Abstract
Background: The regulatory role of ferroptosis in malignant tumours has been recently demonstrated. However, the potential roles of ferroptosis mediation patterns in bladder cancer remain elusive. Materials and Methods: The ferroptosis mediation patterns of 889 bladder cancer samples were comprehensively evaluated based on ferroptosis-related genes. The underlying correlations between these mediation patterns and multi-omic characteristics of bladder cancer were systematically analysed. The ferroptosis mediation patterns of individual samples were quantified by ferropscore using the principal component analysis algorithm. The typical ferroptosis-related genes with prognostic roles were further randomly validated using immunohistochemical staining, real-time polymerase chain reaction and western blotting. Results: Three different ferroptosis mediation patterns were identified. The abundance of infiltration of 23 immune cells was different among the three mediation patterns. The quantification of ferroptosis mediation patterns in individual samples served as a promising tool for predicting patient survival outcomes; immune cell infiltration abundance; tumour mutation burden; oncogenic mutation status and tumour grade, stage and molecular subtypes. Low ferropscore combined with high tumour mutation burden was associated with the best survival prognosis. Expressions of PD-L1 (p < 0.001), PD-1 (p = 0.002) and CTLA-4 (p = 0.003) were all significantly upregulated in the high ferropscore group. Low ferropscores also predicted good immunotherapy response for anti-CTLA4 strategy. The mRNA and protein levels of FADS2, a typical ferroptosis-related gene used in the study, were higher in bladder cancer cell lines than in controlled SV-HUC-1 cells. In addition, immunohistochemical staining revealed significantly higher expression levels of FADS2 in human bladder cancer tumour tissues than in normal tissues. Conclusion: This study identified three distinct ferroptosis mediation patterns in bladder cancer. Quantification of ferroptosis mediation patterns in individual samples may help to improve the understanding of multiomic characteristics and guide future immunotherapy responses to bladder cancer.
Highlights
Cell death plays an essential role during the development and evolution of multicellular organisms
The searched high-quality researches on ferroptosis were defined as novel studies with impact factors >10 points and a total of 60 ferroptosis-related genes were included in this study. (Stockwell et al, 2017; Bersuker et al, 2019; Doll et al, 2019; Hassannia et al, 2019)
The copy number variation (CNV) (Supplementary Table S2) and somatic mutations (Supplementary Table S3) of ferroptosis-related genes were investigated in The Cancer Genome Atlas (TCGA) cohort
Summary
Cell death plays an essential role during the development and evolution of multicellular organisms. The progress of tumour treatments at different stages is always synchronised with human cognition for different modes of cell death. In the last decade, increasing studies have focussed on a new mode of cell death—ferroptosis. (Dixon et al, 2012) It was distinct from previously known cell death modes including apoptosis, necrosis and autophagy in both cell function and morphological characteristics. Its unique morphological characteristics include the increased density of mitochondrial membrane, shrinkage of cell mitochondria and disappearance of mitochondrial cristae. Increasing studies have demonstrated that ferroptosis plays a vital role in regulating malignant cell development, and targeted interference of ferroptosis is a promising strategy for future cancer treatment. Recently discovered that sorafenib played a therapeutic role by inducing ferroptosis in hepatocellular carcinoma. The potential roles of ferroptosis mediation patterns in bladder cancer remain elusive
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
