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Ferroptosis-Related lncRNA Signature Correlates with the Prognosis, Tumor Microenvironment, and Therapeutic Sensitivity of Esophageal Squamous Cell Carcinoma

ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is the most prevalent form of esophageal cancer in China and is closely associated with malignant biological characteristics and poor survival. Ferroptosis is a newly discovered iron-dependent mode of cell death that plays an important role in the biological behavior of ESCC cells. The clinical significance of ferroptosis-related long noncoding RNAs (FRLs) in ESCC remains unknown and warrants further research. The current study obtained RNA sequencing profiles and corresponding clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and FRLs were obtained through coexpression analysis. Consensus clustering was employed to divide the subjects into clusters, and immune-associated pathways were identified by functional analysis. The current study observed significant differences in the enrichment scores of immune cells among different clusters. Patients from TCGA-ESCC database were designated as the training cohort. A ten-FRL prediction signature was established using the least absolute shrinkage and selection operator Cox regression model and validated using the GEO cohort and our own independent validation database. Real-time quantitative polymerase chain reaction was used to verify the expression of the ten FRLs, and the ssGSEA analysis was employed to evaluate their function. In addition, the IMvigor database was used to assess the predictive value of the signature in terms of immunotherapeutic responses. Multivariate Cox and stratification analyses revealed that the ten-FRL signature was an independent predictor of the overall survival (OS). Patients with ESCC in the high-risk group displayed worse survival, a characteristic tumor immune microenvironment, and low immunotherapeutic benefits compared to those in the low-risk group. Collectively, the risk model established in this study could serve as a promising predictor of prognosis and immunotherapeutic response in patients with ESCC.

SUBMITTER: Zhu J

PROVIDER: S-EPMC9315452 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is closely correlated with malignant biological characteristics and poor survival. Recently, chemokines have been reported to be involved in the progression of tumors, and they can also regulate the tumor microenvironment. However, it is unclear whether chemokine-related long noncoding RNAs (lncRNAs) affect the prognosis of ESCC.MethodsWe downloaded RNA-seq and clinical data from the Gene Expression Omnibus (GEO database. Chemokine-related lncRNAs were screened by differential analysis and Pearson correlation analysis. Then, prognosis-related lncRNAs were screened by using univariate COX regression, and risk models were constructed after the least absolute shrinkage and selection operator (LASSO) regression and multivariate COX regression. The predictive value of the signature was assessed using Kaplan-Meier test, time-dependent receiver operating characteristic (ROC) curves, decision curve analysis (DCA) and calibration curve. Moreover, a nomogram to predict patients' 1-year 3-year and 5-year prognosis was constructed. Gene set enrichment analyses (GSEA), Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG), evaluation of immune cell infiltration, and estimation of drug sensitivity were also conducted.ResultsIn this study, 677 chemokine-related lncRNAs were first obtained by differential analysis and Pearson correlation. Then, six chemokine-related lncRNAs were obtained by using univariate COX, LASSO and multivariate COX to construct a novel chemokine-related lncRNAs risk model. The signature manifested favorable predictive validity and accuracy both in the testing and training cohorts. The chemokine-related signature could classify ESCC patients into two risk groups well, which indicated that high-risk group exhibited poor prognostic outcome. In addition, this risk model played an important role in predicting signaling pathways, immune cell infiltration, stromal score, and drug sensitivity in ESCC patients.ConclusionsThese findings elucidated the critical role of novel prognostic chemokine-related lncRNAs in prognosis, immune landscape, and drug therapy, thus throwing light on prognostic evaluation and therapeutic targets for ESCC patients.

Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is correlated with worse clinical prognosis and lacks available targeted therapy. Thus, identification of reliable biomarkers is required for the diagnosis and treatment of ESCC.MethodsWe downloaded the GSE53625 dataset as a training dataset to screen differentially expressed RNAs (DERs) with the criterion of false discovery rate (FDR) < 0.05 and |log2fold change (FC)| > 1. A support vector machine classifier was used to find the optimal feature gene set that could conclusively distinguish different samples. An eight-lncRNA signature was identified by random survival forest algorithm and multivariate Cox regression analysis. The RNA sequencing data from The Cancer Genome Atlas (TCGA) database were used for external validation. The predictive value of the signature was assessed using Kaplan-Meier test, time-dependent receiver operating characteristic (ROC) curves, and dynamic area under the curve (AUC). Furthermore, a nomogram to predict patients' 3-year and 5-year prognosis was constructed. CCK-8 assay, flow cytometry, and transwell assay were conducted in ESCC cells.ResultsA total of 1136 DERs, including 689 downregulated mRNAs, 318 upregulated mRNAs, 74 downregulated lncRNAs and 55 upregulated lncRNAs, were obtained in the GES53625 dataset. From the training dataset, we identified an eight-lncRNA signature, (ADAMTS9-AS1, DLX6-AS1, LINC00470, LINC00520, LINC01497, LINC01749, MAMDC2-AS1, and SSTR5-AS1). A nomogram based on the eight-lncRNA signature, age, and pathologic stage was developed and showed good accuracy for predicting 3-year and 5-year survival probability of patients with ESCC. Functionally, knockdown of LINC00470 significantly suppressed cell proliferation, G1/S transition, and migration in two ESCC cell lines (EC9706 and TE-9). Moreover, knockdown of LINC00470 downregulated the protein levels of PCNA, CDK4, and N-cadherin, while upregulating E-cadherin protein level in EC9706 and TE-9 cells.ConclusionOur eight-lncRNA signature and nomogram can provide theoretical guidance for further research on the molecular mechanism of ESCC and the screening of molecular markers.

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Ferroptosis-Related lncRNA Signature Correlates with the Prognosis, Tumor Microenvironment, and Therapeutic Sensitivity of Esophageal Squamous Cell Carcinoma

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