Akt/FoxM1 信号通路介导的 MYBL2 上调促进了人胶质细胞瘤的进展。
Akt/FoxM1 signaling pathway-mediated upregulation of MYBL2 promotes progression of human glioma.
机构信息
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China.
出版信息
J Exp Clin Cancer Res. 2017 Aug 7;36(1):105. doi: 10.1186/s13046-017-0573-6.
BACKGROUND
MYB-related protein B (B-MYB/MYBL2), a member of the myeloblastosis family of transcription factors, has been reported for its role in the genesis and progression of tumors. Forkhead box M1 (FoxM1), another transcriptional factor, is considered to be an independent predictor of poor survival in many solid cancers. The aim of the present study was to investigate the clinical significance of the correlation between MYBL2 and FoxM1 in glioma and the possible mechanism of FoxM1and MYBL2 expression.
METHODS
MYBL2 and FoxM1expression in cancerous tissues and cell lines were determined by reverse transcription-PCR (RT-PCR), Western blotting and immunostaining. The co-expression of MYBL2 and FoxM1 was analyzed in low-grade glioma (LGG) and glioblastoma (HGG) cohorts of TCGA using cBioportal and UCSC Xena. And, the role of MYBL2 and FoxM1 in glioma cell progression and the underlying mechanisms were studied by using small interfering RNA (si-RNA) and pcDNA3.1 + HAvectors. Furthermore, the effects of MYBL2 and FoxM1 in cell proliferation, cell cycle progression, apoptosis, migration, invasion, and adhesion were determined by cell proliferation assays, flow cytometry analysis, transwell migration and cell adhesion assay.
RESULTS
MYBL2 and FoxM1 expression are significantly associated with clinical stages and overall survival of glioma patients. In cohorts of TCGA, patients with high MYBL2 but without radio-chemotherapy had the highest hazard ratio (adjusted HR = 5.29, 95% CI = 1.475-18.969, P < 0.05). Meanwhile, MYBL2 closely related to the FoxM1 expression in 79 glioma tissues (r = 0.742, p < 0.05) and LGG (r = 0.83) and HGG (r = 0.74) cohorts of TCGA. Down regulation of FoxM1 and MYBL2 by siRNAs induced the cell cycle arrest, apoptosis and EMT of glioma cells. Furthermore, inactivations of Akt/FoxM1 signaling by Akt inhibitor and siRNA-FoxM1 reduce the expression of MYBL2 in glioma cells.
CONCLUSIONS
MYBL2 is a key downstream factor of Akt/FoxM1 signaling to promote progression of human glioma, and could be a new candidate gene for molecular targeting therapy and biomarker for radiotherapy of glioma.
TRIAL REGISTRATION
CTXY-1300041-3-2. ChiCTR-COC-15006186 . Registered date: 13 September 2013.
背景
MYB 相关蛋白 B（B-MYB/MYBL2）是髓样白血病家族转录因子的成员，其在肿瘤的发生和发展中起作用。叉头框 M1（FoxM1）是另一种转录因子，被认为是许多实体瘤中不良预后的独立预测因子。本研究旨在探讨 MYBL2 和 FoxM1 在神经胶质瘤中的相关性及其表达的可能机制。
方法
采用逆转录聚合酶链反应（RT-PCR）、Western blot 和免疫组化检测癌组织和细胞系中 MYBL2 和 FoxM1 的表达。利用 cBioportal 和 UCSC Xena 分析 TCGA 中低级别神经胶质瘤（LGG）和高级别神经胶质瘤（HGG）队列中 MYBL2 和 FoxM1 的共表达。采用小干扰 RNA（siRNA）和 pcDNA3.1+HA 载体研究 MYBL2 和 FoxM1 在神经胶质瘤细胞进展中的作用及其潜在机制。进一步通过细胞增殖试验、流式细胞术分析、Transwell 迁移和细胞黏附试验测定 MYBL2 和 FoxM1 对细胞增殖、细胞周期进展、凋亡、迁移、侵袭和黏附的影响。
结果
MYBL2 和 FoxM1 的表达与神经胶质瘤患者的临床分期和总生存期显著相关。在 TCGA 队列中，未经放疗和化疗的高 MYBL2 患者的危险比（调整后的 HR=5.29，95%CI=1.475-18.969，P<0.05）最高。同时，在 79 例神经胶质瘤组织（r=0.742，P<0.05）和 TCGA 的 LGG（r=0.83）和 HGG（r=0.74）队列中，MYBL2 与 FoxM1 的表达密切相关。siRNAs 下调 FoxM1 和 MYBL2 可诱导神经胶质瘤细胞周期停滞、凋亡和 EMT。此外，Akt 抑制剂和 siRNA-FoxM1 抑制 Akt/FoxM1 信号可降低神经胶质瘤细胞中 MYBL2 的表达。
结论
MYBL2 是 Akt/FoxM1 信号的关键下游因子，可促进人神经胶质瘤的进展，可能成为神经胶质瘤分子靶向治疗和放疗的新候选基因。
试验注册
CTXY-1300041-3-2. ChiCTR-COC-15006186. 注册日期：2013 年 9 月 13 日。
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