Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma

et al. 2022

Front. Genet.

Background: Cuproptosis is a recently discovered form of programmed cell death. Ferredoxin 1 (FDX1) is a key gene that mediates this process. However, the role of FDX1 in human tumors is not clear.Methods: We comprehensively analyzed the differential expression and genetic alterations of FDX1 using multiomics data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. Subsequently, we explored the association between FDX1 and tumor parameters such as genomic instability, RNA methylation modifications, immune infiltration and pathway activity. In addition, we performed functional enrichment analysis and assessed the sensitivity potential of FDX1-related drugs. Finally, we experimentally verified the functional effects of FDX1.Results: The analysis revealed differential expression of FDX1 in a variety of tumors. By analyzing the association of FDX1 expression with genomic instability, immune cell infiltration, signaling pathway etc. We explored the role of FDX1 in regulating cell activity. Also, we evaluated the function of FDX1 in biologic process and drug sensitivity. Our experimental results demonstrated that FDX1 exerts its antitumor effects through cuproptosis in liver hepatocellular carcinoma and non-small cell lung cancer cell lines.Conclusion: Our study reveals the functional effects of FDX1 in tumors and deepens the understanding of the effects of FDX1. We validated the inhibitory effect of FDX1 in copper induced cell-death, confirming the role of FDX1 as a cuproptosis biomarker.

Section: Discussionsupporting

confidence: 93%

Characterization of the functional effects of ferredoxin 1 as a cuproptosis biomarker in cancer

Dai

et al. 2022

Front. Genet.

“…; Zhen Zhang et al.) by conducting Decision Curve Analysis (DCA), which could assess the utility of different models for decision-making ( 26 – 30 ). Additionally, two anti-PD1/PD-L1 inhibitor cohorts (IMVigor 210 and GSE176307) were used to demonstrate the predictive value of immunotherapy response of CRGPI.…”

Section: Methodsmentioning

confidence: 99%

Identification of cuproptosis-related subtypes, cuproptosis-related gene prognostic index in hepatocellular carcinoma

et al. 2022

Front. Immunol.

Cuproptosis is a novel form of cell death, correlated with the tricarboxylic acid (TCA) cycle. However, the metabolic features and the benefit of immune checkpoint inhibitor (ICI) therapy based on cuproptosis have not yet been elucidated in Hepatocellular carcinoma (HCC). First, we identified and validated three cuproptosis subtypes based on 10 cuproptosis-related genes (CRGs) in HCC patients. We explored the correlation between three cuproptosis subtypes and metabolism-related pathways. Besides, a comprehensive immune analysis of three cuproptosis subtypes was performed. Then, we calculated the cuproptosis-related gene prognostic index (CRGPI) score for predicting prognosis and validated its predictive capability by Decision curve analysis (DCA). We as well explored the benefit of ICI therapy of different CRGPI subgroups in two anti-PD1/PD-L1 therapy cohorts (IMvigor210 cohort and GSE176307). Finally, we performed the ridge regression algorithm to calculate the IC50 value for drug sensitivity and Gene set enrichment analysis (GSEA) analysis to explore the potential mechanism. We found that cluster A presented a higher expression of FDX1 and was correlated with metabolism, glycolysis, and TCA cycle pathways, compared with the other two clusters. HCC patients with high CRGPI scores had a worse OS probability, and we further found that the CRGPI-high group had high expression of PD1/PDL1, TMB, and better response (PR/CR) to immunotherapy in the IMvigor210 cohort and GSE176307. These findings highlight the importance of CRGPI serving as a potential biomarker for both prognostic and immunotherapy for HCC patients. Generally, our results provide novel insights about cuproptosis into immune therapeutic strategies.

“…A low EGR1 expression level in ccRCC predicts a poor prognosis ( 29 ). A previous study found that HCC patients with a high cuproptosis-related risk score had an increased infiltration of protumor immune components ( 14 ). However, no previous studies have linked FDX1 genes to immune cells in ccRCC.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the FDX1 gene is strongly linked to glucose, fatty acids, and amino acid metabolism ( 13 ). According to Zhen Zhang, HCC patients with high-FDX1 expression have a significantly longer survival time than HCC patients with low-FDX1 expression ( 14 ). However, the role of the FDX1 gene in ccRCC remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Cuproptosis-related gene FDX1 expression correlates with the prognosis and tumor immune microenvironment in clear cell renal cell carcinoma

Wang

et al. 2022

Front. Immunol.

BackgroundCuproptosis, a newly discovered form of cell death, is regulated by protein lipoylation and is related to mitochondrial metabolism. However, further research is needed to determine how the cuproptosis-related gene ferredoxin 1 (FDX1) affects the tumor immune response and its prognostic significance in clear cell renal cell carcinoma (ccRCC).MethodsThe Cancer Genome Atlas was used to screen for FDX1 gene expression in ccRCC and healthy tissue samples. The results were validated using the Gene Expression Omnibus and the Human Protein Atlas. Multivariable analysis and Kaplan-Meier survival curves were used to examine the relationship between FDX1 gene expression, clinicopathological parameters, and overall survival (OS). The protein network containing FDX1 gene interaction was constructed using the online Search Tool for the Retrieval of Interacting Genes/Proteins. The relationship between FDX1 gene expression and immune cell infiltration in ccRCC was examined using Gene Ontology, gene set enrichment analysis (GSEA), and a single-sample GSEA. Using the Gene Expression Profiling Interactive Analysis and Tumor Immune Estimation Resource databases, we investigated the relationship between FDX1 gene expression, the degree of immune cell infiltration, and the corresponding gene marker sets.ResultsccRCC samples had significantly (p < 0.05) lower FDX1 gene expression levels than normal tissue samples. Lower FDX1 gene expression levels were strongly associated with higher cancer grades and more advanced tumor–node–metastasis stages. The findings of multivariate and univariate analyses illustrated that the OS in ccRCC patients with low FDX1 expression is shorter than in patients with high FDX1 expression (p < 0.05). Ferredoxin reductase and CYP11A1 are key proteins interacting with the FDX1 gene, and ccRCC with an FDX1 enzyme defect was associated with a low number of invading immune cells and their corresponding marker.ConclusionIn ccRCC, decreased FDX1 expression was linked to disease progression, an unfavorable prognosis, and dysregulated immune cell infiltration.