Identification of a Pyroptosis-Related Prognostic Signature Combined With Experiments in Hepatocellular Carcinoma.

Huihui Li,Xiaohua Zhang,Tang Li

doi:10.3389/fmolb.2022.822503

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis. There is a necessary search for improvement in diagnosis and treatment methods to improve the prognosis. Some useful prognostic markers of HCC are still lacking. Pyroptosis is a type of programmed cell death caused by the inflammasome. It is still unknown whether pyroptosis-related genes (PRGs) are involved in the prognosis in HCC. The gene expression and clinical data of LIHC (liver hepatocellular carcinoma) patients were downloaded from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium database (ICGC). In this study, we identified 40 PRGs that were differentially expressed between LIHC and normal liver tissues. Based on the TCGA-LIHC cohort, a 9-gene prediction model was established with the Least absolute shrinkage and selection operator (LASSO)-penalized Cox regression. The risk score was calculated according to the model in the TCGA-LIHC cohort and the ICGC-LIHC cohort. Utilizing the median risk score from the TCGA cohort, LIHC patients from the ICGC-LIHC cohort were divided into two risk subgroups. The Kaplan–Meier (KM) survival curves demonstrated that patients with lower risk scores had significantly favorable overall survival (OS). Combined with the clinical characteristics, the risk score was an independent factor for predicting the OS of LIHC patients in both the TCGA-LIHC cohort and the ICGC-LIHC cohort. Functional enrichment and immune function analysis were carried out. Furthermore, a nomogram based on risk score, age, gender, and tumor stage was used to predict mortality of patients with LIHC. Moreover, KM survival analysis was performed for 9 genes in the risk model, among which CHMP4A, SCAF11, and GSDMC had significantly different results and the ceRNA network was constructed. Based on the core role of SCAF11, we performed loss-of-function experiments to explore the function of SCAF11 in vitro. Suppression of SCAF11 expression inhibited the proliferation, attenuated the migration and invasion, and induced apoptosis of liver cancer cell lines. In conclusion, the pyroptosis-related model and nomogram can be utilized for the clinical prognostic prediction in LIHC. This study has demonstrated for the first time that SCAF11 promotes the progression of liver cancer.

Highlights

Hepatocellular carcinoma (HCC) is the main cause of cancerassociated death worldwide and has high morbidity and mortality (Piñero et al, 2020; Rebouissou and Nault, 2020; Pinter et al, 2021)
As a kind of programmed cell death caused by inflammasomes, pyroptosis results in the cleavage of gasdermin D (GSDMD) and activation of cytokines (Bergsbaken et al, 2009; Ju X. et al, 2021) with features such as cellular membrane pore generation, cytoplasmic swelling, membrane rupture, and release of cytoplasmic cytokines such as IL-18 and IL-1β into the extracellular environment (Zheng and Li, 2020)
This research enrolled a total of 425 liver hepatocellular carcinoma (LIHC) patients from the The Cancer Genome Atlas (TCGA) dataset

Summary

Introduction

Hepatocellular carcinoma (HCC) is the main cause of cancerassociated death worldwide and has high morbidity and mortality (Piñero et al, 2020; Rebouissou and Nault, 2020; Pinter et al, 2021). As a kind of programmed cell death caused by inflammasomes, pyroptosis results in the cleavage of gasdermin D (GSDMD) and activation of cytokines (Bergsbaken et al, 2009; Ju X. et al, 2021) with features such as cellular membrane pore generation, cytoplasmic swelling, membrane rupture, and release of cytoplasmic cytokines such as IL-18 and IL-1β into the extracellular environment (Zheng and Li, 2020). The process leads to the recruitment of caspase-1 protein into the inflammasome complex. The inflammasome complex is composed of the sensor, adaptor-like apoptosis-related speck-like proteins (ASCs), and caspase activation and recruitment domain (CARD) of ASCs (Bergsbaken et al, 2009). The N-terminal domain can cause the formation of cellular membrane pores These pores facilitate cell swelling, membrane rupture, and the release of inflammatory cytokines and lead to pyroptosis (Zheng et al, 2020). Whether these pyroptosis-related genes (PRGs) affect the prognosis of patients with HCC is still unclear

Methods

Results

Conclusion