基于铜绿假单胞菌致细胞凋亡相关RNA甲基化调节因子的全新风险模型的鉴定和开发，用于预测肝细胞癌患者的预后和描述免疫状态。
Identification and development of a novel risk model based on cuproptosis-associated RNA methylation regulators for predicting prognosis and characterizing immune status in hepatocellular carcinoma.
发表日期：2023 Feb
作者：
Duguang Li, Zhaoqi Shi, Xiaolong Liu, Shengxi Jin, Peng Chen, Yiyin Zhang, Guoqiao Chen, Xiaoxiao Fan, Jing Yang, Hui Lin
来源：
Hepatology International
摘要：
铜过量引起的一种新型细胞死亡Cuproptosis，在肝细胞癌（HCC）中常常被忽视，需要更多研究。通过LASSO Cox回归分析，分析了TCGA数据库患者的RNA-seq和临床数据，建立了预测模型，并利用外部数据集ICGC进行了验证。应用GSEA和CIBERSORT研究了HCC的分子机制和免疫微环境。通过多种体外实验确认了Elesclomol引起的Cuproptosis。利用qRT-PCR分析在HCC组织中验证了预后基因的表达。最初选取了18个与Cuproptosis相关的RNA甲基化调节因子（CARMRs）进行预后分析。应用LASSO Cox回归方法创建了一个九基因标志。利用TCGA和ICGC数据库进行了生存和ROC实验来验证模型。此外，在常见药物方面存在明显的药物敏感性差异。高危组中显示出更高的肿瘤突变负荷。通过GSEA分析发现两组在代谢途径和RNA处理方面存在明显差异。同时，CIBERSORT分析显示两组之间各种免疫细胞的浸润水平存在不同。Elesclomol处理引起了一种独特的程序性细胞死亡，并伴随着丢失脂肪酰化线粒体蛋白和Fe-S簇蛋白。qRT-PCR结果表明，大多数预后基因在HCC组织中表达差异明显。总的来说，我们的预测标志显示出在预测HCC患者总生存方面具有潜在价值，可能为个体化治疗提供有价值的线索。 © 2023亚太肝病学会。
Cuproptosis, a novel cell death caused by excess copper, is quite obscure in hepatocellular carcinoma (HCC) and needs more investigation.RNA-seq and clinical data of HCC patients TCGA database were analyzed to establish a predictive model through LASSO Cox regression analysis. External dataset ICGC was used for the verification. GSEA and CIBERSORT were applied to investigate the molecular mechanisms and immune microenvironment of HCC. Cuproptosis induced by elesclomol was confirmed via various in vitro experiments. The expression of prognostic genes was verified in HCC tissues using qRT-PCR analysis.Initially, 18 cuproptosis-associated RNA methylation regulators (CARMRs) were selected for prognostic analysis. A nine-gene signature was created by applying the LASSO Cox regression method. Survival and ROC assays were carried out to validate the model using TCGA and ICGC database. Moreover, there exhibited obvious differences in drug sensitivity in terms of common drugs. A higher tumor mutation burden was shown in the high-risk group. Additionally, significant discrepancies were found between the two groups in metabolic pathways and RNA processing via GSEA analysis. Meanwhile, CIBERSORT analysis indicated different infiltrating levels of various immune cells between the two groups. Elesclomol treatment caused a unique form of programmed cell death accompanied by loss of lipoylated mitochondrial proteins and Fe-S cluster protein. The results of qRT-PCR indicated that most prognostic genes were differentially expressed in the HCC tissues.Overall, our predictive signature displayed potential value in the prediction of overall survival of HCC patients and might provide valuable clues for personalized therapies.© 2023. Asian Pacific Association for the Study of the Liver.