黄芪-莪术影响HIF-1α/VEGF抑制肺癌血管生成相关信号通路的网络药理学研究

Network pharmacology analysis of Astragalus-Curcuma in inhibiting lung cancer angiogenesis related signal pathways

目的:运用网络药理学方法探索黄芪-莪术抑制肺癌血管生成可能的作用靶点,推测其与前期发现的目标通路缺氧诱导因子-1α(HIF-1α)/血管内皮生长因子(VEGF)可能存在的相互关系,为进一步研究其作用机制确定方向。方法:通过TCMSP数据库收集黄芪-莪术有效成分,通过DisGeNET数据库搜索人肺癌和肿瘤血管生成的相关靶点,利用Venny软件获得黄芪、莪术抑制肺癌血管生成的共同作用靶点,利用String数据库及Cytoscape 3.7.2构建黄芪-莪术抑制肺癌血管生成的靶点网络;再通过Cytoscape 3.7.2内置的Network Analyzer分析网络拓扑学参数得到核心作用靶点,最后利用DAVID数据库以及Cytoscape 3.7.2对相关核心靶点进行GO及KEGG生物通路富集分析。结果:通过TCMSP数据库及文献补充得到黄芪、莪术活性成分共28个(黄芪皂苷、黄芪多糖、山奈酚、槲皮素、莪术醇等具有抑制肺癌血管生成的作用),成分靶点共513个;通过Venny及Cytoscape 3.7.2软件分析,获得黄芪-莪术抑制肺癌血管生成的靶点20个,核心靶点为EGFR,其余关键靶点涉及VEGFA、HIF-1α、STAT3等;KEGG分析得到与这些抗肺癌血管生成靶点相关的主要信号通路有HIF-1信号通路、MAPK信号通路等,其中核心靶点EGFR、VEGFA、HIF-1α均在HIF-1信号通路中涉及。结论:黄芪-莪术配伍中以黄芪皂苷(包括Ⅰ、Ⅱ、Ⅲ)、莪术醇、黄芪多糖、槲皮素为主的活性成分与其抑制肺癌血管生成机制关系最为密切,推测其通过作用于EGFR/PI3K/Akt信号通路影响下游HIF-1α/VEGF相关蛋白表达,从而达到抑制肺癌血管生成的效果。

Objective:Based on the method of network pharmacology,to explore the possible targets of AstragalusCurcuma in inhibiting lung cancer angiogenesis,and speculate the possible interaction relationship between it and the target pathway HIF-1α/VEGF discovered in the previous stage,and determine the direction for further study of its mechanism.Methods:The effective components of Astragalus-Curcuma through TCMSP database were collected,related targets of human lung cancer and tumor angiogenesis through DisGeNET database were searched,Venny software was used to obtain the common target of Astragalus and Curcuma turmeric inhibiting lung cancer angiogenesis,String database and Cytoscape 3.7.2 was used to construct a network of targets for Astragalus-Curcuma to inhibit lung cancer angiogenesis;then the network topology parameters were analyzed through Cytoscape 3.7.2 to obtain the core target points,and finally DAVID database and Cytoscape 3.7.2 were used to predict the target of Astragalus-Curcuma inhibitory lung cancer angiogenesis,analyzed by GO and KEGG biological pathway.Results:A total of 28 active ingredients of Astragalus and Curcuma turmeric were obtained through TCMSP database and literature supplements,and a total of 513 component targets were obtained.Among them,total saponins of astragalus,astragalus polysaccharides,kaempferol,quercetin,curcumol,etc..Through the analysis of Venny and Cytoscape 3.7.2 software,20 targets of Astragalus-Curcuma for inhibiting lung cancer angiogenesis were obtained,the core target was EGFR,and the remaining key targets involved VEGFA,HIF-1α,STAT3,etc.;KEGG analysis found that main signaling pathways related to angiogenesis targets included HIF-1 signaling pathway,MAPK signaling pathway,etc..The core targets EGFR,VEGFA,and HIF-1αwere all involved in HIF-1 signaling pathway.Conclusion:Astragalus-Curcuma compatibility mainly contains astragaloside(includeⅠ,Ⅱ,Ⅲ),curcumol,astragalus polysaccharides,and quercetin.The formation mechanism is most closely related to the inhibitory effects on lung cancer vessels.It is speculated that it affects downstream HIF-1α/VEGF by acting on the EGFR/PI3 K/Akt signaling pathway to achieve the effect of inhibiting lung cancer angiogenesis.