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一种针对乙型肝炎病毒感染相关肝细胞癌的新型预后框架:来自铁死亡和铁代谢蛋白质组学的见解

A novel prognostic framework for HBV-infected hepatocellular carcinoma: insights from ferroptosis and iron metabolism proteomics.

作者信息

Cheng Zhiwei, Ren Yongyong, Wang Xinbo, Zhang Yuening, Hua Yingqi, Zhao Hongyu, Lu Hui

机构信息

Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China.

Department of Orthopedic Oncology, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, Shanghai 200080, China.

出版信息

Brief Bioinform. 2025 May 1;26(3). doi: 10.1093/bib/bbaf216.

Abstract

Effective classification methods and prognostic models enable more accurate classification and treatment of hepatocellular carcinoma (HCC) patients. However, the weak correlation between RNA and protein data has limited the clinical utility of previous RNA-based prognostic models for HCC. In this work, we constructed a novel prognostic framework for HCC patients using seven differentially expressed proteins associated with ferroptosis and iron metabolism. Furthermore, this prognostic model robustly classifies HCC patients into three clinically relevant risk groups. Significant differences in overall survival, age, tumor differentiation, microvascular invasion, distant metastasis, and alpha-fetoprotein levels were observed among the risk groups. Based on the prognostic model and known biological pathways, we explored the potential mechanisms underlying the inconsistent differential expression patterns of FTH1 (Ferritin heavy chain 1) mRNA and protein. Our findings demonstrated that tumor tissues in HCC patients promote liver cancer progression by downregulating FTH1 protein expression, rather than upregulating FTH1 mRNA expression, ultimately leading to poor prognosis. Subsequently, based on risk score and tumor size, we developed a nomogram for predicting the prognosis of HCC patients, which demonstrated superior predictive performance in both the training and validation cohorts (C-index: 0.774; AUC for 1-5 years: 0.783-0.964). Additionally, our findings demonstrated that the adverse prognosis of high-risk HCC patients was closely correlated with ferroptosis in liver cancer tissues, alterations in iron metabolism, and changes in the tumor immune microenvironment. In conclusion, our prognostic model and predictive nomogram offer novel insights and tools for the effective classification of HCC patients, potentially enhancing clinical decision-making and outcomes.

摘要

有效的分类方法和预后模型能够更准确地对肝细胞癌(HCC)患者进行分类和治疗。然而,RNA与蛋白质数据之间的弱相关性限制了先前基于RNA的HCC预后模型的临床应用。在这项研究中,我们利用七种与铁死亡和铁代谢相关的差异表达蛋白构建了一种针对HCC患者的新型预后框架。此外,该预后模型能够稳健地将HCC患者分为三个临床相关的风险组。在风险组之间观察到总生存期、年龄、肿瘤分化、微血管侵犯、远处转移和甲胎蛋白水平存在显著差异。基于预后模型和已知的生物学途径,我们探讨了FTH1(铁蛋白重链1)mRNA和蛋白质差异表达模式不一致的潜在机制。我们的研究结果表明,HCC患者的肿瘤组织通过下调FTH1蛋白表达而非上调FTH1 mRNA表达来促进肝癌进展,最终导致预后不良。随后,基于风险评分和肿瘤大小,我们开发了一种用于预测HCC患者预后的列线图,该列线图在训练和验证队列中均表现出卓越的预测性能(C指数:0.774;1至5年的AUC:0.783 - 0.964)。此外,我们的研究结果表明,高危HCC患者的不良预后与肝癌组织中的铁死亡、铁代谢改变以及肿瘤免疫微环境变化密切相关。总之,我们的预后模型和预测列线图为有效分类HCC患者提供了新的见解和工具,可能会改善临床决策和治疗结果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4b6/12085197/105a72fd6f45/bbaf216f1.jpg

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