Abstract
Objective: Hepatocellular carcinoma (HCC) is a genetically and phenotypically heterogeneous tumor, and the prediction of its prognosis remains a challenge. In the past decade, studies elucidating the mechanisms that induce tumor cell pyroptosis has rapidly increased. The elucidation of their mechanisms is essential for the clinical development optimal application of anti-hepatocellular carcinoma therapeutics. Methods: Based on the different expression profiles of pyroptosis-related genes in HCC, we constructed a LASSO Cox regression pyroptosis-related genes signature that could more accurately predict the prognosis of HCC patients. Results: We identified seven pyroptosis-related genes signature (BAK1, CHMP4B, GSDMC, NLRP6, NOD2, PLCG1, SCAF11) in predicting the prognosis of HCC patients. Kaplan Meier survival analysis showed that the pyroptosis-related high-risk gene signature was associated with poor prognosis HCC patients. Moreover, the pyroptosis-related genes signature performed well in the survival analysis and ICGC validation group. The hybrid nomogram and calibration curve further demonstrated their feasibility and accuracy for predicting the prognosis of HCC patients. Meanwhile, the evaluation revealed that our novel signature predicted the prognosis of HCC patients more accurately than traditional clinicopathological features. GSEA analysis further revealed the novel signature associated mechanisms of immunity response in high-risk groups. Moreover, analysis of immune cell subsets with relevant functions revealed significant differences in aDCs, APC co-stimulation, CCR, check-point, iDCs, Macrophages, MHC class-I, Treg, and type II INF response between high- and low-risk groups. Finally, the expression of Immune checkpoints was enhanced in high-risk group, and m6A-related modifications were expressed differently between low- and high-risk groups. Conclusion: The novel pyroptosis-related genes signature can predict the prognosis of patients with HCC and insight into new cell death targeted therapies.
Highlights
Hepatocellular carcinoma (HCC) is the third most aggressive and lethal disease, accounting for approximately 75% of liver cancer cases, and is a highly genetically and phenotypically heterogeneous malignancy with 830,000 deaths in 2020 (Petrick et al, 2016; Moon and Ro, 2021)
Kaplan Meier survival analysis showed that the pyroptosis-related high-risk gene signature was associated with poor prognosis HCC patients
The evaluation revealed that our novel signature predicted the prognosis of HCC patients more accurately than traditional clinicopathological features
Summary
Hepatocellular carcinoma (HCC) is the third most aggressive and lethal disease, accounting for approximately 75% of liver cancer cases, and is a highly genetically and phenotypically heterogeneous malignancy with 830,000 deaths in 2020 (Petrick et al, 2016; Moon and Ro, 2021). Studies elucidating the mechanisms that induce tumor cell pyroptosis has rapidly increased (Derangere et al, 2014; Jiang et al, 2017; Wang Y et al, 2018). Pyroptosis therapies are increasing as opportunities to inhibit cancer development. Apoptosis is widely studied as a major form of regulated cell death underlying tumor pathogenesis and therapy. The clear molecular pathways mediating necrotic types of cell death have recently been uncovered, the long-standing view of apoptosis as a standard regulating mechanism of death programs has changed (Vanden Berghe et al, 2014; Conrad et al, 2016; Wallach et al, 2016). The previously unknown mechanism of pyroptosis as a molecularly targeted pathway to eradicate oncogene addicted tumor cells may have important implications for the clinical development and optimal application of anticancer therapeutics (Lu et al, 2018)
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