Clinical Significance of Disulfidptosis-related Genes and Functional Analysis in Gastric Cancer
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SUBMITTER: Yan J
PROVIDER: S-EPMC10788733 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Disulfidptosis is a newfound programmed cell death (PCD) mode characterized by disulfide stress. Nevertheless, the characteristics and functional significance of disulfidptosis-related genes in head and neck squamous cell carcinoma (HNSCC) are still largely unknown. In this study, several computer-aided bioinformatic analyses were performed. The Nonnegative Matrix Factorization (NMF) method classified The Cancer Genome Atlas (TCGA) patients into two clusters according to the expression of disulfidptosis-related genes. The relative compositions of cells in the tumor microenvironment (TME), mutant landscape, lasso regression analysis, and predicted clinical outcome were performed by analyzing bulk RNA-sequencing data. Besides, single-cell sequencing data (scRNA) was analyzed by Seurat, CopyKAT, and monocle2 to reveal the expression characteristics of disulfidptosis-related genes. Moreover, the spatial distribution characteristics of each cell subgroup in the section and the functional significance of cancer-associated fibroblasts (CAFs) were elucidated by STUtility, SpaCET, and SPATA2. Here, two clusters with different expression characteristics of disulfidptosis-related genes were identified. Cluster 1 (C1) patients had a worse prognosis and a higher proportion of stromal cells but lower effector T cell infiltration than cluster 2 (C2). A novel prognostic model was established and verified in our patient cohort. Additionally, diploid and inflammatory CAFs (iCAFs) showed higher disulfidptosis-related gene expression levels. Furthermore, the CCNC and CHMP1B expressions significantly changed following CAFs differentiation. Disulfidptosis-related genes exhibited extensive and differential spatial expression on tissue sections. Collectively, our study may contribute to revealing the function of disulfidptosis, and improve the expansion of knowledge of crosstalk between cancer cells and CAFs.
| S-EPMC11615178 | biostudies-literature
Project description:ObjectiveDisulfidptosis is a newly identified type of nonapoptotic programmed cell death related to mechanisms such as ferroptosis, cuproptosis, pyroptosis, and necrotic apoptosis. This study explores the role of disulfidptosis-related long non-coding RNAs (DRLs) in gastric cancer and their potential as prognostic biomarkers.MethodWe developed a prognostic model using DRL scores to classify patients based on disulfidptosis activity. We evaluated these scores for correlations with drug sensitivity, tumor microenvironment (TME) features, tumor mutational burden (TMB), and prognosis. Potential disulfidptosis-related signaling pathways were screened, identifying FRMD6-AS as a promising therapeutic target. FRMD6-AS expression was further validated using real-time fluorescent quantitative PCR (qRT-PCR).ResultsThe DRL-based prognostic model, established through univariate and multivariate Cox regression and LASSO regression analyses, outperformed traditional models in predicting prognosis. We divided samples into high-risk and low-risk groups based on DRL scores, finding that the low-risk group had a significantly higher survival rate (P < 0.05). A high-precision prediction model incorporating DRL scores, age, sex, grade, and stage showed strong predictive value and consistency with actual outcomes. High DRL scores correlated with higher TME scores and lower TMB. Key signaling axes identified were AC129507.1/(FLNA, TLN1)/FOCAL ADHESION and AC107021.2/MYH10/(TIGHT JUNCTION, VIRAL MYOCARDITIS, REGULATION OF ACTIN CYTOSKELETON). Potentially effective drugs, including BMS-754807, dabrafenib, and JQ1, were identified. FRMD6-AS emerged as a potential target for gastric cancer treatment.ConclusionsThis study developed a novel prognostic model for gastric cancer using DRLs, identifying two key signaling axes related to prognosis. JQ1 may be an effective treatment, and FRMD6-AS could be a promising therapeutic target.
| S-EPMC11913695 | biostudies-literature
Project description:BackgroundGastric cancer (GC) remains a malignant tumor with high morbidity and mortality, accounting for approximately 1,080,000 diagnosed cases and 770,000 deaths worldwide annually. Disulfidptosis, characterized by the stress-induced abnormal accumulation of disulfide, is a recently identified form of programmed cell death. Substantial studies have demonstrated the significant influence of immune clearance on tumor progression. Therefore, we aimed to explore the intrinsic correlations between disulfidptosis and immune-related genes (IRGs) in GC, as well as the potential value of disulfidptosis-related immune genes (DRIGs) as biomarkers.MethodsThis study incorporated the single-cell RNA sequencing (scRNA-seq) dataset GSE183904 and transcriptome RNA sequencing of GC from the TCGA database. Disulfidptosis-related genes (DRGs) and IRGs were derived from the representative literature on both cell disulfidptosis and immunity. The expression and distribution of DRGs were investigated at the single-cell level in different GC cell types. Pearson correlation analysis was used to identify the IRGs closely related to disulfidptosis. The prognostic signature of DRIGs was established using Cox and LASSO analyses. We then analyzed and evaluated the differences in long-term prognosis, Gene Set Enrichment Analysis (GSEA), immune infiltration, mutation profile, CD274 expression, and response to chemotherapeutic drugs between the two groups. A tissue array containing 63 paired GC specimens was used to verify the expression of 4 DRIGs and disulfidptosis regulator SLC7A11 through immunohistochemistry staining.ResultsThe scRNA-seq analysis found that SLC7A11, SLC3A2, RPN1 and NCKAP1 were enriched in specific cell types and closely related to immune infiltration. Four DIRGs (GLA, HIF-1α, VPS35 and CDC37) were successfully identified to establish a signature to potently predict the survival time of GC patients. Patients with high risk scores generally experienced worse prognoses and exhibited greater resistant to classical chemotherapy drugs. Furthermore, the expression of GLA, HIF-1α, VPS35, CDC37 and SLC7A11 were elevated in GC tissues. A high expression of GLA, HIF-1α, VPS35 or CDC37 was associated with more advanced clinical stage of GC and increased SLC7A11 expression.ConclusionCurrent study first highlights the potential value of DRIGs as biomarkers in GC. We successfully constructed a robust model incorporating four DRIGs to accurately predict the survival time and clinicopathological characteristics of GC patients.
| S-EPMC10962090 | biostudies-literature
Project description:Recent studies have found that disulfidptosis occurs in cells under glucose starvation. The role of this programmed death method in gastric cancer remains to be explored. Cluster analysis based on disulfidptosis related genes to analyze the differential characteristics of disulfidptosis subtypes. We construct a prognostic risk model using 12 differentially expressed genes of disulfidptosis subtypes. We also analyzed the disulfidptosis subtypes at single-cell resolution. We found that cluster 1 has a poor prognosis and is characterized by a younger age. Inhibiting the expression of GAMT genes associated with disulfidptosis subtypes can significantly inhibit the proliferation of gastric cancer cells, which may be an important target for gastric cancer treatment. Cluster 2 patients are more sensitive to various chemotherapy drugs and immunotherapy. Mesenchymal cells, especially myCAF, endothelial cells, and smooth muscle cells, have strong disulfidptosis scores. In summary, our study provides new insights into the role of disulfidptosis in gastric cancer, and this may be used to guide the treatment of gastric cancer.
| S-EPMC11697009 | biostudies-literature
Project description:Ulcerative colitis (UC) is a chronic inflammatory condition of the intestinal tract. Various programmed cell death pathways in the intestinal mucosa are crucial to the pathogenesis of UC. Disulfidptosis, a recently identified form of programmed cell death, has not been extensively reported in the context of UC. This study evaluated the expression of disulfidptosis-related genes (DRGs) in UC through public databases and assessed disulfide accumulation in the intestinal mucosal tissues of UC patients and dextran sulfate sodium (DSS)-induced colitis mice via targeted metabolomics. We utilized various bioinformatics techniques to identify UC-specific disulfidptosis signature genes, analyze their potential functions, and investigate their association with immune cell infiltration in UC. The mRNA and protein expression levels of these signature genes were confirmed in the intestinal mucosa of DSS-induced colitis mice and UC patients. A total of 24 DRGs showed differential expression in UC. Our findings underscore the role of disulfide stress in UC. Four UC-related disulfidptosis signature genes-SLC7A11, LRPPRC, NDUFS1, and CD2AP-were identified. Their relationships with immune infiltration in UC were analyzed using CIBERSORT, and their expression levels were validated by quantitative real-time PCR and western blotting. This study provides further insights into their potential functions and explores their links to immune infiltration in UC. In summary, disulfidptosis, as a type of programmed cell death, may significantly influence the pathogenesis of UC by modulating the homeostasis of the intestinal mucosal barrier.
| S-EPMC11231342 | biostudies-literature
Project description:Disulfidptosis was recently reported to be caused by abnormal disulfide accumulation in cells with high SLC7A11 levels subjected to glucose starvation, suggesting that targeting disulfidptosis was a potential strategy for cancer treatment. We analyzed the relationships between gene expression and mutations and prognoses of patients. In addition, the correlation between gene expression and immune cell infiltration was explored. The potential regulatory mechanisms of these genes were assessed by investigating their related signaling pathways involved in cancer, their expression patterns, and their cellular localization. Most cancer types showed a negative correlation between the gene-set variation analysis (GSVA) scores and infiltration of B cells and neutrophils, and a positive correlation between GSVA scores and infiltration of natural killer T and induced regulatory T cells. Single-cell analysis revealed that ACTB, DSTN, and MYL6 were highly expressed in different bladder urothelial carcinoma subtypes, but MYH10 showed a low expression. Immunofluorescence staining showed that actin cytoskeleton proteins were mainly localized in the actin filaments and plasma membrane. Notably, IQGAP1 was localized in the cell junctions. In conclusion, this study provided an overview of disulfidptosis-related actin cytoskeleton genes in pan-cancer. These genes were associated with the survival of patients and might be involved in cancer-related pathways.
| S-EPMC10997004 | biostudies-literature
Project description:Gastric cancer (GC) is the fourth most common cancer type. "Disulfidptosis," a distinct form of cell death, is initiated through aberrant intracellular disulfide metabolism. Here, we identified various GC subtypes based on disulfidptosis-related genes (DRGs) and constructed a risk score model to identify relevant genes to help predict patient prognosis and guide treatment. We downloaded RNA sequencing (RNA-seq) data from the TCGA-STAD database, performed a difference analysis, and combined the data with GSE84437 to successfully perform an unsupervised clustering analysis based on DRGs and differentially expressed genes (DEGs). Risk-scoring models were established by screening prognosis-related DEGs. The GC samples were segregated into high-risk (HR) and low-risk (LR) groups according to their risk scores. We then evaluated the genes screened with the model in terms of prognosis, tumor, and immune cell infiltration. The response of patients with GC to immunological therapy was assessed using tumor mutational burden, microsatellite instability, and tumor immune dysfunction and exclusion scores. Using unsupervised cluster analysis, we identified two DRG clusters and two gene clusters that differed in prognosis and tumor microenvironment. A six-gene model was developed for risk score assessment. The LR group demonstrated superior performance compared to the HR group in terms of immunity, exhibiting greater sensitivity to immunotherapy. Thereafter, we selected the model gene GPC3 for single-gene analysis and verified it by experimental validation. The results demonstrated that GPC3 can serve as a standalone biomarker with promising clinical applicability in the prognostic prediction and clinical management of GC.
| S-EPMC11655940 | biostudies-literature
Project description:Sepsis represents a critical condition characterized by multiple-organ dysfunction resulting from inflammatory response to infection. Disulfidptosis is a newly identified type of programmed cell death that is intimately associated with the actin cytoskeleton collapse caused by glucose starvation and disulfide stress, but its role in sepsis is largely unknown. The study was to adopt a diagnostic and prognostic signature for sepsis with disulfidptosis based on the differentially expressed genes (DEGs) between sepsis and healthy people from GEO database. The disulfidptosis hub genes associated with sepsis were identified, and then developed consensus clustering and immune infiltration characteristics. Next, we evaluated disulfidptosis-related risk genes by using LASSO and Random Forest algorithms, and constructed the diagnostic sepsis model by nomogram. Finally, immune infiltration, GSVA analysis and mRNA-miRNA networks based on disulfidptosis-related DEGs were screened. There are five upregulated disulfidptosis-related genes and seven downregulated genes were filtered out. The six intersection disulfidptosis-related genes including LRPPRC, SLC7A11, GLUT, MYH9, NUBPL and GYS1 exhibited higher predictive ability for sepsis with an accuracy of 99.7%. In addition, the expression patterns of the critical genes were validated. The study provided a comprehensive view of disulfidptosis-based signatures to predict the prognosis, biological features and potential treatment directions for sepsis.
| S-EPMC11472650 | biostudies-literature
Project description:BackgroundGastric cancer (GC) is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide. Neutrophil extracellular traps (NETs) can enhance the invasion of GC cells and are associated with poor prognosis in patients. However, its mechanism of action is not completely understood.MethodsThe content of NETs in the peripheral blood of patients with GC was detected by enzyme-linked immunosorbent assay. GC AGS cells were treated with or without NETs for 24 h. High-throughput RNA sequencing was performed to screen differentially expressed long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs). Real-time polymerase chain reaction (PCR) was used to verify gene expression. A competing endogenous RNA (ceRNA) regulatory network was constructed. Modules were screened using the molecular complex detection (MCODE) plug-in. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed using the genes in the network. The role and clinical significance of the lncRNA NEAT1-related signaling pathway were validated.ResultsThe content of NETs in the patients with GC was significantly higher than that in healthy controls and was also higher in patients with high-grade (stages III and IV) GC. NETs promoted the invasion of AGS cells. A total of 1,340 lncRNAs, 315 miRNAs, and 1,083 mRNAs were differentially expressed after NET treatment. The expression of five genes was validated using real-time PCR, which were in accordance with the RNA sequencing results. A ceRNA regulatory network was constructed with 1,239 lncRNAs, 310 miRNAs, and 1,009 mRNAs. Four genes (RAB3B, EPB41L4B, ABCB11, and CCDC88A) in the ceRNA network were associated with patient prognosis, with RAB3B being the most prominent and with signaling among the lncRNA NEAT1, the miRNA miR-3158-5p, and RAB3B. NEAT1 was upregulated in AGS cells after NET treatment. RNA interference of NEAT1 inhibited the invasion of AGS cells induced by NETs, inhibited miR-3158-5p expression, and promoted RAB3B expression. NEAT1 and RAB3B expression were positively correlated in patients with GC. Furthermore, RAB3B was upregulated and miR-3158-5p was downregulated in GC tissues compared with adjacent normal tissues, which was also associated with cancer stage.ConclusionThis study provides a comprehensive analysis of differentially expressed genes in NET-treated GC cells and validated the clinical significance of NEAT1-related signaling.
| S-EPMC9160368 | biostudies-literature
Project description:Disulfidptosis is a novel programmed cell death mode that has been reported to play a role in oncogenesis. Increasing evidences suggest that the long non-coding RNAs (lncRNAs) play crucial roles in the initiation and progression of bladder cancer (BLCA). However, the role and prognostic value of disulfidptosis-related lncRNAs in BLCA remain unknown.The aim of this study was to construct and validate a disulfidptosis-related lncRNA risk model for predicting the prognosis of BLCA patients. A risk model consisting of 5 disulfidptosis-related lncRNAs was developed to predict the prognosis of BLCA patients. The overall survival (OS) of BLCA patients in the high-risk group was significantly shorter than that in the low-risk group (P < 0.05). The effectiveness of this model was validated using the receiver operating characteristic (ROC) curve analysis, and this model proved superior in prognostic accuracy compared with other clinical features. Furthermore, the tumor immune dysfunction and exclusion (TIDE) score in the high-risk group was significantly higher than that in the low-risk group, suggesting that the high-risk group had a less favorable response to immunotherapy. Simultaneously, patients in the low-risk group exhibited significantly higher sensitivity to CTLA-4 monoclonal antibody therapy compared to those in the high-risk group, suggesting potential benefits of immunotherapy for patients in the low-risk group. The combination of high risk and low tumor mutational burden (TMB) could further shortened the OS of BLCA patients. Lastly, the drug sensitivity analysis revealed that the BLCA cells in the high-risk group showed an increased sensitivity to cisplatin, sunitinib, cetuximab, axitinib, docetaxel, saracatinib, vinblastine and pazopanib compared with those in the low-risk group. According to the Quantitative real time PCR results, we found that five lncRNAs of the risk model were more highly expressed in BCa cell lines than human immortalized uroepithelial cell line. The disulfidptosis-related lncRNA risk model has a valuable effect in assessing the prognosis of BLCA patients.
| S-EPMC11538480 | biostudies-literature