基于生物信息学和网络药理学的TNBC-PTX耐药机制研究及活性药物预测分析

Mechanism of Paclitaxel Resistance and Prediction of Active Drugs in Triple Negative Breast Cancer Based on Bioinformatics and Network Pharmacology

目的通过生物信息学和网络药理学方法探讨三阴性乳腺癌紫杉醇(TNBC-PTX)耐药机制及其活性药物筛选。方法利用GEO2R在线分析工具对耐紫杉醇的三阴性乳腺癌相关数据集进行差异分析,获得差异表达基因。随后使用STRING数据库构建蛋白质-蛋白质相互作用(PPI)网络,在此基础上使用DAVID数据库分析其生物学过程。使用Cytoscape 3.9.1中的cytoHubba插件筛选枢纽基因,并借助Coremine Medical数据库预测枢纽基因关联中药。使用Autodock 4.6软件进行分子对接模拟,验证活性药物与枢纽基因的结合程度。最后采用PyMOL和ligPlus软件对结果行可视化处理。结果共获得122个差异表达基因,主要参与平滑肌细胞增殖、细胞间信号、促进NO合成、细胞增殖及IL-6反应等生物学过程,参与的信号通路包括癌症通路、磷脂酰肌醇3-蛋白激酶B信号通路、利什曼病和ErB信号通路等。PPI网络中的8个枢纽基因为TLR4、PTGS2、AREG、AR、MMP1、EDN1、EREG和TLR3,其中TLR4分值最高。茯苓的活性药物与TLR4关联性好,分子对接模拟验证去氢齿孔酸与TLR4结合牢固。结论TNBC-PTX耐药机制受多个基因共同调控,其中TLR4在其中起到关键作用,其表达上调与耐药性关系密切,茯苓中的去氢齿孔酸有望成为逆转TNBC-PTX耐药的活性药物,仍需进一步实验验证其干预效果。

Objective To explore the resistance mechanism of triple negative breast cancer(TNBC)to Paclitaxel(PTX)and screen its active drugs via bioinformatics and network pharmacology.Methods The GEO2R online analysis tool was used to conduct differential analysis of the dataset related to PTX-resistant TNBC.A protein-protein interaction(PPI)network was constructed by using the STRING database,on the basis of which the biological processes were analyzed by using the DAVID database.Hub genes were screened using the cytoHubba plugin in Cytoscape 3.9.1 while hub gene-associated TCMs were predicted with the help of the Coremine Medical database.Molecular docking simulations were performed by using Autodock 4.6 software to verify the extent of binding of active drugs to the hub gene.Finally,PyMOL and ligPlus software was used to visualize the results.Results A total of 122 DEGs were obtained,which were mostly involved in such biological processes as smooth muscle cell proliferation,intercellular signaling,promotion of NO synthesis,cell proliferation,and the IL-6 response.The involved signaling pathways included the cancer pathway,PI3K-Akt,leishmaniasis,and ErB signaling pathways.The eight hub genes in the PPI network were TLR4,PTGS2,AREG,AR,MMP1,EDN1,EREG and TLR3,among which TLR4 had the highest score.The active drugs of Poriacocos had a good association with TLR4.Molecular docking simulation confirmed that dehydrotrametenolic acid had a strong binding with TLR4.Conclusion The drug resistance mechanism of TNBC-PTX is regulated by multiple genes,among which TLR4 plays a key role,and its up-regulation is closely related to drug resistance.Dehydrotrametenolic acid from Poriacocos is expected to be an active drug to reverse the drug resistance of TNBC-PTX,but more experiments are needed to verify the intervention effect.