Zhang Jili, Jiang Shaoqin, Gu Di, Zhang Wenhui, Shen Xianqi, Qu Min, Yang Chenghua, Wang Yan, Gao Xu
Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China.
Department of Urology, Fujian Union Hospital, Fujian Medical University, Fuzhou, Fujian, China.
Front Oncol. 2023 May 2;13:1162653. doi: 10.3389/fonc.2023.1162653. eCollection 2023.
Prostate cancer (PCa) is the most common malignant tumor of the male urinary system. Cuproptosis, as a novel regulated cell death, remains unclear in PCa. This study aimed to investigate the role of cuproptosis-related genes (CRGs) in molecular stratification, prognostic prediction, and clinical decision-making in PCa.
Cuproptosis-related molecular subtypes were identified by consensus clustering analysis. A prognostic signature was constructed with LASSO cox regression analyses with 10-fold cross-validation. It was further validated in the internal validation cohort and eight external validation cohorts. The tumor microenvironment between the two risk groups was compared using the ssGSEA and ESTIMATE algorithms. Finally, qRT-PCR was used to explore the expression and regulation of these model genes at the cellular level. Furthermore, 4D Label-Free LC-MS/MS and RNAseq were used to investigate the changes in CRGs at protein and RNA levels after the knockdown of the key model gene B4GALNT4.
Two cuproptosis-related molecular subtypes with significant differences in prognoses, clinical features, and the immune microenvironment were identified. Immunosuppressive microenvironments were associated with poor prognosis. A prognostic signature comprised of five genes (B4GALNT4, FAM83D, COL1A, CHRM3, and MYBPC1) was constructed. The performance and generalizability of the signature were validated in eight completely independent datasets from multiple centers. Patients in the high-risk group had a poorer prognosis, more immune cell infiltration, more active immune-related functions, higher expression of human leukocyte antigen and immune checkpoint molecules, and higher immune scores. In addition, anti-PDL-1 immunotherapy prediction, somatic mutation, chemotherapy response prediction, and potential drug prediction were also analyzed based on the risk signature. The validation of five model genes' expression and regulation in qPCR was consistent with the results of bioinformatics analysis. Transcriptomics and proteomics analyses revealed that the key model gene B4GALNT4 might regulate CRGs through protein modification after transcription.
The cuproptosis-related molecular subtypes and the prognostic signature identified in this study could be used to predict the prognosis and contribute to the clinical decision-making of PCa. Furthermore, we identified a potential cuproptosis-related oncogene B4GALNT4 in PCa, which could be used as a target to treat PCa in combination with cuproptosis.
前列腺癌（PCa）是男性泌尿系统最常见的恶性肿瘤。铜死亡作为一种新型的程序性细胞死亡方式，在PCa中的作用尚不清楚。本研究旨在探讨铜死亡相关基因（CRGs）在PCa分子分层、预后预测及临床决策中的作用。
通过一致性聚类分析确定铜死亡相关分子亚型。采用LASSO Cox回归分析和10倍交叉验证构建预后特征。在内部验证队列和8个外部验证队列中进一步验证。使用ssGSEA和ESTIMATE算法比较两个风险组之间的肿瘤微环境。最后，采用qRT-PCR在细胞水平上探索这些模型基因的表达和调控。此外，使用4D Label-Free LC-MS/MS和RNAseq研究关键模型基因B4GALNT4敲低后CRGs在蛋白质和RNA水平的变化。
鉴定出两种铜死亡相关分子亚型，其预后、临床特征和免疫微环境存在显著差异。免疫抑制微环境与预后不良相关。构建了由五个基因（B4GALNT4、FAM83D、COL1A、CHRM3和MYBPC1）组成的预后特征。该特征的性能和通用性在来自多个中心的八个完全独立的数据集中得到验证。高危组患者预后较差，免疫细胞浸润更多，免疫相关功能更活跃，人类白细胞抗原和免疫检查点分子表达更高，免疫评分更高。此外，还基于风险特征分析了抗PDL-1免疫治疗预测、体细胞突变、化疗反应预测和潜在药物预测。五个模型基因在qPCR中的表达和调控验证与生物信息学分析结果一致。转录组学和蛋白质组学分析表明，关键模型基因B4GALNT4可能在转录后通过蛋白质修饰调控CRGs。
本研究鉴定的铜死亡相关分子亚型和预后特征可用于预测PCa的预后并为临床决策提供参考。此外，我们在PCa中鉴定出一个潜在的铜死亡相关癌基因B4GALNT4，可作为联合铜死亡治疗PCa的靶点。
