MCM8 is regulated by EGFR signaling and promotes the growth of glioma stem cells through its interaction with DNA-replication-initiating factors
MCM8 is regulated by EGFR signaling and promotes the growth of glioma stem cells through its interaction with DNA-replication-initiating factors
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MCM8 受 EGFR 信号传导调节，并通过与 DNA 复制起始因子的相互作用促进神经胶质瘤干细胞的生长
DOI：
10.1038/s41388-021-01888-1
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发表时间：
2021-06
期刊：
影响因子：
8
通讯作者：
Sheng Han
中科院分区：
文献类型：
--
作者：
Xiaoliang Wang;Li Zhang;Yifu Song;Yang Jiang;Di Zhang;Run Wang;Tianhao Hu;Sheng Han
微小染色体维持(MCM)蛋白是DNA复制许可因子的重要组成部分。MCM8是一种MCM蛋白，在多种人类恶性肿瘤中具有致癌功能。然而，MCM8在胶质母细胞瘤中的作用尚不清楚。本研究探讨了MCM8在胶质瘤干细胞(GSCs)中的生物学功能及其作用机制。通过TCGA和伦勃朗数据集探讨MCM8mRNA表达的临床相关性。在体内外检测MCM8对GSCs自我更新和致瘤性的影响。并对MCM8及其相互作用蛋白的表达调控进行了研究。我们发现MCM8在高级别胶质瘤和经典分子亚型中的表达升高，且与患者预后呈负相关。GSCs中MCM8的表达明显高于正常胶质瘤细胞。沉默MCM8可诱导GSCs G0/G1期停滞和细胞凋亡，并抑制GSCs的增殖和自我更新。MCM8的强制表达增强了GSCs的体内外克隆形成能力。MCM8的表达受表皮生长因子受体信号的调节，而该信号是由NF-κB(P65)介导的。MCM8与DNA复制启动因子相互作用，包括EZH2、CDC6和CDCA2，并影响这些因子与染色质相关联。此外，MCM8基因敲除增加了GSC对辐射和TMZ治疗的敏感性。我们的发现表明，受EGFR途径调控的MCM8通过与DNA复制启动因子的相互作用来维持GSCs的克隆形成和致瘤能力；因此，MCM8可能是GMS的一个新的治疗靶点。
Mini-chromosome maintenance (MCM) proteins are critical components of DNA-replication-licensing factors. MCM8 is an MCM protein that exhibits oncogenic functions in several human malignancies. However, the role of MCM8 in glioblastomas (GBMs) has remained unclear. In the present study, we investigated the biological functions and mechanisms of MCM8 in glioma stem cells (GSCs). The clinical relevance of MCM8 mRNA expression was explored via TCGA and REMBRANDT datasets. The effects of MCM8 on the self-renewal and tumorigenicity of GSCs were examined both in vitro and in vivo. The regulation of MCM8 expression and its interacting proteins were also evaluated. We found that the expression of MCM8 was elevated in high-grade gliomas and classical molecular subtypes and was inversely correlated with patient prognosis. GSCs had a significantly higher expression of MCM8 compared with that in normal glioma cells. Silencing of MCM8 induced G0/G1 arrest and apoptosis, as well as inhibited the proliferation and self-renewal of GSCs. Forced expression of MCM8 enhanced clonogenicity of GSCs both in vitro and in vivo. MCM8 expression was regulated by EGFR signaling, which was mediated by NF-κB (p65). MCM8 interacted with DNA-replication-initiating factors—including EZH2, CDC6, and CDCA2—and influenced these factors to associate with chromatin. In addition, MCM8 knockdown increased the sensitivity of GSCs to radiation and TMZ treatments. Our findings suggest that MCM8, regulated by the EGFR pathway, maintains the clonogenic and tumorigenic potential of GSCs through interaction with DNA-replication-initiating factors; hence, MCM8 may represent a novel therapeutic target in GBMs.
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DOI：
--
发表时间：
2000-07
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
H. Friedman;T. Kerby;H. Calvert
通讯作者：
H. Friedman;T. Kerby;H. Calvert
微型染色体维持（MCM）家族作为人类神经胶质瘤的潜在诊断和预后肿瘤标志物
影响因子：
3.8
作者：
Hua C;Zhao G;Li Y;Bie L
通讯作者：
Bie L
GEPIA：用于癌症和正常基因表达谱和交互式分析的网络服务器。
影响因子：
14.9
作者：
Tang Z;Li C;Kang B;Gao G;Li C;Zhang Z
通讯作者：
Zhang Z
影响因子：
1.4
作者：
L. Cai;K. Zhao;Xuejie Yuan
通讯作者：
L. Cai;K. Zhao;Xuejie Yuan
NFAT1 介导的 NDEL1 调节促进胶质瘤干细胞样细胞的生长和侵袭
影响因子：
11.2
作者：
Jiang, Yang;Song, Yifu;Han, Sheng
通讯作者：
Han, Sheng