鉴定 ROS 和 KEAP1 相关基因,验证 α-hederin 诱导 CRC 细胞死亡的靶点。

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2024-05-15 DOI:10.1002/ddr.22200
Gang Wang, Zhi-Min Zhu, Kun Wang
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引用次数: 0

摘要

在本研究中,我们利用 GEO 数据集(GSE4107 和 GSE41328)分析并验证了 ROS 和 KEAP1 交叉作用致癌特征中的差异表达基因(DEGs)。根据 DEGs 完成了多通路富集分析。利用 Cox 回归分析确定了结直肠腺癌(COAD)的基因特征。采用卡普兰-梅耶生存率和接收者操作特征曲线分析来探讨 COAD 中特定基因的预后价值。此外,还分析了潜在的免疫特征和药物敏感性预测。通过分子对接验证了SuperPred中预测的α-hederin靶点。此外,还进行了基因表达水平和 Western 印迹分析。共有 48 个基因被鉴定为 DEGs,其中包括 COL1A1、CXCL12、COL1A2、FN1、CAV1、TIMP3 和 IGFBP7 等枢纽基因。研究发现,潜在的抗结直肠癌(CRC)药物α-hederin能提高HCT116细胞的敏感性,调节CAV1和COL1A1,并显著降低KEAP1、Nrf2和HO-1的表达。KEAP1相关基因可能是ROS在CRC中的重要介质,KEAP1相关基因可有效预测CRC的预后并评估个体化治疗。因此,α-hederin可能是临床治疗CRC的有效化疗增敏剂。
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Identification of ROS and KEAP1-related genes and verified targets of α-hederin induce cell death for CRC

In this study, we analyzed and verified differentially expressed genes (DEGs) in ROS and KEAP1 crosstalk in oncogenic signatures using GEO data sets (GSE4107 and GSE41328). Multiple pathway enrichment analyses were finished based on DEGs. The genetic signature for colorectal adenocarcinoma (COAD) was identified by using the Cox regression analysis. Kaplan–Meier survival and receiver operating characteristic curve analysis were used to explore the prognosis value of specific genes in COAD. The potential immune signatures and drug sensitivity prediction were also analyzed. Promising small-molecule agents were identified and predicted targets of α-hederin in SuperPred were validated by molecular docking. Also, expression levels of genes and Western blot analysis were conducted. In total, 48 genes were identified as DEGs, and the hub genes such as COL1A1, CXCL12, COL1A2, FN1, CAV1, TIMP3, and IGFBP7 were identified. The ROS and KEAP1-associated gene signatures comprised of hub key genes were developed for predicting the prognosis and evaluating the immune cell responses and immune infiltration in COAD. α-hederin, a potential anti-colorectal cancer (CRC) agent, was found to enhance the sensitivity of HCT116 cells, regulate CAV1 and COL1A1, and decrease KEAP1, Nrf2, and HO-1 expression significantly. KEAP1-related genes could be an essential mediator of ROS in CRC, and KEAP1-associated genes were effective in predicting prognosis and evaluating individualized CRC treatment. Therefore, α-hederin may be an effective chemosensitizer for CRC treatments in clinical settings.

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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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