背景:胶质瘤被认为是中枢神经系统最常见的原发性恶性肿瘤。虽然传统的治疗方法没有取得令人满意的效果,最近,针对神经胶质瘤的靶向治疗已显示出有希望的疗效.然而,由于靶向治疗的单一靶点性质,传统的靶向治疗是无效的;因此,迫切需要新的治疗靶点。
方法:神经胶质瘤患者的基因表达数据来自GEO(GSE4290,GSE50161),TCGA和CGGA数据库。接下来,从上述数据库获得的上调基因进行交叉分析,最后,10个重叠基因(BIRC5、FOXM1、EZH2、CDK1、KIF11、KIF4A、NDC80,PBK,最终筛选出RRM2和TOP2A),只有KIF4A的表达与神经胶质瘤患者的临床特征具有最强的相关性。Futher,利用TCGA和CGGA数据库探讨KIF4A表达与胶质瘤预后的相关性。然后,qRT-PCR和Westernblot检测胶质瘤细胞KIF4AmRNA和蛋白表达水平,分别。而靶向KIF4A的小分子抑制剂WZ-3146,通过Cmap分析进行筛选。随后,用MTT法测定KIF4A敲低或WZ-3146治疗对胶质瘤的影响,EdU,集落形成测定和Transwell测定。最终,进行GSEA富集分析,发现神经胶质瘤中的凋亡途径可以被KIF4A调节,此外,流式细胞术和Westernblot检测WZ-3146对胶质瘤细胞凋亡的影响。
结果:在本研究中,我们证实KIF4A在神经胶质瘤中异常过度表达。此外,KIF4A过表达是胶质瘤预后的关键指标;抑制KIF4A的表达可以抑制胶质瘤的进展。我们还发现KIF4A的小分子抑制剂WZ-3146,可以诱导胶质瘤细胞凋亡并表现出抗胶质瘤作用。
结论:结论:这些观察结果表明,靶向KIF4A可以抑制神经胶质瘤的进展.随着进一步的研究,KIF4A的小分子抑制剂WZ-3146,可与其他分子靶向药物联合协同抑制胶质瘤进展。
BACKGROUND: Glioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes, recently, targeted therapies for glioma have shown promising efficacy. However, due to the single-target nature of targeted therapy, traditional targeted therapies are ineffective; thus, novel therapeutic targets are urgently needed.
METHODS: The gene expression data for glioma patients were derived from the GEO (GSE4290, GSE50161), TCGA and CGGA databases. Next, the upregulated genes obtained from the above databases were cross-analyzed, finally, 10 overlapping genes (BIRC5, FOXM1, EZH2, CDK1, KIF11, KIF4A, NDC80, PBK, RRM2, and TOP2A) were ultimately screened and only KIF4A expression has the strongest correlation with clinical characteristics in glioma patients. Futher, the TCGA and CGGA database were utilized to explore the correlation of KIF4A expression with glioma prognosis. Then, qRT-PCR and Western blot was used to detect the KIF4A mRNA and protein expression level in glioma cells, respectively. And WZ-3146, the small molecule inhibitor targeting KIF4A, were screened by Cmap analysis. Subsequently, the effect of KIF4A knockdown or WZ-3146 treatment on glioma was measured by the MTT, EdU, Colony formation assay and Transwell assay. Ultimately, GSEA enrichment analysis was performed to find that the apoptotic pathway could be regulated by KIF4A in glioma, in addition, the effect of WZ-3146 on glioma apoptosis was detected by flow cytometry and Western blot.
RESULTS: In the present study, we confirmed that KIF4A is abnormally overexpressed in glioma. In addition, KIF4A overexpression is a key indicator of glioma prognosis; moreover, suppressing KIF4A expression can inhibit glioma progression. We also discovered that WZ-3146, a small molecule inhibitor of KIF4A, can induce apoptosis in glioma cells and exhibit antiglioma effects.
CONCLUSIONS: In conclusion, these observations demonstrated that targeting KIF4A can inhibit glioma progression. With further research, WZ-3146, a small molecule inhibitor of KIF4A, could be combined with other molecular targeted drugs to cooperatively inhibit glioma progression.