A novel signature constructed by ferroptosis-associated genes (FAGs) for the prediction of prognosis in bladder urothelial carcinoma (BLCA) and associated with immune infiltration

Abstract

Background Ferroptosis, a novel form of regulated cell death, has been implicated in the pathogenesis of cancers. Nevertheless, the potential function and prognostic values of ferroptosis in bladder urothelial carcinoma (BLCA) are complex and remain to be clarified. Therefore, we proposed to systematically examine the roles of ferroptosis-associated genes (FAGs) in BLCA. Methods According to The Cancer Genome Atlas (TCGA) database, differently expressed FAGs (DEFAGs) and differently expressed transcription factors (DETFs) were identified in BLCA. Next, the network between DEFAGs and DETFs, GO annotations and KEGG pathway analyses were performed. Then, through univariate, LASSO and multivariate regression analyses, a novel signature based on FAGs was constructed. Moreover, survival analysis, PCA analysis, t-SNE analysis, ROC analysis, independent prognostic analysis, clinicopathological and immune correlation analysis, and experimental validation were utilized to evaluate the signature. Results Twenty-eight DEFAGs were identified, and four FAGs (CRYAB, TFRC, SQLE and G6PD) were finally utilized to establish the FAGs based signature in the TCGA cohort, which was subsequently validated in the GEO database. Moreover, we found that immune cell infiltration, immunotherapy-related biomarkers and immune-related pathways were significantly different between two risk groups. Besides, nine molecule drugs with the potential to treat bladder cancer were identified by the connectivity map database analysis. Finally, the expression levels of crucial FAGs were verified by the experiment, which were consistent with our bioinformatics analysis, and knockdown of TFRC could inhibit cell proliferation and colony formation in BLCA cell lines in vitro. Conclusions Our study identified prognostic ferroptosis-associated genes and established a novel FAGs signature, which could accurately predict prognosis in BLCA patients.

LncRNA RP11-89 facilitates tumorigenesis and ferroptosis resistance through PROM2-activated iron export by sponging miR-129-5p in bladder cancer

“…For example, a novel agent called AuNRs&IONs@Gel constructed by Pengyu Guo was reported to induce ferroptosis and trigger a potent immune response through a triple therapy strategy using FDA-approved nanoparticles in BLCA [ 39 ]. The relationship between immune statue and ferroptosis in BLCA has been explored by accumulating studies [ 40 , 41 ]. Luan et al found that immune cell infiltration and immune checkpoints in BLCA were dysregulated in BLCA patients with different levels of ferroptosis related genes using multiple experimental and bioinformatic models [ 41 ].…”

“…The relationship between immune statue and ferroptosis in BLCA has been explored by accumulating studies [ 40 , 41 ]. Luan et al found that immune cell infiltration and immune checkpoints in BLCA were dysregulated in BLCA patients with different levels of ferroptosis related genes using multiple experimental and bioinformatic models [ 41 ]. The immune microenvironment is critical in BLCA treatments, especially in immunotherapies such as BCG instillation and immune checkpoint inhibitor [ 42 , 43 ].…”

The Pyroptosis-Related Long Noncoding RNA Signature Predicts Prognosis and Indicates Immunotherapeutic Efficiency in Hepatocellular Carcinoma

“…The currently acknowledged computational methods, including TIMER ( Li et al, 2020 ), CIBERSORT ( Chen et al, 2018 ), CIBERSORT-AB ( Luan et al, 2021 ), QUANTISEQ ( Plattner et al, 2020 ), MCPCOUNT ( Zhang et al, 2020b ), XCELL ( Aran et al, 2017 ), and EPIC ( Racle et al, 2017 ), were used to calculate the immune infiltration score between different risk score groups. Single-sample GSEA (ssGSEA) with the “gsva” package was implemented to calculate the score of 16 infiltrating immune cells and the 13 activities of immune-related pathways ( Rooney et al, 2015 ).…”

Roles of ferroptosis in urologic malignancies

“…Yang et al [ 105 ] have discovered a novel prognostic model in bladder cancer integrating nine ferroptosis-related differentially expressed genes, including ALB, BID, FADS2, FANCD2, IFNG, MIOX, PLIN4, SCD, and SLC2A3, which could be applied for prognostic prediction in bladder cancer patients. Luan et al [ 106 ] have identified four ferroptosis-associated genes in bladder urothelial carcinoma (CRYAB, TFRC, SQLE and G6PD) by conducting a bioinformatics analysis, which may accurately predict prognosis in bladder cancer patients. Liang et al [ 107 ] constructed a new prognostic model with seven ferroptosis-related genes, including NOX1, GCLM, ACSL4, ALOX5, ACACA, ZEB1, and FADS2.…”