Abstract
Background: Ferroptosis is closely related to the occurrence and development of cancer. An increasing number of studies have induced ferroptosis as a treatment strategy for cancer. However, the predictive value of ferroptosis-related lncRNAs in bladder cancer (BC) still need to be further elucidated. The purpose of this study was to construct a predictive signature based on ferroptosis-related long noncoding RNAs (lncRNAs) to predict the prognosis of BC patients. Methods: We downloaded RNA-seq data and the corresponding clinical and prognostic data from The Cancer Genome Atlas (TCGA) database and performed univariate and multivariate Cox regression analyses to obtain ferroptosis-related lncRNAs to construct a predictive signature. The Kaplan-Meier method was used to analyze the overall survival (OS) rate of the high-risk and low-risk groups. Gene set enrichment analysis (GSEA) was performed to explore the functional differences between the high- and low-risk groups. Single-sample gene set enrichment analysis (ssGSEA) was used to explore the relationship between the predictive signature and immune status. Finally, the correlation between the predictive signature and the treatment response of BC patients was analyzed. Results: We constructed a signature composed of nine ferroptosis-related lncRNAs (AL031775.1, AL162586.1, AC034236.2, LINC01004, OCIAD1-AS1, AL136084.3, AP003352.1, Z84484.1, AC022150.2). Compared with the low-risk group, the high-risk group had a worse prognosis. The ferroptosis-related lncRNA signature could independently predict the prognosis of patients with BC. Compared with clinicopathological variables, the ferroptosis-related lncRNA signature has a higher diagnostic efficiency, and the area under the receiver operating characteristic curve was 0.707. When patients were stratified according to different clinicopathological variables, the OS of patients in the high-risk group was shorter than that of those in the low-risk group. GSEA showed that tumor- and immune-related pathways were mainly enriched in the high-risk group. ssGSEA showed that the predictive signature was significantly related to the immune status of BC patients. High-risk patients were more sensitive to anti-PD-1/L1 immunotherapy and the conventional chemotherapy drugs sunitinib, paclitaxel, cisplatin, and docetaxel. Conclusion: The predictive signature can independently predict the prognosis of BC patients, provides a basis for the mechanism of ferroptosis-related lncRNAs in BC and provides clinical treatment guidance for patients with BC.
Highlights
Bladder cancer (BC) is the ninth most common malignant cancer in the world and the most common tumor in the urinary system (Bray et al, 2018)
Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that ferroptosis-related differentially expressed genes (DEGs) were mainly enriched in the p53 signaling pathway, ferroptosis, kaposi sarcoma-associated herpesvirus infection, the IL-17 signaling pathway, microRNAs in cancer, the TNF signaling pathway, fluid shear stress and atherosclerosis, insulin resistance, the PI3K-Akt signaling pathway and the HIF-1 signaling pathway (Figure 2B)
In the cellular components category, the DEGs were mainly enriched in heterochromatin, melanosomes, the endoplasmic reticulum lumen, etc., In the molecular function category, the DEGs were mainly enriched in iron ion binding, ferric iron binding, DNA-binding transcription repressor activity, etc (Figure 2C)
Summary
Bladder cancer (BC) is the ninth most common malignant cancer in the world and the most common tumor in the urinary system (Bray et al, 2018). The 5-years survival rate of NMIBC is more than 90% (Knowles and Hurst, 2015). 50–70% of patients with NMIBC will relapse, and approximately 10–20% will develop MIBC (Rübben et al, 1988). The 5-years survival rate of patients with MIBC is less than 50% (Alfred-Witjes et al, 2017). For advanced BC, cisplatin-based combination chemotherapy is the first-line treatment option. Ferroptosis is closely related to the occurrence and development of cancer. An increasing number of studies have induced ferroptosis as a treatment strategy for cancer. The predictive value of ferroptosis-related lncRNAs in bladder cancer (BC) still need to be further elucidated. The purpose of this study was to construct a predictive signature based on ferroptosis-related long noncoding RNAs (lncRNAs) to predict the prognosis of BC patients
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