Abstract
Hepatocellular carcinoma (HCC) is the second most lethal malignant tumor worldwide, with an increasing incidence and mortality. Due to general resistance to antitumor drugs, only limited therapies are currently available for advanced HCC patients, leading to a poor prognosis with a 5-year survival rate less than 20%. Pyroptosis is a type of inflammation-related programmed cell death and may become a new potential target for cancer therapy. However, the function and prognostic value of pyroptosis-related genes (PRGs) in HCC remain unknown. Here, we identified a total of 58 PRGs reported before and conducted a six-PRG signature via the LASSO regression method in the GEO training cohort, and model efficacy was further validated in an external dataset. The HCC patients can be classified into two subgroups based on the median risk score. High-risk patients have significantly shorter overall survival (OS) than low-risk patients in both training and validation cohorts. Multivariable analysis indicated that the risk score was an independent prognostic factor for OS of HCC patients. Functional enrichment analysis and immune infiltration evaluation suggested that immune status was more activated in the low-risk group. In summary, PRGs can be a prediction factor for prognosis of HCC patients and targeting pyroptosis is a potential therapeutic alternative in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the second most lethal malignant tumor worldwide with an increasing incidence (Torre et al, 2015)
A total of 58 pyroptosis-related gene expression levels were evaluated in 221 HCC and 220 normal liver tissues in the GSE14520 cohort (Supplementary Table 1)
We identified 35 differently expressed genes (DEGs), including 13 upregulated genes (CHMP2A, GPX4, HMGB1, DHX9, BAX, TP53, BAK1, CASP3, DFNA5, CASP8, APIP, CHMP2B, and CYCS) and 22 downregulated genes (CHMP6, TNF, CHMP7, CASP5, NLRP3, IL1A, ZBP1, CHMP4A, PYCARD, CASP4, CASP1, GZMA, IL18, GZMB, AIM2, IL1B, IL6, NLRP1, NOD1, IRF2, PRKACA, and CASP9) in HCC tissue
Summary
Hepatocellular carcinoma (HCC) is the second most lethal malignant tumor worldwide with an increasing incidence (Torre et al, 2015). Pyroptosis is a new identified form of cell death usually triggered by inflammasomes (Kesavardhana et al, 2020). Inflammasomes recruit apoptosis-associated speck-like protein (ASC), which can activate caspase-1, resulting in cytokine secretion and gasdermin D (GSDMD) cleavage (Liu et al, 2016). The N-terminal of GSDMD forms pores in the plasma membrane, leading to the dysregulated discharge of inflammatory factors and cell lysis. As for the non-canonical inflammasome pathways, caspase-4/5 is activated by lipopolysaccharide to initiate cleavage of GSDMD and cell pyroptosis (Kovacs and Miao, 2017). A new pathway has been revealed, showing that some stimulations can activate caspase-3, inducing the cleavage of gasdermin E (GSDME) and the N-terminal of GSDME can lead to the pore formation (Wang et al, 2017)
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