Ferroptosis-related lncRNAs: Distinguishing heterogeneity of the tumour microenvironment and predicting immunotherapy response in bladder cancer

Abstract

Ferroptosis, a cell death pathway dependent on iron, has been shown in research to play a role in the development, advancement, and outlook of tumours through ferroptosis-related lncRNAs (FRLRs). However, the value of the FRLRs in bladder cancer (BLCA) has not been thoroughly investigated. This research project involved developing a predictive model using ten specific FRLRs (AC099850.4, AL731567.1, AL133415.1, AC021321.1, SPAG5-AS1, HMGA2-AS1, RBMS3-AS3, AC006160.1, AL583785.1, and AL662844.4) through univariate COX and LASSO regression techniques. The validation of this signature as a standalone predictor was confirmed in a group of 65 patients from the urology bladder tumour database at the First Affiliated Hospital of Wenzhou Medical University in Wenzhou, China. Patients were categorized based on their median risk score into either a low-risk group or a high-risk group. Enrichment analysis identified possible molecular mechanisms that could explain the variations in clinical outcomes observed in high-risk and low-risk groups. Moreover, we explored the correlation between FLPS and immunotherapy-related indicators. The ability of FLPS to forecast the effectiveness of immunotherapy was validated by the elevated levels of immune checkpoint genes (PD-L1, CTLA4, and PD-1) in the group at high risk. We also screened the crucial FRLR (HMGA2-AS1) through congruent expression and prognostic conditions and established a ceRNA network, indicating that HMGA2-AS1 may affect epithelial-mesenchymal transition by modulating the Wnt signalling pathway through the ceRNA mechanism. We identified the top five mRNAs (NFIB, NEGR1, JAZF1, JCAD, and ESM1) based on random forest algorithm and analysed the relationship between HMGA2-AS1, the top five mRNAs, and immunotherapy, and their interactions with drug sensitivities. Our results suggest that patients with BLCA have a greater sensitivity to four drugs (dasatinib, pazopanib, erismodegib and olaparib). Our study provides new insights into the TME, key signalling pathways, genome, and potential therapeutic targets of BLCA, with future guidance for immunotherapy and targeted precision drugs.