A Ferroptosis-Related Gene Prognostic Index Associated With Biochemical Recurrence and Radiation Resistance for Patients With Prostate Cancer Undergoing Radical Radiotherapy

Abstract

Background: Ferroptosis is a new type of programmed cell death which has been reported to be involved in the development of various cancers. In this study, we attempted to explore the possible links between ferroptosis and prostate cancer (PCa), and a novel ferroptosis-related gene prognostic index (FGPI) was constructed to predict biochemical recurrence (BCR) and radiation resistance for PCa patients undergoing radical radiotherapy (RRT). Moreover, the tumor immune microenvironment (TME) of PCa was analyzed.Methods: We merged four GEO datasets by removing batch effects. All analyses were conducted with R version 3.6.3 and its suitable packages. Cytoscape 3.8.2 was used to establish a network of transcriptional factor and competing endogenous RNA.Results: We established the FGPI based on ACSL3 and EPAS1. We observed that FGPI was an independent risk factor of BCR for PCa patients (HR: 3.03; 95% CI: 1.68–5.48), consistent with the result of internal validation (HR: 3.44; 95% CI: 1.68–7.05). Furthermore, FGPI showed high ability to identify radiation resistance (AUC: 0.963; 95% CI: 0.882–1.00). LncRNA PART1 was significantly associated with BCR and might modulate the mRNA expression of EPAS1 and ACSL3 through interactions with 60 miRNAs. Gene set enrichment analysis indicated that FGPI was enriched in epithelial–mesenchymal transition, allograft rejection, TGF beta signaling pathway, and ECM receptor interaction. Immune checkpoint and m6A analyses showed that PD-L2, CD96, and METTL14 were differentially expressed between BCR and no BCR groups, among which CD96 was significantly associated with BCR-free survival (HR: 1.79; 95% CI: 1.06–3.03). We observed that cancer-related fibroblasts (CAFs), macrophages, stromal score, immune score, estimate score, and tumor purity were differentially expressed between BCR and no BCR groups and closely related to BCR-free survival (HRs were 2.17, 1.79, 2.20, 1.93, 1.92, and 0.52 for cancer-related fibroblasts, macrophages, stromal score, immune score, estimate score, and tumor purity, respectively). Moreover, cancer-related fibroblasts (coefficient: 0.20), stromal score (coefficient: 0.14), immune score (coefficient: 0.14), estimate score (coefficient: 0.15), and tumor purity (coefficient: −0.15) were significantly related to FGPI, among which higher positive correlation between cancer-related fibroblasts and FGPI was observed.Conclusion: We found that FGPI based on ACSL3 and EPAS1 might be used to predict BCR and radiation resistance for PCa patients. CD96 and PD-L2 might be a possible target for drug action. Besides, we highlighted the importance of immune evasion in the process of BCR.

A novel ferroptosis-related gene prognostic index for prognosis and response to immunotherapy in patients with prostate cancer

“…Feng et al. established a two-gene ferroptosis-related prognostic index for PCa patients undergoing radical radiotherapy rather than radical prostatectomy that provides far better long-term prognostic outcomes for patients with localized disease ( 65 ). These suggest that our FRGPI possessed a better performance for predicting the prognosis in PCa patients after radical prostatectomy as compared to previous gene signatures or models, probably due to the highly comprehensive and integrated data proceeding and analysis process used in this study.…”

The Roles of Ferroptosis-related Long Non-coding RNAs in Urologic Cancers

“…Through a ferroptosis-related gene prognostic index (FGPI) analysis combiningg four Gene Expression Omnibus (GEO) database, Feng et al found that lncRNA PART1 was significantly associated with the prediction biochemical recurrence (BCR) of PCa [8]. Subsequently, ferroptosis-related lncRNA (frlncRNAs) signature was established to predict PCa prognosis, and 5 frlncRNAs (AP006284.1, AC132938.1, BCRP3, AL360181.4 and AL135999.1) were identified for the prediction of PCa BCR [9].…”

“…In non-smallcell lung cancer, overexpression of lncRNA NEAT1 can inhibit the expression of ACSL4 but increase the expression of SLC7A11, and decreased ferroptosis and cell apoptosis [23]. In PCa, LncRNA PART1 was speculated to modulate the mRNA expression of endothelial PAS domain containing protein-1 (EPAS1) and ACSL3 through interacting with 60 miRNAs [8]. LncRNA OIP5-AS1 was shown to inhibit ferroptosis of PCa cells after long-term cadmium exposure through miR-128-3p/SLC7A11 signaling [24].…”

Exosomes in Liquid Biopsy: A Nanotool for Postradiotherapy Cancer Monitoring

“…Although radiotherapy can locally control tumors and improve the quality of life of patients [4], some problems often occur after radiotherapy. These include poor efficacy [5], tumor recurrence [6,7], poor prognosis [8], and resistance to radiotherapy [9]. As a noninvasive and precise detection tool, liquid biopsy has great potential to address these problems of tumor radiotherapy [10].…”