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A Newly Established Cuproptosis-Associated Long Non-Coding RNA Signature for Predicting Prognosis and Indicating Immune Microenvironment Features in Soft Tissue Sarcoma

ABSTRACT: Cuproptosis, a new type of programmed cell death, is involved in the development and progression of malignancies. The study of cuproptosis-associated long non-coding RNAs (lncRNAs) in soft tissue sarcomas (STSs) is however limited. There is also uncertainty regarding the prognostic accuracy of cuproptosis-associated lncRNAs in STSs and their relationship to the tumor immune microenvironment. The aim of this study was to determine the prognostic significance of cuprotosis-associated lncRNAs in STSs and their relationship to the tumor immune microenvironment. Transcriptomic and clinical data from patients with STSs were obtained through The Cancer Genome Atlas (TCGA). Overall, 259 patients were randomly allocated to a training group or a testing group. In the training group, a cuproptosis-associated lncRNA signature was constructed, and the signature was verified in the testing group. On the basis of risk scores and clinical features, we later developed a hybrid nomogram. We also performed functional and tumor immune microenvironment analysis based on the cuproptosis-associated lncRNA signature. A signature of 5 cuproptosis-associated lncRNAs was created. Based on this signature, we categorized STS patients into high-risk and low-risk groups. The study showed that patients at high risk had a worse prognosis than those at low risk. A nomogram was then constructed combining clinical characteristics with the risk scores, and it was shown to have credible predictive power. Functional enrichment and tumor immune microenvironmental analyses showed that high-risk STSs tend to be immunologically sensitive tumors. In our study, we found a cuproptosis-associated lncRNAs signature, which serves as an independent prognostic indicator. Cuproptosis-associated lncRNAs may play a role in the tumor immune microenvironment, which might be a therapeutic target for patients with STSs.

SUBMITTER: Han J

PROVIDER: S-EPMC9279026 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCuproptosis or copper-dependent cell death is a newly identified non-apoptotic cell death pathway which plays a critical role in the development of multiple cancers. Long non-coding RNAs (lncRNAs) are increasingly recognized as crucial regulators of programmed cell death and lung adenocarcinoma (LUAD) development, and a comprehensive understanding of cuproptosis-related lncRNAs may improve prognosis prediction of LUAD. However, few studies have explored the association of cuproptosis-related lncRNAs with the prognosis of LUAD.MethodsThe RNA sequencing data and corresponding clinical information of patients were extracted from The Cancer Genome Atlas (TCGA) database. Five hundred LUAD patients were randomly divided into a training (n=250) and a testing cohort (n=250). Pearson correlations were performed to identify cuproptosis-related lncRNAs, and univariate Cox regression was performed to screen prognostic lncRNAs. A cuproptosis-related lncRNAs prognostic signature (CLPS) was constructed by the least absolute shrinkage and selection operator Cox regression. Kaplan-Meier analysis, receiver operating characteristic curves, and multivariate Cox regression were performed to verify the prognostic performance of CLPS. Additionally, immune cell infiltration was estimated using the single-sample gene-set enrichment analysis. pRRophetic algorithm and Tumor Immune Dysfunction and Exclusion algorithm were used to assess the immunotherapy and chemotherapy response, respectively.ResultsCLPS was established based on 61 cuproptosis-related prognostic lncRNAs and exhibited a satisfactory performance predicting LUAD patients' survival (area under the curve at 1, 3, 5 years was 0.784, 0.749, 0.775, respectively). multivariate Cox analysis confirmed the independent prognostic effect of CLPS (hazard ratio: 1.128; 95% confidence interval: 1.071-1.189; P<0.001), and a nomogram containing it exhibited robust validity in prognostic prediction. We further demonstrated a higher CLPS-risk score was associated with lower levels of signatures including immune cell infiltration, immune activation, and immune checkpoints.ConclusionsThe CLPS serves as an effective predictor for the prognosis and therapeutic responses of LUAD patients. Our findings provide promising novel biomarkers and therapeutic targets for LUAD.

Project description:BackgroundGastric cancer (GC) is one of the most common malignancies. Cuproptosis is a newly discovered type of cell death caused by protein toxicity stress, with copper having considerable importance in GC development.MethodsFirst, differentially expressed (DE) cuproptosis-related genes (CRGs) were screened in GC. The tumor mutation burden (TMB) of CRGs was analyzed. We then performed enrichment analyses of DE-CRGs. Next, we constructed a GC cuproptosis-related (CR) signature (CRs) using Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. The predictive efficacy was assessed using receiver operating characteristic (ROC) curves. Furthermore, we performed gene set enrichment analysis (GSEA). Different methods were used to assess tumor immunity of the CRs, and the Wilcoxon test was used to examine the expressions of m6A-, m7G-, and ferroptosis-related genes. The "pRRophetic" R package (The R Foundation for Statistical Computing) was used to predict the half maximal inhibitory concentration IC50 of common chemotherapeutic agents. Finally, the expression of CRGs in different clusters was analyzed using single-cell RNA sequencing (scRNA-seq).ResultsWe identified 8 DE-CRGs in GC. There were 9 CRGs with TMB values >1%. We constructed gene expression networks and CRs for GC. The DE-CRGs were involved in important mitochondrial metabolic pathways, and the CRs was a valuable independent prognosis factor. The GSEA revealed that angiogenesis and metabolic-related pathways were enriched in the high-risk group, whereas the low-risk group showed enrichment in DNA replication mismatch and repair pathways. The expressions of immunological checkpoints, ferroptosis-, m6A-, and m7G-related genes, type II interferon (INF) response, major histocompatibility complex (MHC class-I), and the IC50 of the copper-based carrier drug elesclomol were significantly different between the 2 groups of the CRs. Furthermore, the scRNA-seq analysis showed that most CRGs were mainly upregulated in endothelial cells.ConclusionsThe novel CRs could predict the prognosis of GC.

Project description:Breast cancer (BC) is the most diagnosed cancer in women. Cuproptosis is new regulated cell death, distinct from known death mechanisms and dependent on copper and mitochondrial respiration. However, the comprehensive relationship between cuproptosis and BC is still blank until now. In the present study, we acquired 13 cuproptosis-related regulators (CRRs) from the previous research and downloaded the RNA sequencing data of TCGA-BRCA from the UCSC XENA database. The 13 CRRs were all differently expressed between BC and normal samples. Using consensus clustering based on the five prognostic CRRs, BC patients were classified into two cuproptosis-clusters (C1 and C2). C2 had a significant survival advantage and higher immune infiltration levels than C1. According to the Cox and LASSO regression analyses, a novel cuproptosis-related prognostic signature was developed to predict the prognosis of BC effectively. The high- and low-risk groups were divided based on the risk scores. Kaplan-Meier survival analysis indicated that the high-risk group had shorter overall survival (OS) than the low-risk group in the training, test and entire cohorts. GSEA indicated that the immune-related pathways were significantly enriched in the low-risk group. According to the CIBERSORT and ESTIMATE analyses, patients in the high-risk group had higher infiltrating levels of antitumor lymphocyte cell subpopulations and higher immune score than the low-risk group. The typical immune checkpoints were all elevated in the high-risk group. Furthermore, the high-risk group showed a better immunotherapy response than the low-risk group based on the Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenoscore (IPS). In conclusion, we identified two cuproptosis-clusters with different prognoses using consensus clustering in BC. We also developed a cuproptosis-related prognostic signature and nomogram, which could indicate the outcome, the tumor immune microenvironment, as well as the response to immunotherapy.

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A Newly Established Cuproptosis-Associated Long Non-Coding RNA Signature for Predicting Prognosis and Indicating Immune Microenvironment Features in Soft Tissue Sarcoma

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