A novel cuproptosis-related immune checkpoint gene signature identification and experimental validation in hepatocellular carcinoma

Xie, Yusai; Zhang, Wei; Sun, Jia; Sun, Lingyan; Meng, Fanbin; Yu, Haoran

doi:10.1038/s41598-022-22962-y

Cited by 7 publications

(8 citation statements)

References 61 publications

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“…HCC patients' prognoses could be well predicted with the model, and clinical characteristics were combined with risk scores to construct a nomogram model for facilitating clinical research and application. Several studies have examined the relationship between cuproptosis and patient prognosis in HCC (Ding et al, 2022;Peng et al, 2022;Xie et al, 2022;Zhang et al, 2022). For example, Peng et al developed a prognostic model based on cuproptosis-related genes (Peng et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…For example, Peng et al developed a prognostic model based on cuproptosis-related genes (Peng et al, 2022). Xie et al built a cuproptosisrelated immune checkpoint gene signature to identify the prognosis of HCC patients (Xie et al, 2022). Ding et al also built a cuproptosis-related prognosis model and discussed it in different cuproptosis subtypes (Ding et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

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A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response

Yang

Wang

et al. 2023

Front. Pharmacol.

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Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive.Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells’ pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes’ expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation.Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-Ⅱ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines.Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response

Yang

Wang

et al. 2023

Front. Pharmacol.

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“…Since the discovery of cuproptosis, the role of cuptoptosis in liver cancer prognosis and TME has been gradually evaluated. Previous studies mainly explored this issue by constructing Lasso cox model, which directly entered the target genes as model inputs (47)(48)(49)(50)(51)(52)(53). The Lasso model is applied to analyze multicollinearity data (54).…”

Section: Discussionmentioning

confidence: 99%

A cuproptosis random forest cox score model-based evaluation of prognosis, mutation characterization, immune infiltration, and drug sensitivity in hepatocellular carcinoma

Liu

Zhang

et al. 2023

Front. Immunol.

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BackgroundHepatocellular carcinoma is the third most deadly malignant tumor in the world with a poor prognosis. Although immunotherapy represents a promising therapeutic approach for HCC, the overall response rate of HCC patients to immunotherapy is less than 30%. Therefore, it is of great significance to explore prognostic factors and investigate the associated tumor immune microenvironment features.MethodsBy analyzing RNA-seq data of the TCGA-LIHC cohort, the set of cuproptosis related genes was extracted via correlation analysis as a generalization feature. Then, a random forest cox prognostic model was constructed and the cuproptosis random forest cox score was built by random forest feature filtering and univariate multivariate cox regression analysis. Subsequently, the prognosis prediction of CRFCS was evaluated via analyzing data of independent cohorts from GEO and ICGC by using KM and ROC methods. Moreover, mutation characterization, immune cell infiltration, immune evasion, and drug sensitivity of CRFCS in HCC were assessed.ResultsA cuproptosis random forest cox score was built based on a generalization feature of four cuproptosis related genes. Patients in the high CRFCS group exhibited a lower overall survival. Univariate multivariate Cox regression analysis validated CRFCS as an independent prognostic indicator. ROC analysis revealed that CRFCS was a good predictor of HCC (AUC =0.82). Mutation analysis manifested that microsatellite instability (MSI) was significantly increased in the high CRFCS group. Meanwhile, tumor microenvironment analysis showed that the high CRFCS group displayed much more immune cell infiltration compared with the low CRFCS group. The immune escape assessment analysis demonstrated that the high CRFCS group displayed a decreased TIDE score indicating a lower immune escape probability in the high CRFCS group compared with the low CRFCS group. Interestingly, immune checkpoints were highly expressed in the high CRFCS group. Drug sensitivity analysis revealed that HCC patients from the high CRFCS group had a lower IC50 of sorafenib than that from the low CRFCS group.ConclusionsIn this study, we constructed a cuproptosis random forest cox score (CRFCS) model. CRFCS was revealed to be a potential independent prognostic indicator of HCC and high CRFCS samples showed a poor prognosis. Interestingly, CRFCS were correlated with TME characteristics as well as clinical treatment efficacy. Importantly, compared with the low CRFCS group, the high CRFCS group may benefit from immunotherapy and sorafenib treatment.

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“…The relationship between PANRG-score and the enrichment score (ES) of ferroptosis and cuproptosis, which were figured out by the gene-set-based Gene Set Variation Analysis (GSVA) approach, were analyzed using Spearman method. Therein, the genes for ferroptosis pathway were extracted from the Molecular Signatures Database ( https://www.gsea-msigdb.org/gsea/msigdb ) and the cuproptosis-related genes were collected from the prior literature 47 , 48 .…”

Section: Methodsmentioning

confidence: 99%

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

Wei,

Lan,

Yang

et al. 2023

Sci Rep

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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.

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A novel cuproptosis-related immune checkpoint gene signature identification and experimental validation in hepatocellular carcinoma

Cited by 7 publications

References 61 publications

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response

A cuproptosis random forest cox score model-based evaluation of prognosis, mutation characterization, immune infiltration, and drug sensitivity in hepatocellular carcinoma

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

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