Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.
J Cell Mol Med. 2020 Sep;24(17):9613-9626. doi: 10.1111/jcmm.15435. Epub 2020 Jul 15.
Gliomas are the most common form of malignant tumour in the central nervous system. However, the molecular mechanism of the tumorigenesis and progression of gliomas remains unclear. In this study, we used the GEO database to identify genes differentially expressed in gliomas and predict the prognosis of glioma. We observed that ASPM mRNA was increased obviously in glioma tissue, and higher ASPM mRNA expression predicted worse disease prognosis. ASPM was highly expressed in glioma cell lines U87-MG and U251, and knockdown of ASPM expression in these cells significantly repressed the proliferation, migration and invasion ability and induced G0/G1 phase arrest. In addition, down-regulation of ASPM suppressed the growth of glioma in nude mice. Five potential binding sites for transcription factor FoxM1 were predicted in the ASPM promoter. FoxM1 overexpression significantly increased the expression of ASPM and promoted the proliferation and migration of glioma cells, which was abolished by ASPM ablation. ChIP and dual-luciferase reporter analysis confirmed that FoxM1 bound to the ASPM promoter at -236 to -230 bp and -1354 to -1348 bp and activated the transcription of ASPM directly. Collectively, our results demonstrated for the first time that aberrant ASPM expression mediated by transcriptional regulation of FoxM1 promotes the malignant properties of glioma cells.
神经胶质瘤是中枢神经系统中最常见的恶性肿瘤。然而，神经胶质瘤的发生和发展的分子机制仍不清楚。在这项研究中，我们使用 GEO 数据库来鉴定神经胶质瘤中差异表达的基因，并预测神经胶质瘤的预后。我们观察到 ASPM mRNA 在神经胶质瘤组织中明显增加，并且较高的 ASPM mRNA 表达预示着较差的疾病预后。ASPM 在神经胶质瘤细胞系 U87-MG 和 U251 中高表达，并且这些细胞中 ASPM 表达的下调显著抑制增殖、迁移和侵袭能力，并诱导 G0/G1 期阻滞。此外，下调 ASPM 抑制了裸鼠中神经胶质瘤的生长。ASPM 启动子中预测到 5 个潜在的转录因子 FoxM1 结合位点。FoxM1 的过表达显著增加了 ASPM 的表达，并促进了神经胶质瘤细胞的增殖和迁移，而 ASPM 的消融则消除了这种作用。ChIP 和双荧光素酶报告分析证实 FoxM1 在-236 到-230bp 和-1354 到-1348bp 处与 ASPM 启动子结合，并直接激活 ASPM 的转录。总之，我们的研究结果首次表明，FoxM1 转录调控介导的异常 ASPM 表达促进了神经胶质瘤细胞的恶性特性。
