Feng Dechao, Shi Xu, Xiong Qiao, Zhang Facai, Li Dengxiong, Wei Wuran, Yang Lu
Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
Front Cell Dev Biol. 2022 Feb 10;10:803766. doi: 10.3389/fcell.2022.803766. eCollection 2022.
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. 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. 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. 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.
铁死亡是一种新型的程序性细胞死亡，据报道其参与了多种癌症的发展。在本研究中，我们试图探索铁死亡与前列腺癌（PCa）之间的可能联系，并构建了一种新型的铁死亡相关基因预后指数（FGPI），以预测接受根治性放疗（RRT）的PCa患者的生化复发（BCR）和放射抗性。此外，还分析了PCa的肿瘤免疫微环境（TME）。我们通过消除批次效应合并了四个GEO数据集。所有分析均使用R 3.6.3版本及其合适的软件包进行。使用Cytoscape 3.8.2建立转录因子和竞争性内源性RNA网络。我们基于ACSL3和EPAS1建立了FGPI。我们观察到FGPI是PCa患者BCR的独立危险因素（HR：3.03；95%CI：1.68 - 5.48），与内部验证结果一致（HR：3.44；95%CI：1.68 - 7.05）。此外，FGPI显示出较高的识别放射抗性的能力（AUC：0.963；95%CI：0.882 - 1.00）。LncRNA PART1与BCR显著相关，可能通过与60种miRNA相互作用调节EPAS1和ACSL3的mRNA表达。基因集富集分析表明，FGPI在上皮 - 间质转化、同种异体移植排斥、TGFβ信号通路和ECM受体相互作用中富集。免疫检查点和m6A分析表明，PD - L2、CD96和METTL14在BCR组和无BCR组之间差异表达，其中CD96与无BCR生存期显著相关（HR：1.79；95%CI：1.06 - 3.03）。我们观察到癌症相关成纤维细胞（CAFs）、巨噬细胞、基质评分、免疫评分、估计评分和肿瘤纯度在BCR组和无BCR组之间差异表达，且与无BCR生存期密切相关（癌症相关成纤维细胞、巨噬细胞、基质评分、免疫评分、估计评分和肿瘤纯度的HR分别为2.17、1.79、2.20、1.93、1.92和0.52）。此外，癌症相关成纤维细胞（系数：0.20）、基质评分（系数：0.14）、免疫评分（系数：0.14）、估计评分（系数：0.15）和肿瘤纯度（系数： - 0.15）与FGPI显著相关，其中观察到癌症相关成纤维细胞与FGPI之间的正相关性更高。我们发现基于ACSL3和EPAS1的FGPI可用于预测PCa患者的BCR和放射抗性。CD96和PD - L2可能是药物作用的潜在靶点。此外，我们强调了免疫逃逸在BCR过程中的重要性。
