlation respectively. Spearman correlation was carried out to analyze the associations between the risk score and immune checkpoint-related genes, cell cycle-related genes, and multidrug resistance-related genes. Gene set enrichment analysis was conducted to further explore the underlying molecular mechanisms. Finally, real-time quantitative polymerase chain reaction and immunohistochemistry were applied to analyze the mRNA and protein expression levels between HCC tissues and adjacent non-tumorous tissues in an independent sample cohort.Results: A pyroptosis-related gene signature was constructed to classify patients into two risk groups. Compared with the low-risk group, patients in the high-risk group showed significantly reduced overall survival (OS). The risk score was an independent predictor of OS. Tumor-related pathways were enriched in the high-risk group and patients with different risk scores showed different immune status. Immune checkpoint-related genes, cell cycle-related genes, and multidrug resistance-related genes were overexpressed in the high-risk group compared with the low-risk group. The expression level of each prognostic gene was negatively related to the anti-tumor drug sensitivity. Furthermore, the expression level of each prognostic gene in HCC tissues was higher than that in adjacent non-tumorous tissues in an independent sample cohort and similar results were found in most cancer types.Conclusions: A novel pyroptosis-related gene signature is a promising biomarker for estimating the OS and immune status of HCC, which is beneficial to the realization of individualized treatment.