A novel pyroptosis risk model composed of NLRP6 effectively predicts the prognosis of hepatocellular carcinoma patients

• Published in: Cancer medicine (Malden, MA) MA), 2023-01, Vol.12 (1), p.808-823
• Main Authors: Gao, Xin, Wang, Wen‐Xin, Zhang, Xiao‐Lan
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor - genetics; Carcinoma, Hepatocellular - genetics; Cell death; E2F protein; Gene expression; Gene set enrichment analysis; Genes, Regulator; Genomes; Hepatitis; Hepatocellular carcinoma; Humans; immune alterations; Inflammation; Intracellular Signaling Peptides and Proteins; Liver cancer; Liver Neoplasms - genetics; Medical prognosis; Metastases; molecular classification; Mutation; Myc protein; NLRP6; NOD2 protein; Pore Forming Cytotoxic Proteins; Prognosis; prognostic signature; Proteins; Pyroptosis; Pyroptosis - genetics; pyroptosis landscape; Risk factors; Risk groups; Survival analysis; tumor microenvironment; Tumor suppressor genes; Tumors
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.4898

Background Pyroptosis is a unique inflammatory‐related cell death process, and inflammation is considered to be a key factor in hepatocellular carcinoma (HCC). However, the pyroptosis landscape in HCC has not been thoroughly studied. Methods Clinical data and RNA sequencing data of HCC patients were collected from The Cancer Genome Atlas database, and differentially expressed genes (DEGs) associated with pyroptosis were discovered. The relationship between DEGs and prognosis was studied. Using The Cancer Genome Atlas cohort, a least absolute shrinkage and selection operator regression model was built on the basis of pyroptosis‐related DEGs, which was then verified by the Gene Expression Omnibus (GEO) cohort. Functional enrichment analysis and immunological states were also studied between distinct risk subgroups. Finally, the potential tumor suppressive function of NLRP6 in HCC was analyzed. Results In total, 26 pyroptosis‐related DEGs were identified. Consensus clustering results showed patients with high levels of pyroptosis were associated with higher tumor stage, grade, and poor prognosis. The least absolute shrinkage and selection operator risk model was built using six genes linked with prognosis (GSDMC, GSDME, NOD2, NLRP6, CASP8, and SCAF11). Risk score was an independent risk factor that suggested shortened overall survival in both the training cohort (HR: 3.52, 95% CI: 1.351–9.193) and validation cohort (HR: 3.31, 95% CI: 1.435–7.617). Meanwhile, the low‐risk population had higher immunological activity. We also found a novel potential tumor suppressor gene NLRP6, which may negatively regulate the E2F and MYC pathways and be associated with higher immune cell infiltration levels, which lead to better prognosis. Conclusions This study revealed the pyroptosis landscape of HCC and provided a promising clinical prognosis evaluation model. Additionally, some new targets related to prognosis such as NLRP6 are proposed for further study. In this study, we constructed a risk model using six genes linked with prognosis, which can accurately predict the overall survival of patients with hepatocellular carcinoma in both the training cohort and the validation cohort. Further, we highlighted that NLRP6 is a novel protective gene, may negatively regulate E2F and MYC pathways, resulting in better prognosis.