构建铜死亡相关LncRNA风险模型预测肝细胞癌的预后及分子特征

Construction of a Cuproptosis-related LncRNA Risk Model to Predict the Prognosis and Molecular Characteristics of Hepatocellular Carcinoma

铜死亡是一种新的程序性细胞死亡途径,由铜与脂酰化三羧酸循环蛋白直接结合而启动。调节肿瘤细胞中的铜死亡是一种新的治疗方法。然而,铜死亡相关长链非编码RNA(LncRNA)在肝细胞癌(HCC)中的潜在作用和临床意义尚不明确。本研究基于TCGA-LIHC数据集对19个铜死亡相关基因进行共表达分析,共鉴定出994个铜死亡相关LncRNA。采用LASSO回归和多因素Cox回归分析筛选出4个与铜死亡相关的预后LncRNA(TMCC1-AS1、AC009974.2、AL355574.1和DDX11-AS1)构建预后风险模型,并计算所有HCC患者样本的风险评分。按1:1的比例将肝癌患者分为高风险组和低风险组。Kaplan-Meier生存曲线分析显示,高风险组患者的总生存率(OS)明显低于低风险组。回归分析和ROC曲线证实了风险评分的预后价值。此外,本研究分析了风险评分与通路富集分析、免疫检查点基因、免疫细胞浸润、抗癌药物敏感性和体细胞基因突变之间的相关性。差异表达分析结果表明,TMCC1-AS1、AC009974.2、AL355574.1和DDX11-AS1在肿瘤组织中的表达均升高。最后,利用收集的8例行根治性手术肝癌患者的癌组织及癌旁肝组织进行实时荧光定量PCR(qRT-PCR)验证,以增加本模型的组织学证据。本研究构建了一个由4种铜死亡相关LncRNA组成的风险模型,该模型与患者的预后及免疫浸润环境明显相关,在预测患者免疫治疗效果及指导化疗药物选择方面具有一定的临床应用价值。

Cuproptosis is a new programmed cell death pathway,which is initiated by the direct binding of copper to the fatty acyl tricarboxylic acid cycle proteins.Modulation of cuproptosis in tumor cells is a novel therapeutic approach.However,the potential role and clinical significance of cuproptosis-related long non-coding RNA(lncRNA)in hepatocellular carcinoma(HCC)remain unclear.In this study,a total of 994 cuproptosis-related lncRNA were identified by co-expression analysis of 19 cuproptosis-related genes based on the TCGA-LIHC dataset.LASSO regression and multivariate Cox regression analysis were used to screen out four prognostic lncRNA(TMCC1-AS1,AC009974.2,AL355574.1 and DDX11-AS1)related to copper mortality to construct a prognostic risk model,and the risk scores of all HCC patient samples were calculated.HCC patients were divided into high risk and low risk groups at a 1:1 ratio.Kaplan-Meier survival curve analysis showed that the overall survival rate(OS)of the high risk group was significantly lower than that of the low risk group.Regression analysis and ROC curve confirmed the prognostic value of the risk score.In addition,we analyzed the correlation between risk scores and pathway enrichment analysis,immune checkpoint genes,immune cell infiltration,anticancer drug sensitivity,and somatic gene mutations.The results of differential expression analysis showed that TMCC1-AS1,AC009974.2,AL355574.1 and DDX11-AS1 were all up-regulated in tumor tissues,which were verified by real-time fluorescent quantitative PCR(qRT-PCR)in tumor tissues and adjacent liver tissues collected from 8 patients with hepatocellular carcinoma undergoing radical surgery.This give histological evidence for this model.In conclusion,a risk model composed of four cuproptosis-related lncRNA was constructed,which was significantly related to the prognosis and immune infiltration environment of patients.This model has certain clinical application value in predicting the effects of immunotherapy and guiding the selection of chemotherapy drugs.