Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance
Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance
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DOI：
10.1093/neuonc/noy012
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发表时间：
2018-08-01
期刊：
影响因子：
15.9
通讯作者：
Hjelmeland, Anita B.
中科院分区：
文献类型：
--
作者：
Anh Nhat Tran;Walker, Kiera;Hjelmeland, Anita B.
背景：根据水平、分化状态和肿瘤分期，活性氮和活性氧抑制或增加肿瘤生长和肿瘤启动细胞维持。在胶质母细胞瘤（GBM； IV级星形细胞瘤）中，调节活性物质产生的途径中的限速酶是三磷酸鸟苷（GTP）环水解酶1 (GCH1)，但尚未被彻底研究。我们试图确定GCH1在GBM生长和脑肿瘤起始细胞（BTIC）维持的调节中的作用。方法：我们检测了患者来源的异种移植物、临床样本和胶质瘤基因表达数据集中的GCH1 mRNA和蛋白表达。使用慢病毒表达系统调节GCH1水平，并确定对原位患者来源的异种移植模型中细胞生长、自我更新、反应性物种产生和存活的影响。结果：GCH1在GBMs中表达，与非btic相比，btic中RNA和蛋白水平升高，但不是唯一的。GCH1在GBM细胞中的过表达增加了体外细胞生长，降低了颅内GBM小鼠模型的存活率。在反向实验中，短发夹RNA敲低GCH1导致GBM细胞生长抑制和自我更新减少，与CD44表达降低相关。GCH1对控制活性物质平衡至关重要，包括抑制活性氧的产生，从而介导GCH1细胞的生长效应。计算机分析表明，胶质瘤患者中较高的GCH1水平与较高的胶质瘤分级、复发和较差的生存率相关。结论：在已建立的GBMs中，GCH1的表达具有促瘤性，导致生长增加，部分原因是促进BTIC维持和抑制活性氧。
Background: Depending on the level, differentiation state, and tumor stage, reactive nitrogen and oxygen species inhibit or increase cancer growth and tumor initiating cell maintenance. The rate-limiting enzyme in a pathway that can regulate reactive species production but has not been thoroughly investigated in glioblastoma (GBM; grade IV astrocytoma) is guanosine triphosphate (GTP) cyclohydrolase 1 (GCH1). We sought to define the role of GCH1 in the regulation of GBM growth and brain tumor initiating cell (BTIC) maintenance.Methods: We examined GCH1 mRNA and protein expression in patient-derived xenografts, clinical samples, and glioma gene expression datasets. GCH1 levels were modulated using lentiviral expression systems, and effects on cell growth, self-renewal, reactive species production, and survival in orthotopic patient-derived xenograft models were determined.Results: GCH1 was expressed in GBMs with elevated but not exclusive RNA and protein levels in BTICs in comparison to non-BTICs. Overexpression of GCH1 in GBM cells increased cell growth in vitro and decreased survival in an intracranial GBM mouse model. In converse experiments, GCH1 knockdown with short hairpin RNA led to GBM cell growth inhibition and reduced self-renewal in association with decreased CD44 expression. GCH1 was critical for controlling reactive species balance, including suppressing reactive oxygen species production, which mediated GCH1 cell growth effects. In silico analyses demonstrated that higher GCH1 levels in glioma patients correlate with higher glioma grade, recurrence, and worse survival.Conclusions: GCH1 expression in established GBMs is pro-tumorigenic, causing increased growth due, in part, to promotion of BTIC maintenance and suppression of reactive oxygen species.