A pyroptosis-related gene signature for prognosis prediction in hepatocellular carcinoma

Abstract

IntroductionHepatocellular carcinoma (HCC) is one of the most invasive cancers with a low 5-year survival rate. Pyroptosis, a specialized form of cell death, has shown its association with cancer progression. However, its role in the prognosis of HCC has not been fully understood.MethodsIn our study, clinical information and mRNA expression for 1076 patients with HCC were obtained from the five public cohorts. Pyroptotic clusters were generated by unsupervised clustering based on 40 pyroptosis-related genes (PRGs) in the TCGA and ICGC cohort. A pyroptosis-related signature was constructed using least absolute shrinkage and selection operator (LASSO) regression according to differentially expressed genes (DEGs) of pyroptotic clusters. The signature was then tested in the validation cohorts (GES10142 and GSE14520) and subsequently validated in the CPTAC cohort (n=159) at both mRNA and protein levels. Response to sorafenib was explored in GSE109211.ResultsThree clusters were identified based on the 40 PRGs in the TCGA cohort. A total of 24 genes were selected based on DEGs of the above three pyroptotic clusters to construct the pyroptotic risk score. Patients with the high-risk score showed shorter overall survival (OS) compared to those with the low-risk score in the training set (P<0.001; HR, 3.06; 95% CI, 2.22-4.24) and the test set (P=0.008; HR, 1.61; 95% CI, 1.13-2.28). The predictive ability of the risk score was further confirmed in the CPTAC cohort at both mRNAs (P<0.001; HR, 2.99; 95% CI, 1.67-5.36) and protein levels (P<0.001; HR, 2.97; 95% CI 1.66-5.31). The expression of the model genes was correlated with immune cell infiltration, angiogenesis-related genes, and sensitivity to antiangiogenic therapy (P<0.05).DiscussionIn conclusion, we established a prognostic signature of 24 genes based on pyroptosis clusters for HCC patients, providing insight into the risk stratification of HCC.

Mechanistic Insights about Sorafenib-, Valproic Acid- and Metformin-Induced Cell Death in Hepatocellular Carcinoma

“…A list of markers associated with pyroptosis in HCC was published, which includes BAK, BAX, caspase 1, 3 and 5, gasdermin A and E, high-mobility group box 1, interleukin 18, 1A and 1B, p53, tumor protein 63, among others [135,136]. Of importance, among these genes, p53 is of interest, given its involvement in metformin-and sorafenib-related mechanisms of cell death.…”

“…Of importance, among these genes, p53 is of interest, given its involvement in metformin-and sorafenib-related mechanisms of cell death. It was shown that the analysis of the clusters of pyroptosis is useful to predict prognosis in patients with HCC [135].…”