CYP2E1 的下调与胶质瘤的不良预后和肿瘤进展有关。
Downregulation of CYP2E1 is associated with poor prognosis and tumor progression of gliomas.
机构信息
Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China.
出版信息
Cancer Med. 2021 Nov;10(22):8100-8113. doi: 10.1002/cam4.4320. Epub 2021 Oct 6.
OBJECTIVE
To explore the role and possible regulatory mechanisms of CYP2E1 in gliomas.
METHODS
RNA-seq data and corresponding clinical information of glioma patients were collected from The Cancer Genome Atlas and Chinese Glioma Genome Atlas, and mRNA data of normal brain tissues were obtained by the Genotype-Tissue Expression project. The Wilcoxon test was performed to analyze the correlation between CYP2E1 expression and glioma subtypes. Univariate and multivariate Cox proportional hazards regression, receiver operating characteristic curves, and Kaplan-Meier plots were used to evaluate the prognostic value of CYP2E1 in glioma. Functional enrichment analyses and immune infiltration analyses were performed to investigate the potential function of CYP2E1 in gliomas. Moreover, we investigated the miRNA and epigenetic mechanisms that regulate CYP2E1 expression. Finally, network pharmacology and molecular docking experiments were used to predict drugs that target CYP2E1.
RESULTS
The downregulation of CYP2E1 expression may predict a poor prognosis for glioma patients. CYP2E1 expression decreased with increasing WHO grade (II-IV), and its level was correlated with clinical features, including age, 1p19q codeletion status, and IDH state in glioma tissues. Furthermore, CYP2E1 was involved in lipid metabolism and ferroptosis and related to the tumor immune microenvironment due to its strong correlation with the levels of infiltrating monocytes and Tregs. Moreover, variation in the total methylation level and copy number of CYP2E1 was moderately correlated with its mRNA expression (p < 0.05). CYP2E1 was predicted to be targeted by hsa-miR-527, whose expression was negatively related to CYP2E1 mRNA expression (p < 0.05). In addition, effective compounds that target CYP2E1, including 18beta-glycyrrhetinic acid, styrene, toluene, nicotine, m-xylene, p-xylene, and colchicine, were identified.
CONCLUSION
The downregulation of CYP2E1, which affects lipid metabolism and the ferroptosis signaling pathway, promotes the progression of gliomas.
目的
探讨 CYP2E1 在神经胶质瘤中的作用及可能的调控机制。
方法
从 The Cancer Genome Atlas 和 Chinese Glioma Genome Atlas 中收集神经胶质瘤患者的 RNA-seq 数据及相应的临床资料，从 Genotype-Tissue Expression project 中获得正常脑组织的 mRNA 数据。采用 Wilcoxon 检验分析 CYP2E1 表达与神经胶质瘤亚型之间的相关性。采用单因素和多因素 Cox 比例风险回归、受试者工作特征曲线和 Kaplan-Meier 图评估 CYP2E1 对神经胶质瘤的预后价值。进行功能富集分析和免疫浸润分析，以探讨 CYP2E1 在神经胶质瘤中的潜在功能。此外，我们还研究了调节 CYP2E1 表达的 miRNA 和表观遗传机制。最后，通过网络药理学和分子对接实验预测靶向 CYP2E1 的药物。
结果
CYP2E1 表达下调可能预示神经胶质瘤患者预后不良。CYP2E1 表达随 WHO 分级（Ⅱ-Ⅳ级）的升高而降低，其水平与年龄、1p19q 共缺失状态和胶质瘤组织中 IDH 状态等临床特征相关。此外，由于与浸润单核细胞和 Tregs 的水平具有很强的相关性，CYP2E1 参与脂质代谢和铁死亡，并与肿瘤免疫微环境相关。此外，CYP2E1 的总甲基化水平和拷贝数的变化与 mRNA 表达呈中度相关（p<0.05）。CYP2E1 被预测为 hsa-miR-527 的靶基因，其表达与 CYP2E1 mRNA 表达呈负相关（p<0.05）。此外，还鉴定出了靶向 CYP2E1 的有效化合物，包括 18β-甘草次酸、苯乙烯、甲苯、尼古丁、间二甲苯、对二甲苯和秋水仙碱。
结论
CYP2E1 的下调影响脂质代谢和铁死亡信号通路，促进神经胶质瘤的进展。
Zotero 插件