抗HER2药物联合治疗通过靶向KIF23基因抑制卵巢癌细胞增殖

The combination therapy of anti-HER2 drugs inhibits the proliferation of ovarian cancer cell by targeting the KIF23 gene

目的:利用生物信息学方法探索抗HER2药物曲妥珠单抗和帕妥珠单抗联合治疗卵巢癌的潜在治疗靶点。方法:从GEO数据库中提取基因芯片数据GSE31432。使用GEO2R工具在对照组、两种单药治疗组和联合治疗组中找出差异表达基因。随后进行GO功能和KEGG途径富集分析,以鉴定差异表达基因的途径和功能。对这些基因进行PPI分析,并通过Cytoscape软件进行可视化,再使用GEPIA和Kaplan-Meier分析工具评估卵巢癌患者关键基因的差异表达和预后价值。随后在卵巢癌细胞系中验证KIF23基因的表达,敲除KIF23基因观察细胞系的增殖改变以及对动物成瘤的影响。再验证联合用药组中KIF23基因的表达差异,并且过表达KIF23基因后观察联合用药组卵巢癌细胞系增殖的改变。结果:总共确定了342个下调的差异表达基因,其中KIF23基因被确定为卵巢癌联合化疗机制中的潜在关键基因。KIF23基因在卵巢癌细胞系中的表达高于正常细胞系,且敲除KIF23基因后,卵巢癌细胞的增殖降低。与对照组、单药治疗组相比,联合治疗组KIF23基因的mRNA表达显著降低。联合治疗组显著抑制卵巢癌的增殖,而KIF23基因过表达可降低抗HER2联合治疗对增殖的抑制作用。结论:曲妥珠单抗和帕妥珠单抗联合治疗可能通过调控KIF23基因抑制卵巢癌增殖,KIF23基因可能成为抗肿瘤靶向治疗的新靶标和预后标记物。

Objective:To detect potential therapeutic targets for combination therapy with trastuzumab and pertuzumab in ovarian cancer.Methods:The microarray datasets(GSE31432)was derived from the Gene Expression Omnibus(GEO)database.Then the GEO2 R tool was used to locate differentially expressed genes(DEGs)control group,trastuzumab treatment group,pertuzumab treatment group,and combination group.Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to identify the pathways and functional annotation of downregulated DEGs.Protein-protein interaction of these DEGs was analyzed based on the Search Tool for the Retrieval of Interacting Genes database and visualized by Cytoscape software.Besides,GEPIA and Kaplan-Meier plotter analysis tool were also be performed to evaluate the differential expressions and prognostic value of hub genes expression in ovarian cancer patients.Then in vitro and in vivo experiments related were accomplished.Subsequently,the expression of KIF23 was verified in ovarian cancer cell lines.KIF23 was knocked down to observe the changes of cell line’s growth and the effect on tumorigenesis in animals.Afterwards,the expression of KIF23 in the combination group was verified.The changes of ovarian cancer cell lines in the combination group after overexpression of KIF23 were observed.Result:A total of 342 downregulated DEGs were ascertained.KIF23 were identified to be a potential key gene in the mechanism of combination chemotherapy in ovarian cancer.The expression of KIF23 in ovarian cancer cells was higher than that in normal cell lines,and the proliferation of related cancer cells was reduced after the knockdown of KIF23.In addition,Compared with the control group,the trastuzumab-treated group and the pertuzumab-treated group,the mRNA expression of KIF23 in the combined treatment group of trastuzumab and pertuzumab was significantly reduced.The combination therapy group significantly inhibited the proliferation of ovarian cancer,and overexpression of KIF23 could reduce the inhibitory effect of HER2 combination therapy on ovarian cancer proliferation.Conclusion:The combination therapy of trastuzumab and partuzumab may inhibit the proliferation of ovarian cancer by regulating KIF23 gene,which may become a new target for anti-tumor targeted therapy.