Li Lei, Sun Fengyuan, Kong Fanyang, Feng Yongpu, Song Yingxiao, Du Yiqi, Liu Feng, Kong Xiangyu
Digestive Endoscopy Center, Shanghai Tenth People's Hospital, Shanghai, China.
Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Front Oncol. 2023 Jun 13;13:1083956. doi: 10.3389/fonc.2023.1083956. eCollection 2023.
Cuproptosis is a newly discovered type of cell death. Little is known about the roles that cuproptosis related genes (CRGs) play in colorectal cancer (CRC). The aim of this study is to evaluate the prognostic value of CRGs and their relationship with tumor immune microenvironment.
TCGA-COAD dataset was used as the training cohort. Pearson correlation was employed to identify CRGs and paired tumor-normal samples were used to identify those CRGs with differential expression pattern. A risk score signature was constructed using LASSO regression and multivariate Cox stepwise regression methods. Two GEO datasets were used as validation cohorts for confirming predictive power and clinical significance of this model. Expression patterns of seven CRGs were evaluated in COAD tissues. experiments were conducted to validate the expression of the CRGs during cuproptosis.
A total of 771 differentially expressed CRGs were identified in the training cohort. A predictive model termed riskScore was constructed consisting of 7 CRGs and two clinical parameters (age and stage). Survival analysis suggested that patients with higher riskScore showed shorter OS than those with lower (0.0001). ROC analysis revealed that AUC values of cases in the training cohort for 1-, 2-, and 3-year survival were 0.82, 0.80, 0.86 respectively, indicating its good predictive efficacy. Correlations with clinical features showed that higher riskScore was significantly associated with advanced TNM stages, which were further confirmed in two validation cohorts. Single sample gene set enrichment analysis (ssGSEA) showed that high-risk group presented with an immune-cold phenotype. Consistently, ESTIMATE algorithm analysis showed lower immune scores in riskScore-high group. Expressions of key molecules in riskScore model are strongly associated with TME infiltrating cells and immune checkpoint molecules. Patients with a lower riskScore exhibited a higher complete remission rate in CRCs. Finally, seven CRGs involved in riskScore were significantly altered between cancerous and paracancerous normal tissues. Elesclomol, a potent copper ionophore, significantly altered expressions of seven CRGs in CRCs, indicating their relationship with cuproptosis.
The cuproptosis-related gene signature could serve as a potential prognostic predictor for colorectal cancer patients and may offer novel insights into clinical cancer therapeutics.
铜死亡是一种新发现的细胞死亡类型。关于铜死亡相关基因（CRGs）在结直肠癌（CRC）中所起的作用知之甚少。本研究旨在评估CRGs的预后价值及其与肿瘤免疫微环境的关系。
将TCGA-COAD数据集用作训练队列。采用Pearson相关性分析来识别CRGs，并使用配对的肿瘤-正常样本识别具有差异表达模式的CRGs。使用LASSO回归和多变量Cox逐步回归方法构建风险评分特征。使用两个GEO数据集作为验证队列，以确认该模型的预测能力和临床意义。在COAD组织中评估了7个CRGs的表达模式。进行实验以验证CRGs在铜死亡过程中的表达。
在训练队列中总共鉴定出771个差异表达的CRGs。构建了一个名为riskScore的预测模型，该模型由7个CRGs和两个临床参数（年龄和分期）组成。生存分析表明，风险评分较高的患者的总生存期（OS）比风险评分较低的患者短（P<0.0001）。ROC分析显示，训练队列中病例1年、2年和3年生存的AUC值分别为0.82、0.80、0.86，表明其具有良好的预测效能。与临床特征的相关性表明，较高的风险评分与晚期TNM分期显著相关，这在两个验证队列中得到了进一步证实。单样本基因集富集分析（ssGSEA）显示，高风险组呈现免疫冷表型。同样，ESTIMATE算法分析显示，风险评分高的组免疫评分较低。riskScore模型中的关键分子表达与肿瘤微环境浸润细胞和免疫检查点分子密切相关。风险评分较低的患者在CRC中的完全缓解率较高。最后，参与riskScore的7个CRGs在癌组织和癌旁正常组织之间有显著差异。强效铜离子载体埃拉莫林显著改变了CRC中7个CRGs的表达，表明它们与铜死亡的关系。
铜死亡相关基因特征可作为结直肠癌患者潜在的预后预测指标，并可能为临床癌症治疗提供新的见解。
