Comprehensive Analysis of Ferroptosis-Related Markers for the Clinical and Biological Value in Gastric Cancer
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ABSTRACT:
SUBMITTER: Shao Y
PROVIDER: S-EPMC8566081 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveThis study aims to build a prognostic model of hepatocellular carcinoma (HCC) with ferroptosis-associated genes and explore their molecular function.MethodsGene expression data and clinical information were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and the International Cancer Genome Consortium (ICGC). A ferroptosis-associated gene set was obtained from the FerrDb database to identify differentially expressed genes. Then, we performed pathway enrichment analysis and immune infiltration analysis. A combined model based on ferroptosis-associated genes for predicting the overall survival of HCC was built by univariate and multivariate Cox regression analyses. Quantitative real-time polymerase chain reaction, Western blotting, colony formation, CCK-8, and EdU incorporation assays were performed to clarify the function of CAPG in the regulation of cell proliferation in human HCC. Ferroptosis was evaluated by glutathione (GSH), malondialdehyde (MDA), and total iron detection.ResultsForty-nine ferroptosis-related genes were significantly correlated with HCC, 19 of which had prognostic significance. CAPG, SLC7A11 and SQSTM1 were used to construct a novel risk model. The areas under the curves (AUCs) were 0.746 and 0.720 (1 year) in the training and validation groups, respectively. The survival analysis indicated that patients with high risk scores exhibited worse survival in the training and validation groups. The risk score was also identified as an independent prognostic factor of overall survival (OS), which established and validated the predictive abilities of the nomogram. The risk score was also significantly correlated with the expression of immune checkpoint genes. In vitro data showed that CAPG knockdown dramatically suppressed HCC cell proliferation, and the underlying molecular mechanisms might be that the silencing of CAPG reduced the expression of SLC7A11 and promoted ferroptosis.ConclusionThe established risk model can be used to predict the prognosis of HCC. At the mechanistic level, CAPG may drive HCC progression by regulating SLC7A11, and ferroptosis activation in HCC patients with high CAPG expression may serve as a potential therapeutic strategy.
| S-EPMC10192498 | biostudies-literature
Project description:Background: Every year, nearly 170,000 people die from bladder cancer worldwide. A major problem after transurethral resection of bladder tumor is that 40-80% of the tumors recur. Ferroptosis is a type of regulatory necrosis mediated by iron-catalyzed, excessive oxidation of polyunsaturated fatty acids. Increasing the sensitivity of tumor cells to ferroptosis is a potential treatment option for cancer. Establishing a diagnostic and prognostic model based on ferroptosis-related genes may provide guidance for the precise treatment of bladder cancer. Methods: We downloaded mRNA data in Bladder Cancer from The Cancer Genome Atlas and analyzed differentially expressed genes based on and extract ferroptosis-related genes. We identified relevant pathways and annotate the functions of ferroptosis-related DEGs using Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and Gene Ontology functions. On the website of Search Tool for Retrieving Interacting Genes database (STRING), we downloaded the protein-protein interactions of DEGs, which were drawn by the Cytoscape software. Then the Cox regression analysis were performed so that the prognostic value of ferroptosis-related genes and survival time are combined to identify survival- and ferroptosis-related genes and establish a prognostic formula. Survival analysis and receiver operating characteristic curvevalidation were then performed. Risk curves and nomograms were generated for both groups to predict survival. Finally, RT-qPCR was applied to analyze gene expression. Results: Eight ferroptosis-related genes with prognostic value (ISCU, NFE2L2, MAFG, ZEB1, VDAC2, TXNIP, SCD, and JDP2) were identified. With clinical data, we established a prognostic model to provide promising diagnostic and prognostic information of bladder cancer based on the eight ferroptosis-related genes. RT-qPCR revealed the genes that were differentially expressed between normal and cancer tissues. Conclusion: This study found that the ferroptosis-related genes is associated with bladder cancer, which may serve as new target for the treatment of bladder cancer.
| S-EPMC8635965 | biostudies-literature
Project description:Background Ferroptosis is an iron-dependent mode of cell death that could be induced by erastin and exert antitumor effects. However, the clinical and biological roles of ferroptosis-related gene (FRG) signature and the therapeutic value of erastin in multiple myeloma (MM) remained unknown. Methods Clinical and gene expression data of MM subjects were extracted from the Gene Expression Omnibus (GEO) public database. Univariable cox analysis was applied to determine FRGs related to survival and the least absolute shrinkage and selection operator (LASSO) regression analysis was used to develop a prognostic model. Prediction accuracy of the model was estimated by receiver operating characteristic (ROC) curves. Functional pathway enrichments and infiltrating immune status were also analyzed. We conducted in vitro experiments to investigate the combination therapy of erastin and doxorubicin. Results 17 FRGs were strongly associated with patient survival and 11 genes were identified to construct the prognostic model. ROC curves indicated great predictive sensitivity and specificity of the model in all cohorts. Patients were divided into low- and high-risk groups by median risk score in each cohort and the survival of the low-risk group was significantly superior than that of the high-risk group. We also observed a close relevance between functional pathways and immune infiltration with risk scores. Moreover, we combined erastin and doxorubicin in our in vitro experiments and found synergetic antitumor effects of the two agents, and the underlying mechanism is the overgeneration of intracellular Reactive Oxygen Species (ROS). Conclusions We demonstrated the important value of ferroptosis in patient prognosis and as a potential antitumor target for MM. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02742-4.
| S-EPMC9588243 | biostudies-literature
Project description:Bladder cancer (BC), as a genitourinary system tumor, is a highly prevalent tumor type. Ferroptosis is an iron-dependent oxidative cell death mechanism that is becoming increasingly recognized as a promising avenue for cancer therapy. However, further determination of the prospective prognostic value of ferroptosis for BC and investigation of the underlying mechanisms is required. The mRNA expression profiles and associated clinical data were downloaded from public databases such as The Cancer Genome Atlas, Gene Expression Omnibus and the IMvigor210 database. To construct a predictive formula, the least absolute shrinkage and selection operator Cox regression algorithm was used. In addition, a prognostic multigene signature was constructed using previously selected ferroptosis-related genes (FRGs). A total of 28 FRGs were differentially expressed between tumor and normal samples with |log2 fold change| >1 and adjusted P<0.05. A prognostic model was then established and it was validated in the GEO cohort using six genes: Glutamate-cysteine ligase modifier subunit, crystallin α-B, transferrin receptor, zinc finger E-box binding homeobox 1, squalene epoxidase and glucose-6-phosphate dehydrogenase (G6PD). Numerous important pathways involved in the development of the immune system and cancer were indicated to be significantly different between the two risk groups. In addition, it was discovered that G6PD expression subgroups that were associated with immunotherapy response in patients with BC had similar prognostic features to risk score subgroups. In the present study, a gene signature with a prognostic value for ferroptosis in BC was successfully developed and the potential value of G6PD was identified for future research.
| S-EPMC9353228 | biostudies-literature
Project description:SLC2A3 is a ferroptosis marker engaged in transmembrane glucose transport. However, the effect of SLC2A3 on the prognosis of patients with cancer remains unclear. This study aimed to explore the prognostic implications of SLC2A3 and its underlying immune mechanisms in gastric cancer. The mRNA expression profiles and corresponding clinical data of patients with gastric cancer were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Differentially expressed genes related to SLC2A3 were identified using the R package "limma." Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, gene set enrichment analysis, and gene set variation analysis were used to explore the underlying mechanisms. The protein-protein and miRNA interaction networks were analyzed using Cytoscape software. Immune cell infiltration was assessed using single-sample gene set enrichment analysis. Univariate and multivariate Cox regression analyses revealed the relationship between SLC2A3 expression and prognosis. SLC2A3 was found to be highly expressed in tumor tissues and was associated with an unfavorable prognosis in patients with gastric cancer. Functional enrichment analysis showed that SLC2A3 is related to cytokine-cytokine receptor interaction, epithelial-mesenchymal transition, T cell receptor signaling pathway, B cell receptor signaling pathway, and immune checkpoints. SLC2A3 is also involved in immune response regulation and is regulated by multiple miRNAs, including miR-195-5p, miR-106a-5p, miR-424-5p, and miR-16-5p. Univariate and multivariate Cox regression analyses indicated that SLC2A3 can be used as an independent prognostic factor for predicting the outcome in patients with gastric cancer. SLC2A3 and related miRNAs are potential prognostic biomarkers and therapeutic targets.
| S-EPMC9358142 | biostudies-literature
Project description:Objective: Ferroptosis is a type of iron-dependent necrosis related to cancer. Nevertheless, the features of ferroptosis in gastric cancer (GC) remain poorly understood. This study conducted a systematic analysis of ferroptosis regulators in GC. Methods: We gathered five GC cohorts, namely, TCGA-STAD, GSE84437, GSE62254, GSE26901, and GSE15459. Unsupervised clustering analysis was adopted to cluster GC patients into different ferroptosis subtypes based on ferroptosis regulators. Immune cell infiltration and hallmark pathway activity were estimated via ssGSEA. The ferroptosis index was developed with the PCA computational method. Response to chemotherapy agents and small molecular compounds was inferred via GDSC, CTRP, and PRISM projects. Two anti-PD-1 therapy cohorts were gathered and the potential of FPI in predicting immune response was assessed. Results: Expression profiles, genetic mutations, DNA methylation, prognostic implications, and drug sensitivity of ferroptosis regulators were characterized in GC. Three ferroptosis subtypes were clustered with distinct prognosis, hallmark pathway activity, and tumor-infiltrating immune cells. Ferroptosis levels were quantified based on the expression of prognostic ferroptosis-related signatures. The significant relationships between FPI and clinicopathological characteristics were observed. Furthermore, high FPI was in relation to poor prognosis, inflamed tumor microenvironment (TME) as well as high sensitivity to chemotherapy agents (docetaxel and cisplatin), and CTRP- and PRISM-derived compounds. Also, FPI acted as a promising predictor of immune response. Conclusion: Collectively, our findings identified a novel ferroptosis-based subtype classification of GC, and revealed the potential of ferroptosis in forming TME diversity and complexity, and guiding individualized treatment.
| S-EPMC9315307 | biostudies-literature
Project description:BACKGROUND AND OBJECTIVE: The prognosis varied among the patients with the same stage, therefore there was a need for new prognostic and predictive factors. The aim of this study was to evaluate the relationship of apoptosis-related biological markers such as p53, bcl-2, bax, and c-myc, and clinicopathological features and their prognostic value. METHODS: From 1996 to 2007, 4426 patients had undergone curative D2 gastrectomy for gastric cancer at Fudan University Shanghai Cancer Center. Among 501 patients, the expression levels of p53, bcl-2, bax, and c-myc were examined by immunohistochemistry. The prognostic value of biological markers and the correlation between biological markers and other clinicopathological factors were investigated. RESULTS: There were 339 males and 162 females with a mean age of 57. The percentages of positive expression of p53, bcl-2, bax, and c-myc were 65%, 22%, 43%, and 58%, respectively. There was a strong correlation between p53, bax, and c-myc expression (P=0.00). There was significant association between bcl-2, and bax expression (P<0.05). p53 expression correlated with histological grade (P=0.01); bcl-2 expression with pathological stage (P=0.00); bax expression with male (P=0.02), histological grade (P=0.01), Borrmann type (P=0.01), tumor location (P=0.00), lymph node metastasis (P=0.03), and pathological stage (P=0.03); c-myc expression with Borrmann type (P=0.00). bcl-2 expression was related with good survival in univariate analysis (P=0.01). Multivariate analysis showed that bcl-2 expression and pathological stage were defined as independent prognostic factors. There were significant differences of overall 5-year survival rates according to bcl-2 expression or not in stage IIB (P=0.03). CONCLUSION: The expression of bcl-2 was an independent prognostic factor for patients with gastric cancer; it might be a candidate for the gastric cancer staging system.
| S-EPMC3247293 | biostudies-literature
Project description:BackgroundThe transcription factor Spi-1 proto-oncogene (SPI1, also known as PU.1) is a key regulator of signal communication in the immune system and is essential for the development of myeloid cells and lymphocytes. However, the potential role of SPI1 in gastric cancer (GC) and the correlations between SPI1 and immune infiltration remain unclear.MethodsIn the present study, multiple databases including ONCOMINE, TIMER, Kaplan-Meier Plotter, and The Cancer Genome Atlas were used to explore the expression levels and prognostic value of SPI1 in GC. cBioPortal was used to explore the possible reasons for the increased expression of SPI1 in GC. The correlations between SPI1 expression and tumor-infiltrating immune cells (TICs) were analyzed using CIBERSORT and TIMER. Gene set enrichment analysis was used to determine the biological function of SPI1 in the development of GC. In addition, a risk signature based on SPI1-related immunomodulators was constructed to accurately evaluate the prognosis of patients with GC. The upregulation of SPI1 expression in GC was further confirmed through immunohistochemistry, western blotting, and real-time quantitative PCR (RT-qPCR) assay.ResultsThe expression of SPI1 was increased significantly in GC according to multiple databases, and high expression of SPI1 was related to poor prognosis and progression of GC. The main factor influencing the high expression of SPI1 mRNA in GC may be diploidy, not DNA methylation. Moreover, immunohistochemistry, western blotting, and RT-qPCR assays also confirmed the upregulated expression of SPI1 in GC. CIBERSORT analysis revealed that SPI1 expression was correlated with seven types of TICs (naive B cells, resting memory CD4 T cells, activated memory CD4 T cells, activated natural killer cells, resting natural killer cells, M2 macrophages, and resting dendritic cells). Gene set enrichment analysis indicated that SPI1 might be related to immune activation in GC and participate in cell cycle regulation. In addition, based on SPI1-related immunomodulators, we developed multiple-gene risk prediction signatures and constructed a nomogram that can independently predict the clinical outcome of GC.ConclusionThe results of the present study suggest that SPI1 has a critical role in determining the prognosis of GC patients and may be a potential immunotherapeutic target.
| S-EPMC8882873 | biostudies-literature
Project description:BackgroundSolute carrier family 38 member 2 (SLC38A2) has previously been reported to participate in carcinogenesis. However, its expression and function in gastric cancer (GC) remain unclear. The present study aimed to investigate the role of SLC38A2 in GC.MethodsThe prognostic value and expression of SLC38A2 in GC was analyzed by combining bioinformatics and experimental analyses. Colony formation, Cell Counting Kit-8, wound healing, Transwell and tumor formation assays were performed to assess the biological function of SLC38A2. The cBioPortal, GeneMANIA and LinkedOmics databases were mined to determine the underlying regulatory mechanisms of SLC38A2. The role of SLC38A2 in tumor immune infiltration was explored using the TIMER database.ResultsOur results demonstrated that SLC38A2 was upregulated and was correlated with a poor prognosis in GC patients. SLC38A2 downregulation significantly inhibited the proliferation, invasion and migration of GC cells. Abnormal genetic alteration and epigenetic regulation may contribute to the upregulation of SLC38A2 expression levels in GC. The results of enrichment analysis demonstrated that SLC38A2 was associated with 'hippo signaling' and 'ubiquitinyl hydrolase activity'. The results also indicated that SLC38A2 may be a key factor in GC immune infiltration and M2 macrophage polarization.ConclusionOverall, these data identified that SLC38A2 may serve as a potential prognostic biomarker and therapeutic target in GC.
| S-EPMC10015769 | biostudies-literature
Project description:The early diagnosis of ovarian cancer (OC) is critical to improve the prognosis and prevent recurrence of patients. Nevertheless, there is still a lack of factors which can accurately predict it. In this study, we focused on the interaction of immune infiltration and ferroptosis and selected the ESTIMATE algorithm and 15 ferroptosis-related genes (FRGs) to construct a novel E-FRG scoring model for predicting overall survival of OC patients. The gene expression and corresponding clinical characteristics were obtained from the TCGA dataset (n = 375), GSE18520 (n = 53), and GSE32062 (n = 260). A total of 15 FRGs derived from FerrDb with the immune score and stromal score were identified in the prognostic model by using least absolute shrinkage and selection operator (LASSO)-penalized COX regression analysis. The Kaplan-Meier survival analysis and time-dependent ROC curves performed a powerful prognostic ability of the E-FRG model via multi-validation. Gene Set Enrichment Analysis and Gene Set Variation Analysis elucidate multiple potential pathways between the high and low E-FRG score group. Finally, the proteins of different genes in the model were verified in drug-resistant and non-drug-resistant tumor tissues. The results of this research provide new prospects in the role of immune infiltration and ferroptosis as a helpful tool to predict the outcome of OC patients.
| S-EPMC8634641 | biostudies-literature