Changes in expression of cancer-associated fibroblast marker genes in mouse cervical cancer subcutaneously implanted tumor tissues after intragastric administration of BDE-209 and its significance
Objective To observe the changes in expression of cancer-associated fibroblasts(CAFs)marker genes of mouse cervical cancer subcutaneously implanted tumor tissues after intragastric administration of decabromodiphenyl ether(BDE-209)and to explore their possible mechanisms.Methods Forty female C57BL/6 mice were randomly divid-ed into the control group,low-dose BDE-209 group,medium-dose BDE-209 group,and high-dose BDE-209 group,with 10 mice in each group.All mice were used to establish the subcutaneous graft tumor models of cervical cancer by inocula-tion of cervical cancer U14 cell suspension in the right anterior axilla.Mice in the low-dose,medium-dose,and high-dose BDE-209 groups were given 20,100,and 500 mg/kg BDE-209 by oral gavage,and mice in the control group were given an equal volume of corn oil for 21 consecutive days.Transcriptome sequencing was performed on the subcutaneously trans-planted tumor tissues of mice in each group to screen the differentially expressed genes.The differential expressed genes and mouse CAFs marker genes were intersected to obtain CAFs marker differentially expressed genes.Gene ontology(GO)function and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed on CAFs marker differentially expressed genes,and the top ten CAFs marker differentially expressed genes were identified as CAFs marker differentially hub genes by using the Betweenness algorithm after the establishment of protein-protein interac-tion(PPI)network graphs.Some cervical cancer tissues from mice in the high-dose BDE-209 group and control group were taken,and their CAFs differential hub genes expression was detected by real-time fluorescence quantitative PCR.Results Thirty CAFs marker differential genes were screened out,including 29 up-regulated genes and 1 down-regulated gene.GO functional enrichment analysis showed that CAFs marker differential genes were mainly enriched in the extracel-lular matrix(ECM),reproductive structure development,PI3K/Akt signaling.KEGG pathway enrichment analysis showed that CAFs marker differential genes were mainly enriched in signaling pathways such as complement and coagula-tion cascade reactions and tumor pathways.The top ten hub genes identified by the PPI graphs and Betweenness algorithm were decorin(Dcn),intercellular adhesion molecule 1(Icam1),C-X-C motif chemokine ligand 12(Cxcl12),matrix me-tallopeptidase 2(MMP-2),platelet-derived growth factor receptor,beta polypeptide(Pdgfrb),Col5a2,complement com-ponent 1,s subcomponent 1(C1s1),hepatocyte growth factor(Hgf),complement component 3(C3),and plasminogen activator(Plat).Compared with the control group,the relative expression levels of Dcn,Icam1,Cxcl12,MMP-2,Pdg-frb,Col5a2,C1s1,Hgf,C3,and Plat mRNAs were elevated in the cancer tissues of mice in the high-dose BDE-209 group(all P<0.05),whereas there was no change in the relative expression of Pdgfrb mRNA(P>0.05).Conclusion Intra-gastric administration of BDE-209 resulted in elevated expression levels of CAFs-related marker genes Dcn,Icam1,Cx-cl12,MMP-2,Col5a2,C1s1,Hgf,C3,and Plat in mouse cervical cancer subcutaneously implanted tumor tissues,and the above-mentioned changes in gene expression may be involved in the occurrence and development of cervical cancer by inducing the ECM changes of CAFs and activating the PI3K/Akt signaling pathway.
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