Department of Gastroenterology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
Front Immunol. 2022 Oct 25;13:1008146. doi: 10.3389/fimmu.2022.1008146. eCollection 2022.
Cuproptosis is a recently discovered form of programmed cell death; however, its role in ulcerative colitis (UC) remains a void.
Three gene expression profiles were acquired from the GEO database. Subsequently, the single sample gene set enrichment analysis (ssGSEA) was performed to identify the immune infiltration characteristics of UC. Correlation analysis between cuproptosis and immune infiltration was further conducted, and the cuproptosis-related genes were applied to construct a UC diagnostic model. Subsequently, analysis results of microarray data were experimentally validated by DSS-induced colitis in mice. Finally, therapeutic agents for the cuproptosis-related genes were screened owing to the gaping field of therapeutic agents on cuproptosis.
Three gene expression profiles with 343 samples (290 UC and 53 healthy samples) were included. Immune infiltration revealed that UC patients had a higher level of DCs, B cells, CD8 T cells, iDCs, Macrophages, neutrophils, pDCs, T helper cells, Tfh, Th1 cells, Th2 cells, TIL and Treg than normal subjects. Moreover, almost all cuproptosis-related genes were significantly negatively associated with immune infiltration in UC patients. The risk prediction model based on cuproptosis-related genes showed an excellent discrimination for UC. Animal experiments revealed significant alterations in genes essential for cuproptosis between DSS-induced colitis mice and healthy controls, providing experimental validation for the analysis results of microarray data. Further analysis revealed that latamoxef, vitinoin, clomipramine, chlorzoxazone, glibenclamide, pyruvic acid, clindamycin, medrysone, caspan, and flavin adenine dinucleotide might be the target agents for cuproptosis-related genes.
In conclusion, cuproptosis was significantly associated with immune infiltration in UC, and the cuproptosis-related genes showed an excellent discrimination for UC.
铜死亡是一种新发现的细胞程序性死亡形式，但在溃疡性结肠炎（UC）中的作用尚不清楚。
从 GEO 数据库中获取了三个基因表达谱。随后，进行了单样本基因集富集分析（ssGSEA），以鉴定 UC 的免疫浸润特征。进一步进行了铜死亡与免疫浸润的相关性分析，并应用铜死亡相关基因构建了 UC 诊断模型。随后，通过 DSS 诱导的小鼠结肠炎对微阵列数据的分析结果进行了实验验证。最后，由于铜死亡治疗药物领域存在空白，筛选了铜死亡相关基因的治疗药物。
纳入了 343 例样本（290 例 UC 和 53 例健康对照）的三个基因表达谱。免疫浸润分析显示，UC 患者的树突状细胞（DCs）、B 细胞、CD8 T 细胞、iDCs、巨噬细胞、中性粒细胞、pDCs、辅助性 T 细胞、滤泡辅助性 T 细胞（Tfh）、Th1 细胞、Th2 细胞、肿瘤浸润淋巴细胞（TIL）和调节性 T 细胞（Treg）水平明显高于健康对照。此外，UC 患者中几乎所有的铜死亡相关基因与免疫浸润均呈显著负相关。基于铜死亡相关基因的风险预测模型对 UC 具有很好的鉴别能力。动物实验显示，DSS 诱导的结肠炎小鼠与健康对照组之间铜死亡相关基因存在显著变化，为微阵列数据的分析结果提供了实验验证。进一步分析显示，拉氧头孢、维生素 K2、氯米帕明、氯唑沙宗、格列本脲、丙酮酸、克林霉素、甲泼尼龙、胱天蛋白酶、黄素腺嘌呤二核苷酸可能是铜死亡相关基因的靶标药物。
总之，铜死亡与 UC 中的免疫浸润显著相关，铜死亡相关基因对 UC 具有很好的鉴别能力。
