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

Abstract

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.

Exploration of prognostic and treatment markers in hepatocellular carcinoma via GPCR-related genes analysis

“…NLRP6, a novel member of the nucleotide binding domain and leucine-rich repeat-containing (NLR) family, shows abundant expression in the liver and intestine and plays an essential role in regulating inflammation and shaping intestine microbiota [ 58 ]. It is demonstrated that NLRP6 drives the progression of liver diseases by causing dysbiosis of the intestine, and its expression level is strongly related to the prognosis of HCC by regulating the progress of pyroptosis [ 59 , 60 ]. GRM8 modulates glutamatergic and gamma-aminobutyric acid (GABA) neurotransmission, and HTR5A belongs to the 5-HT receptor family and is deeply involved in regulating the nervous system [ 61 , 62 ].…”

Adverse clinical outcomes and immunosuppressive microenvironment of RHO-GTPase activation pattern in hepatocellular carcinoma

“…Second, compared to traditional TNM stage and other published prediction models [ 20 – 23 , 34 ], we developed a 16-gene prognostic model with a better and more robust predictive accuracy (most of AUC value > 0.8). These sixteen genes collectively contribute to HCC biology by either promoting cancer development or inhibiting tumor growth, depending on their specific functions.…”

“…The correlations between RGPRG score and clinical characteristics were further estimated using the Wilcoxon rank sum test. Decision curve analysis (DCA) was used to evaluate and compare multiple published clinical prediction models [ 20 – 23 ]. None and ALL are two reference lines, and the closer the curves of other models are to these two lines, the less clinical utility they have.…”

Inflammasome and pyroptosis in autoimmune liver diseases

“…In addition, further experimental research on the inflammasome and pyroptosis in relation to intestinal microbiota and the gut–liver axis is required. As a potential key molecule in the gut–liver axis, NLRP6 is not only highly expressed in intestinal epithelial cells ( 45 ) but also specifically expressed in liver parenchymal cells ( 195 ). In alcoholic liver disease, the gut microbiota and its components, including LPS and dsDNA ( 196 ), activate the TLR4/MyD88–ROS pathway in the portal circulation, thereby triggering NLRP6 inflammasome-mediated pyroptosis ( 196 ).…”

“…NLRP6 is a protective factor against the development of nonalcoholic fatty liver disease (NAFLD) and has been found to play a crucial role in inflammatory and immunological responses ( 44 ). Reports have suggested that the NLPR6 gene is a candidate tumor suppressor gene ( 45 ). This gene has been shown to be capable of inducing pyroptosis in hepatocellular carcinoma and is linked to higher levels of immune cell infiltration, both of which are associated with a more favorable prognosis.…”