摘要
Abstract
Objective To investigate the effect of combined use of CDK12 inhibitor and PARP inhibitor on tumor and in-testinal flora in nude mice with pancreatic cancer.Methods PANC-1 pancreatic cancer cell suspension was subcutaneously inocu-lated into the right back of nude mice to establish a model of pancreatic cancer.After successful modeling,the mice were randomly divided into control group(corn oil by gavage),CDK12 inhibitor group(CDK12 inhibitor+corn oil by gavage),PARP inhibitor group(PARP inhibitor+corn oil by gavage),and combination group(CDK12 inhibitor+PARP inhibitor+corn oil by gavage).Af-ter gavage for 4 consecutive weeks,tumor tissue and intestinal fecal samples were collected from the nude mice in each group,and tumor weight and volume were measured.Transcriptome sequencing was performed for tumor tissue to identify differentially ex-pressed genes(DEGs),and then GO functional enrichment analysis and KEGG pathway enrichment analysis were performed for these genes.Metagenomic sequencing was performed for fecal samples,and the Last Common Ancestor algorithm was used to ana-lyze the abundance of species in intestinal flora;KEGG pathway functional annotation was performed to analyze functional diffe-rences between flora,a principal coordinate analysis(PCoA)was used to visualize spatial distribution differences in flora structure and function between groups.Results The combination group had significantly lower tumor volume and weight than the other three groups(F=22.81,27.09,P＜0.05).There were 139 DEGs between the control group and the combination group,which was the highest number of DEGs between any two groups.The KEGG pathway enrichment analysis showed that these DEGs were mainly enriched in the pathways such as plasma membrane composition,cell adhesion and extracellular matrix interaction,immune response,and inflammatory response,while the GO functional enrichment analysis showed that these DEGs were mainly enriched in the functions such as cell surface,immune response,and cell signal transduction.There was a significant difference in the com-position of intestinal flora between the four groups,and the results of PCoA showed that the control group was clearly separated from the other three groups in terms of flora structure,and the combination group was significantly separated from the other three groups in terms of flora function(P＜0.05).Conclusion The combined use of CDK12 inhibitor and PARP inhibitor can signifi-cantly inhibit tumor growth in nude mice with pancreatic cancer and exert an antitumor effect by affecting the expression and func-tion of related genes in tumor tissue and regulating the structure and function of intestinal flora in nude mice.关键词
胰腺肿瘤/胃肠道微生物组/多(ADP核糖)聚合酶抑制剂/蛋白激酶抑制剂/转录组Key words
Pancreatic neoplasms/Gastrointestinal microbiome/Poly(ADP-ribose)polymerase inhibitors/Protein ki-nase inhibitors/Transcriptome分类
医药卫生
