Identification of molecular subtypes based on PANoptosis-related genes and construction of a signature for predicting the prognosis and response to immunotherapy response in hepatocellular carcinoma

Abstract

BackgroundPrevious studies have demonstrated that PANoptosis is strongly correlated with cancer immunity and progression. This study aimed to develop a PANoptosis-related signature (PANRS) to explore its potential value in predicting the prognosis and immunotherapy response of hepatocellular carcinoma (HCC).MethodsBased on the expression of PANoptosis-related genes, three molecular subtypes were identified. To construct a signature, the differentially expressed genes between different molecular subtypes were subjected to multivariate least absolute shrinkage and selection operator Cox regression analyses. The risk scores of patients in the training set were calculated using the signature. The patients were classified into high-risk and low-risk groups based on the median risk scores. The predictive performance of the signature was evaluated using Kaplan-Meier plotter, receiving operating characteristic curves, nomogram, and calibration curve. The results were validated using external datasets. Additionally, the correlation of the signature with the immune landscape and drug sensitivity was examined. Furthermore, the effect of LPCAT1 knockdown on HCC cell behavior was verified using in vitro experiments.ResultsThis study developed a PANRS. The risk score obtained by using the PANRS was an independent risk factor for the prognosis of patients with HCC and exhibited good prognostic predictive performance. The nomogram constructed based on the risk score and clinical information can accurately predicted the survival probability of patients with HCC. Patients with HCC in the high-risk groups have high immune scores and tend to generate an immunosuppressive microenvironment. They also exhibited a favorable response to immunotherapy, as evidenced by high tumor mutational burden, high immune checkpoint gene expression, high human leukocyte antigen gene expression, low tumor immune dysfunction and low exclusion scores. Additionally, the PANRS enabled the identification of 15 chemotherapeutic agents, including sorafenib, for patients with HCC with different risk levels, guiding clinical treatment. The signature gene LPCAT1 was upregulated in HCC cell lines. LPCAT1 knockdown markedly decreased HCC cell proliferation and migration.ConclusionPANRS can accurately predict the prognosis and immunotherapy response of patients with HCC and consequently guide individualized treatment.

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] .…”