目的:胶质母细胞瘤(GBM)是颅内胶质瘤中侵袭性最强的。尽管有最大的治疗干预,中位生存率仍约为14-16个月.核受体结合蛋白1(NRBP1)对细胞的生物学功能具有潜在的促生长作用。在这项研究中,我们调查了NRBP1是否促进GBM恶性表型和潜在机制.
方法:NRBP1与胶质瘤分级的相关性,分析TCGA/CGGA数据库中的预后和我们的临床数据。接下来,我们在GBM细胞上进行NRBP1的敲除和过表达,以验证NRBP1促进细胞增殖,入侵,以及体外和体内的迁移。最后,我们检测了NRBP1对PI3K/Akt信号通路和EMT的影响。
结果:NRBP1表达升高与晚期胶质瘤之间存在相关性,以及总体生存率和无病生存率下降。抑制扩散,入侵,NRBP1敲除后观察到肿瘤细胞的迁移,体外研究也证明了细胞凋亡的诱导。然而,它的过度表达与高增殖率有关,迁移,入侵,和凋亡逃逸。GO富集和KEGG分析显示,NRBP1调控的差异表达基因簇参与PI3K/Akt信号通路,以及该途径介导的EMT。此外,MK-2206和SC79减轻了NRBP1敲低和过表达对GBM的影响,两者分别充当PI3K/Akt信号通路的抑制剂和激活剂.同样,抑制NRBP1导致肿瘤生长减少,而它的过表达在小鼠模型中促进肿瘤生长。
结论:本研究显示NRBP1通过激活PI3K/Akt通路促进GBM的恶性表型。因此,它可以作为GBM治疗的预测指标和新的治疗靶点。
OBJECTIVE: Glioblastoma (GBM) is the most aggressive of intracranial gliomas. Despite the maximal treatment intervention, the median survival rate is still about 14-16 months. Nuclear receptor-binding protein 1 (NRBP1) has a potential growth-promoting role on biology function of cells. In this study, we investigated whether NRBP1 promotes GBM malignant phenotypes and the potential mechanisms.
METHODS: The correlation between NRBP1 and glioma grade, prognosis in TCGA/CGGA databases and our clinical data were analyzed. Next, we conducted knockout and overexpression of NRBP1 on GBM cells to verify that NRBP1 promoted cell proliferation, invasion, and migration in vitro and in vivo. Finally, we detected the impact of NRBP1 on PI3K/Akt signaling pathway and EMT.
RESULTS: There was a correlation between elevated NRBP1 expression and advanced stage glioma, as well as decreased overall and disease-free survival. The suppression of proliferation, invasion, and migration of tumor cells was observed upon NRBP1 knockout, and in vitro studies also demonstrated the induction of apoptotic cell death. Whereas, its overexpression is associated with high multiplication rate, migration, invasion, and apoptotic escape. GO enrichment and KEGG analysis revealed that NRBP1 regulated differentially expressed gene clusters are involved in PI3K/Akt signaling pathway, as well as EMT mediated by this pathway. Moreover, the effects of NRBP1 knockdown and overexpression on GBM were mitigated by MK-2206 and SC79, both of which respectively function as an inhibitor and an activator of the PI3K/Akt signaling pathway. Similarly, the suppression of NRBP1 led to a decrease in tumor growth, whereas its overexpression promoted tumor growth in a mouse model.
CONCLUSIONS: This study shows that NRBP1 promotes malignant phenotypes in GBM by activating PI3K/Akt pathway. Hence, it can function as both a predictive indicator and a new target for therapies in GBM treatment.