Identification and analysis of necroptosis-associated signatures for prognostic and immune microenvironment evaluation in hepatocellular carcinoma

Abstract

BackgroundHepatocellular carcinoma remains the third most common cause of cancer-related deaths worldwide. Although great achievements have been made in resection, chemical therapies and immunotherapies, the pathogenesis and mechanism of HCC initiation and progression still need further exploration. Necroptosis genes have been reported to play an important role in HCC malignant activities, thus it is of great importance to comprehensively explore necroptosis-associated genes in HCC.MethodsWe chose the LIHC cohort from the TCGA, ICGC and GEO databases for this study. ConsensusClusterPlus was adopted to identify the necroptosis genes-based clusters, and LASSO cox regression was applied to construct the prognostic model based on necroptosis signatures. The GSEA and CIBERSORT algorithms were applied to evaluate the immune cell infiltration level. QPCR was also applied in this study to evaluate the expression level of genes in HCC.ResultsWe identified three clusters, C1, C2 and C3. Compared with C2 and C3, the C1 cluster had the shortest overall survival time and highest immune score. The C1 was samples were significantly enriched in cell cycle pathways, some tumor epithelial-mesenchymal transition related signaling pathways, among others. The DEGs between the 3 clusters showed that C1 was enriched in cell cycle, DNA replication, cellular senescence, and p53 signaling pathways. The LASSO cox regression identified KPNA2, SLC1A5 and RAMP3 as prognostic model hub genes. The high risk-score subgroup had an elevated expression level of immune checkpoint genes and a higher TIDE score, which suggested that the high risk-score subgroup had a lower efficiency of immunotherapies. We also validated that the necroptosis signatures-based risk-score model had powerful prognosis prediction ability.ConclusionBased on necroptosis-related genes, we classified patients into 3 clusters, among which C1 had significantly shorter overall survival times. The proposed necroptosis signatures-based prognosis prediction model provides a novel approach in HCC survival prediction and clinical evaluation.

Necroptosis-related lncRNAs: Combination of bulk and single-cell sequencing reveals immune landscape alteration and a novel prognosis stratification approach in lung adenocarcinoma

“…There were already necroptosis-related models developed in other cancers. For instance, in hepatocellular carcinoma, consistent with our result, the higher necroptosis risk patients had shorter overall survival and lower efficiency of immunotherapies ( 69 ). In addition, a cell necroptosis index (CNI) was established in triple-negative breast cancer (TNBC) and exactly showed that the poor prognosis of TNBC patients with high-CNI was linked to chemotherapy resistance ( 70 ).…”

Construction and validation of a prognostic signature based on necroptosis-related genes in hepatocellular carcinoma

“…In this study, we explored the relationship between necroptosis and hepatocellular carcinoma. Although similar studies are available, our study was validated with immunohistochemical experiments in 10 pairs of hepatocellular carcinoma and paraneoplastic samples [ 29 ].…”

A novel cuproptosis-related prognostic gene signature and validation of differential expression in hepatocellular carcinoma

“…Disrupting pyruvate uptake, which affected TCA cycle, might impair hepatocellular tumorigenesis (Tompkins et al, 2019). In recent years, studies have been reported the relationship between programmed cell death-related phenotypes and HCC, and established corresponding prognostic models (Li and Zeng, 2022;Lu et al, 2022). However, the relationship between a newly found programmed cell death form cuproptosis and HCC was unclear.…”