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A Novel Ferroptosis-Related LncRNA Pair Prognostic Signature Predicts Immune Landscapes and Treatment Responses for Gastric Cancer Patients.

ABSTRACT: Background: The construction of ferroptosis-related lncRNA prognostic models in malignancies has been an intense area of research recently. However, most of the studies focused on the exact expression of lncRNAs and had limited application values. Herein, we aim to establish a novel prognostic model for gastric cancer (GC) patients and discuss its correlation with immune landscapes and treatment responses. Methods: The present study retrieved transcriptional data of GC patients from the Cancer Genome Atlas (TCGA) database. We identified differentially expressed ferroptosis-related lncRNAs between tumor and normal controls of GC samples. Based on a new method of cyclically single pairing, we constructed a 0 or 1 matrix of ferroptosis-related lncRNA pairs (FRLPs). A risk score signature consisting of 10 FRLPs was established using multi-step Cox regression analysis. Next, we performed a series of systematic analyses to investigate the association of the FRLP model and tumor microenvironment, biological function, and treatment responses. An alternative model to the FRLP risk score signature, the gene set score (GS) model was also constructed, which could represent the former when lncRNA expression was not available. Results: We established a novel prognostic signature of 10 ferroptosis-related lncRNA pairs. High-risk patients in our risk score model were characterized by high infiltration of immune cells, upregulated carcinogenic and stromal activities, and heightened sensitivity to a wide range of anti-tumor drugs, whereas low-risk patients were associated with better responses to methotrexate treatment and elevated immunotherapeutic sensitivity. The practicability of the FRLP risk score model was also validated in two independent microarray datasets downloaded from Gene Expression Omnibus (GEO) using the GS model. Finally, two online dynamic nomograms were built to enhance the clinical utility of the study. Conclusion: In this study, we developed a ferroptosis-related lncRNA pair-based risk score model that did not rely on the exact lncRNA expression level. This novel model might provide insights for the accurate prediction and comprehensive management for GC patients.

SUBMITTER: Li J

PROVIDER: S-EPMC9250987 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGastric cancer (GC), the most commonly diagnosed cancer worldwide with poor 5-year survival rate in advanced stages. Although immune-related and survival-related biomarkers, which typically comprise aberrantly expressed long non-coding RNAs (lncRNAs) and genes, have been identified, there are no reports of immune-related lncRNA pair (IRLP) signatures for GC.MethodsIn this study, we acquired lncRNA expression profiles from The Cancer Genome Atlas (TCGA) and used the least absolute shrinkage and selection operator (LASSO) Cox proportional hazards model (iteration = 1000) to develop a IRLP prognostic signature. The area under curve (AUC) was used to assess the prognosis predictive power. The multivariate Cox regression analysis was performed to identify whether this signature was an independent prognostic factor. The immune cell infiltration analysis was performed between the two risk groups. Last, molecular experiments were performed to explore LINC01082 is involved in the development of GC.ResultsWe acquired lncRNA expression profiles and used the LASSO Cox model to develop an 18-IRLP signature with a strong prognostic predictive power. The 5-year AUC values of the training, validation, and overall TCGA datasets were 0.77, 0.86, and 0.80, respectively. The different prognostic outcomes between the high- and low-risk groups were determined using our 18-IRLP signature. Moreover, our 18-IRLP signature was an independent prognostic factor as per the multivariate Cox regression analysis, and showed better prognostic evaluation than the traditional TNM staging system as well as other clinical features. We also found differences in cancer-associated fibroblast and macrophage M2 infiltration and the expression of PD-L1, CTLA4, LAG3, and HLA were also observed between the two risk groups (P < 0.05). Analysis of biological functions revealed that target genes of the lncRNAs in the IRLP signature were enriched in focal adhesion and regulation of actin cytoskeleton. Finally, as one of significant candidates of IRLP signature, overexpression of LINC01082 suppressed the invasion ability of GC cells as well as PD-L1 expression profiles.ConclusionsOur novel 18-IRLP signature provides new insights regarding immunological biomarkers, imparts a better understanding of the tumor immune microenvironment, and can be used for predicting prognosis and evaluating immune response in GC.

Project description:BackgroundGastric cancer (GC) is an important disease and the fifth most common malignancy worldwide. Autophagy is an important process for the turnover of intracellular substances. Autophagy-related genes (ARGs) are crucial in cancer. Accumulating evidence indicates the clinicopathological significance of the tumor microenvironment (TME) in predicting prognosis and treatment efficacy.MethodsClinical and gene expression data of GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. A total of 22 genes with differences in expression and prognosis were screened from 232 ARGs. Three autophagy patterns were identified using an unsupervised clustering algorithm and scored using principal component analysis to predict the value of autophagy in the prognosis of GC patients. Finally, the relationship between autophagy and ferroptosis was validated in gastric cancer cells.ResultsThe expression of ARGs showed obvious heterogeneity in GC patients. Three autophagy patterns were identified and used to predict the overall survival of GC patients. These three patterns were well-matched with the immunophenotype. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses showed that the biological functions of the three autophagy patterns were different. A scoring system was then set up to quantify the autophagy model and further evaluate the response of the patients to the immunotherapy. Patients with high autophagy scores had a more severe tumor mutation burden and better prognosis. High autophagy scores were accompanied by high microsatellite instability. Patients with high autophagy scores had significantly higher PD-L1 expression and increased survival. The experimental results confirmed that the expression of ferroptosis genes was positively correlated with the expression of autophagy genes in different autophagy clusters, and inhibition of autophagy dramatically reversed the decrease in ferroptotic cell death and lipid accumulation.ConclusionsAutophagy patterns are involved in TME diversity and complexity. Autophagy score can be used as an independent prognostic biomarker in GC patients and to predict the effect of immunotherapy and ferroptosis-based therapy. This might benefit individualized treatment for GC.

Project description:BackgroundDepression and long non-coding RNA (lncRNA) have been reported to be associated with tumor progression and prognosis in gastric cancer (GC). This study aims to build a GC risk classification and prognosis model based on depression-related lncRNAs (DRLs).MethodsTo develop a risk model, we performed univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses using RNA sequencing data of GC from The Cancer Genome Atlas (TCGA) and depression-related genes (DRGs) from previous studies. Kaplan-Meier analysis, receiver operating characteristic (ROC) curve analysis, nomogram construction, pathway enrichment analysis, assessment of immunological features, and drug sensitivity testing were conducted using a series of bioinformatics methods.ResultsSeven DRLs were identified to build a prognostic model, whose robustness was verified in an internal cohort. Subsequent prognostic analyses found that high risk scores were associated with worse overall survival (OS). Univariate and multivariate analyses revealed that the risk score could be used as an independent prognostic factor. Furthermore, the ROC curve indicated that the risk score had higher diagnostic efficiency than traditional clinicopathological features. The calibration curve confirmed the accuracy and reliability of the nomogram. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that there were differences in digestive system and nervous system-related pathways between the high- and low-risk groups. Results of tumor mutational burden (TMB) and tumor immune dysfunction and exclusion (TIDE) analyses indicated that patients in the low-risk group had a better response rate to immunotherapy. Finally, the results of drug sensitivity analysis showed that risk score could influence sensitivity to EHT 1864 in GC.ConclusionWe have successfully developed and verified a 7-DRL risk model which can assess the prognosis and immunological features and guide individualized therapy of GC patients.

Project description:Background: RNA-editing refers to post-transcriptional transcript alterations that lead to the formation of protein isoforms and the progression of various tumors. However, little is known about its roles in gliomas. Aim: The aim of this study is to identify prognosis-related RNA-editing sites (PREs) in glioma, and to explore their specific effects on glioma and potential mechanisms of action. Methods: Glioma genomic and clinical data were obtained from TCGA database and SYNAPSE platform. The PREs was identified with regression analyses and the corresponding prognostic model was evaluated with survival analysis and receiver operating characteristic curve. Functional enrichment of differentially expressed genes between risk groups was performed to explore action mechanisms. The CIBERSORT, ssGSEA, gene set variation analysis, and ESTIMATE algorithms were employed to assess the association between PREs risk score and variations of tumor microenvironment, immune cell infiltration, immune checkpoints, and immune responses. The maftools and pRRophetic packages were used to evaluate tumor mutation burden and predict drug sensitivity. Results: A total of thirty-five RNA-editing sites were identified as prognosis-related in glioma. Functional enrichment implied variation of immune-related pathways between groups. Notably, glioma samples with higher PREs risk score exhibited higher immune score, lower tumor purity, increased infiltration of macrophage and regulatory T cells, suppressed NK cell activation, elevated immune function score, upregulated immune checkpoint gene expression, and higher tumor mutation burden, all of which implied worse response to immune therapy. Finally, high-risk glioma samples are more sensitive to Z-LLNle-CHO and temozolomide, while the low-risk ones respond better to Lisitinib. Conclusion: We identified a PREs signature of thirty-five RNA editing sites and calculated their corresponding risk coefficients. Higher total signature risk score indicates worse prognosis and worse immune response and lower sensitivity to immune therapy. The novel PREs signature could help risk stratification, immunotherapy response prediction, individualized treatment strategy-making for glioma patients, and development of novel therapeutic approaches.

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A Novel Ferroptosis-Related LncRNA Pair Prognostic Signature Predicts Immune Landscapes and Treatment Responses for Gastric Cancer Patients.

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