Robust analysis of a novel PANoptosis-related prognostic gene signature model for hepatocellular carcinoma immune infiltration and therapeutic response

Abstract

PANoptosis, an interplay between pyroptosis, apoptosis, and necroptosis, is deeply involved in cancer development and immunity. However, the influence of PANoptosis in hepatocellular carcinoma (HCC) remains to be further investigated. The differentially expressed PANoptosis-related genes (PANRGs) was screened in The Cancer Genome Atlas (TCGA) database. Accordingly, mutation, bioinformatics, and consensus clustering analyses were performed. Then, a prognostic risk model was developed by least absolute shrinkage and selection operator (LASSO) Cox regression. Furthermore, the prognostic value, immunity correlation and therapeutic response prediction ability of risk model were explored. A total of 18 PANRGs were differently expressed in the TCGA-HCC cohort and were mainly involved in cancer- and cell death-related signal pathways. Using unsupervised clustering method, we identified two PANRGs-mediated clustering patterns. The remarkable differences between the two clusters on overall survival (OS) and clinical features were demonstrated respectively. Based on the five-gene prognostic risk model, the calculated PANRG-scores were used to categorize the subgroups as high- and low-risk. Notably, the high-risk subgroup had a dismal prognosis and exhibited much lower immune infiltration levels of mast cells, nature killer cells and pDCs, but higher levels of aDCs, iDCs and Treg cells than those in the low-risk subgroup. Furthermore, we constructed a reliable nomogram combining clinical traits and PANRG-score to predict the OS of HCC patients. The significantly negative correlation between PANoptosis and tumor mutation burden (TMB), ferroptosis were revealed. In drug sensitivity analysis, the high-risk subgroup had a considerably lower TIDE score, suggesting a preferable response to immunotherapy, and may be more sensitive to Tipifarnib, Imatinib, Doxorubicin, and Gemcitabine. The upregulated mRNA expressions of FADD were validated in 16 paired HCC tissues of Guangxi cohort. Based on PANoptosis-related genes, an integrated risk signature was constructed to provide a roadmap for patient stratification and predict HCC patient's prognosis. The patients with the higher PANRG-score may carry a dismal survival and relatively low immune infiltration, but a potential better immunotherapy response. Therefore, future HCC therapy perspectives should emphasize the setting of PANoptosis to achieve a personalized, practicable and effective therapeutic regimen.

Identification of PANoptosis-related subtypes, construction of a prognosis signature, and tumor microenvironment landscape of hepatocellular carcinoma using bioinformatic analysis and experimental verification

“…The 1-,3-,5-year AUC was 0.735, 0.706, 0.638 in the present model, while another study PANoptosis-related gene signature model showed 1-,3-,5-year AUC was 0.707, 0.622, and 0.562, respectively. This indicating that the efficiency of diagnosis of our model was superior than previous prognostic model ( 38 ).…”

Identification of PANoptosis-related biomarkers and analysis of prognostic values in head and neck squamous cell carcinoma

“…Xiong et al identified that PANoptosis might be an important indicator for efficacy of immunotherapy and chemotherapy in hepatocellular carcinoma (HCC) 22 . Wei et al also showed that PANoptosis was associated with HCC overall survival, immune infiltration, and immunotherapy response 23 , suggesting that PANoptosis showed promise to be a therapeutic target. The dysregulation of cell proliferation and death plays a crucial role in the tumorigenesis of HNSCC, which is characterized by therapy resistance and infiltration of immune cells, contributing to unfavorable prognosis 24 , 25 .…”

“…We found that FADD was related to poor overall survival, and enhanced chemotherapy resistance. Wei et al also suggested that FADD as the critical regulator of PANoptosis was related to therapy resistance in HCC 23 . On the other hand, we identified that high FADD expression might inhibit the immune process via regulating NK cells and TIL, which contributed to immune escape of cancer cells.…”

A novel PANoptosis-related lncRNA model for forecasting prognosis and therapeutic response in hepatocellular carcinoma

“…The data of gene counts was used to perform differential expression analysis by a "limma" R package, the standardized TPM matrix was utilized for correlation, survival, mutation, immune, gene set enrichment analysis (GSEA) and drug sensitivity analysis. We extracted 85 PANoptosis-related genes included necroptosis, apoptosis and pyroptosis genes according to previous literatures 13,14,21 , and conducted correlation analysis by "limma" package to identify PANoptosis-related lncRNAs, the ltering criteria was cor 0.3 and pvalue 0.001. Finally, we compared the expression of PANoptosis-related lncRNAs by Wilcoxon test to identify differentially expressed and PANoptosis-related lncRNAs (DPRLs) between normal and tumour tissue.…”

“…Recently, it has been reported that PANoptosis against viral infection through innate immune pathway 10 , the tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) induced PANoptosis were found to inhibit tumor growth 11 , and suppression of PANoptosis was proved to promote tumorigenesis 12 . In HCC, some studies have shown that PANoptosis-related genes can predict the prognosis and immunotherapy response [13][14][15] .…”