Abstract
BackgroundFerroptosis is a newly found non-apoptotic forms of cell death that plays an important role in tumors. However, the prognostic value of ferroptosis-related genes (FRG) in bladder cancer (BLCA) have not been well examined.MethodsFRG data and clinical information were collected from The Cancer Genome Atlas (TCGA). Then, significantly different FRGs were investigated by functional enrichment analyses. The prognostic FRG signature was identified by univariate cox regression and least absolute shrinkage and selection operator (LASSO) analysis, which was validated in TCGA cohort and Gene Expression Omnibus (GEO) cohort. Subsequently, the nomogram integrating risk scores and clinical parameters were established and evaluated. Additionally, Gene Set Enrichment Analyses (GSEA) was performed to explore the potential molecular mechanisms underlying our prognostic FRG signature. Finally, the expression of three key FRGs was verified in clinical specimens.ResultsThirty-two significantly different FRGs were identified from TCGA–BLCA cohort. Enrichment analyses showed that these genes were mainly related to the ferroptosis. Seven genes (TFRC, G6PD, SLC38A1, ZEB1, SCD, SRC, and PRDX6) were then identified to develop a prognostic signature. The Kaplan–Meier analysis confirmed the predictive value of the signature for overall survival (OS) in both TCGA and GEO cohort. A nomogram integrating age and risk scores was established and demonstrated high predictive accuracy, which was validated through calibration curves and receiver operating characteristic (ROC) curve [area under the curve (AUC) = 0.690]. GSEA showed that molecular alteration in the high- or low-risk group was closely associated with ferroptosis. Finally, experimental results confirmed the expression of SCD, SRC, and PRDX6 in BLCA.ConclusionHerein, we identified a novel FRG prognostic signature that maybe involved in BLCA. It showed high values in predicting OS, and targeting these FRGs may be an alternative for BLCA treatment. Further experimental studies are warranted to uncover the mechanisms that these FRGs mediate BLCA progression.
Highlights
Bladder cancer (BLCA) is the second most frequently diagnosed urinary cancer, with an estimated 573,000 new cases and 213,000 deaths worldwide in 2020 [1]
A total of 402 BLCA samples and 19 normal samples with gene expression profiles and clinical information were retrieved from The Cancer Genome Atlas (TCGA) dataset
10 ferroptosis-related genes (FRG) were downregulated in BLCA, and 22 genes were upregulated
Summary
Bladder cancer (BLCA) is the second most frequently diagnosed urinary cancer, with an estimated 573,000 new cases and 213,000 deaths worldwide in 2020 [1]. As it is a heterogeneous disease with various great challenges [2], patients with BLCA often suffer from high rates of tumor recurrence, progression, and metastasis. Gene signature, which is a combined group of genes in a cell or tissue [6], has been widely used for risk stratification of patients with cancer [7]. Via data mining and bioinformatics analysis, it is feasible to develop an accurate survival risk stratification model based on gene signature for patients with BLCA. The prognostic value of ferroptosis-related genes (FRG) in bladder cancer (BLCA) have not been well examined
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