Integrated analysis of a competing endogenous RNA network reveals a ferroptosis-related 6-lncRNA prognostic signature in clear cell renal cell carcinoma

Abstract

Background: Establishing a robust signature for prognostic prediction and precision treatment is necessary due to the heterogeneous prognosis and treatment response of clear cell renal cell carcinoma (ccRCC).

Objectives: This study set out to elucidate the biological functions and prognostic role of ferroptosis-related long non-coding RNAs (lncRNAs) based on a synthetic analysis of competing endogenous RNA networks in ccRCC.

Material and methods: Ferroptosis-related genes were obtained from the FerrDb database. The expression data and matched clinical information of lncRNAs, miRNAs and mRNAs from The Cancer Genome Atlas (TCGA) database were obtained to identify differentially expressed RNAs. The lncRNA-miRNA-mRNA ceRNA network was established utilizing the common miRNAs that were predicted in the RNAHybrid, StarBase and TargetScan databases. Then, using progressive univariate Cox regression, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis of gene expression data and clinical information, a ferroptosis-related lncRNA prognosis signature was constructed based on the lncRNAs in ceRNA. Finally, the influence of independent lncRNAs on ccRCC was explored.

Results: A total of 35 ferroptosis-related mRNAs, 356 lncRNAs and 132 miRNAs were sorted out after differential expression analysis in the TCGA-KIRC. Subsequently, overlapping lncRNA-miRNA and miRNA-mRNA interactions among the RNAHybrid, StarBase and TargetScan databases were constructed and identified; then a ceRNA network with 77 axes related to ferroptosis was established utilizing mutual miRNAs in 2 interaction networks as nodes. Next, a 6-ferroptosis-lncRNA signature including PVT1, CYTOR, MIAT, SNHG17, LINC00265, and LINC00894 was identified in the training set. Kaplan-Meier analysis, PCA, t-SNE analysis, risk score curve, and receiver operating characteristic (ROC) curve were performed to confirm the validity of the signature in the training set and verified in the validation set. Finally, single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) analysis showed that the signature was related to immune cell infiltration.

Conclusions: Our research underlines the role of the 6-ferroptosis-lncRNA signature as a predictor of prognosis and a therapeutic alternative for ccRCC.

Keywords: bioinformatics analysis; clear cell renal cell carcinoma; competing endogenous RNA network; ferroptosis-related lncRNA; prognostic signature.