中药复方肠复康抗结直肠癌血管生成作用靶基因网络药理学研究

Pharmacological Study on Target Gene Network of Traditional Chinese Medicine Compound Changfukang Against Angiogenesis in Colorectal Cancer

目的运用网络药理学方法,研究中药复方肠复康(CFK)对结直肠癌(colorectal cancer,CRC)血管生成作用靶基因,为揭示其作用机制奠定理论基础。方法采用TTD、DrugBank数据库、OMIM数据库、GAD和PharmGKB等5个数据库分别检索CRC基因;采用TSMSP数据库及基于VBA工具的有效成分筛选方式检索CFK所含的5味中药,利用ADME参数进行有效成分筛选,通过TCMSP数据库检索各个有效成分的靶基因,利用cytoscape 3.2.1软件及其插件ClueGO、Bisogenet、CytoNCA对靶基因进行分析并构建CFK成分靶点网络图,并结合KEGG数据库进一步说明CFK与CRC血管生成靶基因的关系。结果 CRC靶基因339个,CFK靶基因182个;通过cytoscape构建并结合网络拓扑分析,ADRA1A、ADRA1B、ADRA1D、ADRB1、CHRM1、CHRM2、CHRM3、CHRM4、INSR、PIK3CG、RXRA、BAX、BCL2、CASP8、ICAM1、NFKBIA、CASP9、KDR、MAP2、PRKCA、PTGS2等靶点与血管生成相关;CFK治疗CRC过程中BRCA1、CDK2、CDKN1A、ITGA4、MDM2、YWHAG、CREBBP、CUL2、EP300、VHL、FLNA、SHC1、TRAF6、XPO1、EGFR、GRB2、IKBKG、NTRK1、TP53、 YWHAB、YWHAE与血管生成相关;主要通过调控PI3K-Akt、MAPK、HIF-1及VEGF信号通路抑制CRC患者新生血管生成。结论 CFK可能会通过VBRCA1、CDK2、CDKN1A、ITGA4、MDM2、YWHAG、CREBBP、CUL2、EP300、VHL、FLNA、SHC1、TRAF6、XPO1、EGFR、GRB2、IKBKG、NTRK1、TP53、 YWHAB、YWHAE等靶点调控PI3K-Akt、MAPK、HIF-1及VEGF等信号通路,进而发挥抑制CRC患者新生血管生成作用,具体机制有待进一步研究。

Objective To study the angiogenesis target gene of traditional Chinese medicine compound Changfukang(CFK) on colorectal cancer(CRC) by network pharmacology and lay a theoretical foundation for revealing its mechanism. Methods Colorectal cancer genes were searched using TTD, DrugBank database, OMIM database, GAD and PharmGKB. The TMSSP database and VBA tool-based active ingredient screening methods were used to search 5 Chinese medicines contained in CFK, using ADME parameters. The active ingredient was screened, and the relevant target genes of each active ingredient were searched by TCMSP database. The target gene was analyzed by cytoscape 3.2.1 software and its plug-ins ClueGO, Bisogenet and CytoNCA, and the target network map of CFK component was constructed, and further explained with KEGG database. The relationship between CFK and CRC angiogenesis target genes was further explained. Results There were 339 colorectal cancer target genes and 182 CFK target genes. ADRA1 A, ADRA1 B, ADRA1 D, ADRB1, CHRM1, CHRM2, CHRM3, CHRM4, INSR targets such as PIK3 CG, RXRA, BAX, BCL2, CASP8, ICAM1, NFKBIA, CASP9, KDR, MAP2, PRKCA, PTGS2 were related to angiogenesis. BRCA, CDK2, CDKN1 A, ITGA4, MDM2, YWHAG and CREBBP in the treatment of CRC by CFK, CUL2, EP300, VHL, FLNA, SHC1, TRAF6, XPO1, EGFR, GRB2, IKBKG, NTRK1, TP53, YWHAB and YWHAE were related to angiogenesis,mainly through regulation of PI3 K-Akt, MAPK, HIF-1 and VEGF signaling pathways neovascularization in patients with colorectal cancer. Conclusion CFK may regulate VBRCA1, CDK2, CDKN1 A, ITGA4, MDM2, YWHAG, CREBBP, CUL2, EP300, VHL, FLNA, SHC1, TRAF6, XPO1, EGFR, GRB2, IKBKG, NTRK1, TP53, YWHAB, YWHAE and other targets to affect these signaling pathways such as PI3 K-Akt, MAPK, HIF-1 and VEGF in order to inhibit the neovascularization of colorectal cancer patients. But the specific mechanism needs further study.