基于网络药理学探讨长春新碱治疗乳腺癌的作用机制

Action Mechanism of Vincristine in Treatment of Breast Cancer Based on Network Pharmacology

目的 基于网络药理学预测长春新碱治疗乳腺癌的作用机制,并进行实验验证。方法 通过靶点预测技术与生物信息学相结合的方法,预测长春新碱治疗乳腺癌的作用靶点并对其进行功能/通路富集分析,利用Westernblot检测NPM1,DHX9,EEF1A及HSP90蛋白表达。结果 利用SwissTargetPrediction数据库检索出长春新碱具有107个靶点基因,在OMIM中获得506个与乳腺癌密切相关的靶点基因。利用Cytoscape软件绘制长春新碱与乳腺癌的蛋白互作关系网络图,采用网络拓扑分析方法获得70个关键基因。利用ClueGO对70个关键基因进行富集分析。结果显示,长春新碱影响包括白介素7(IL-7)介导的信号通路、mRNA稳定性、蛋白质-DNA复合体、蛋白质定位于线粒体的正向调控等生物过程,也能作用于分子功能如泛素蛋白连接酶、淀粉样蛋白的反应等,并通过调控转录失调、细胞周期、抗原处理和递呈等相关信号通路影响癌细胞生命活动。同时Western blot结果表明长春新碱(200 nmol/L)能下调NPM1,DHX9,EEF1A及HSP90蛋白表达。结论 长春新碱通过多途径多靶点接作用于乳腺癌细胞从而达到抑制乳腺癌的作用。

Objective To predict the action mechanism of vincristine in the treatment of breast cancer based on network pharmacology.Methods The target of vincristine in the treatment of breast cancer was predicted,and its function/pathway enrichment analysis was carried out to reveal the mechanism through the combination of target prediction technology and bioinformatics.The protein expressions of NPM1,DHX9,EEF1A and HSP90 were detected via western blot.Results Totally 107 target genes of vincristine were retrieved by the target prediction technology in SwissTargetPrediction,and 506 target genes closely related to breast cancer were obtained in OMIM.The network maps of protein interaction between vincristine and breast cancer were drawn by using the network visualization software Cytoscape,and 70 key genes were screened and obtained by using GluoGO.The results showed that vincristine affected the following biological processes,including IL-7-mediated signaling pathway,mRNA stability,protein-DNA complex,positive regulation of protein localization in mitochondria,etc.,and affected the molecular function such as ubiquitin protein ligase,amyloid reaction,etc.,and regulated signal pathways including transcription disorders,cell cycle,antigen processing and presentation.The protein expressions of NPM1,DHX9,EEF1A and HSP90 were downregulated after vincristine treatment.Conclusion Vincristine had the characteristic of multiple targets in the treatment of breast cancer.