Tiburcio Patricia D B, Xiao Bing, Chai Yi, Asper Sydney, Tripp Sheryl R, Gillespie David L, Jensen Randy L, Huang L Eric
Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
Oncotarget. 2018 Oct 12;9(80):35100-35113. doi: 10.18632/oncotarget.26203.
Recurrent heterozygous mutation of isocitrate dehydrogenase 1 gene (), predominantly resulting in histidine substitution at arginine 132, was first identified in glioma. The biological significance of IDH1, however, has been controversial, and its prevalent association with glioma remains enigmatic. Although recent studies indicate that IDH1 is nonessential to tumor growth or even anti-tumor growth, whether IDH1 initiates gliomagenesis remains obscure. In this study, we report that IDH1 is intrinsically tumor-suppressive but the activity can be attenuated by glutamate-the cerebral neurotransmitter. We observed that IDH1 was highly suppressive of subcutaneous tumor growth driven by platelet-derived growth factor B (PDGFB), but IDH1 tumor growth and glioma penetrance were virtually indistinguishable from those of IDH1-wildtype tumors in orthotopic models. , addition of glutamate compromised IDH1 inhibition of neurosphere genesis, indicating glutamate promotion of oncogenic dominance. Furthermore, we observed that expression was markedly decreased in tumors but became more permissible upon the deletion of tumor-suppressor gene . To provide direct evidence for the opposing effect of IDH1 on PDGFB-driven glioma development, we explored tandem expression of the two molecules from a single transcript to preclude selection against expression. Our results demonstrate that when juxtaposed with oncogenic PDGFB, IDH1 overrides the oncogenic activity and obliterates neurosphere genesis and gliomagenesis even in the glutamate-rich microenvironment. We propose therefore that IDH1 is intrinsically suppressive of glioma initiation and growth but such tumor-suppressive activity is compromised by the glutamate-rich cerebral cortex, thereby offering a unifying hypothesis for the perplexing role of IDH1 in glioma initiation and growth.
异柠檬酸脱氢酶1基因（）的复发性杂合突变主要导致精氨酸132位点被组氨酸取代，该突变最初在胶质瘤中被发现。然而，IDH1的生物学意义一直存在争议，其与胶质瘤的普遍关联仍不明确。尽管最近的研究表明IDH1对肿瘤生长并非必需，甚至具有抗肿瘤生长的作用，但IDH1是否启动胶质瘤发生仍不清楚。在本研究中，我们报告IDH1本质上具有肿瘤抑制作用，但其活性可被脑内神经递质谷氨酸减弱。我们观察到IDH1对血小板衍生生长因子B（PDGFB）驱动的皮下肿瘤生长具有高度抑制作用，但在原位模型中，IDH1肿瘤生长和胶质瘤侵袭与IDH1野生型肿瘤几乎没有区别。此外谷氨酸的添加削弱IDH1对神经球形成的抑制作用，表明谷氨酸促进致癌优势。此外，我们观察到在肿瘤中表达明显降低，但在肿瘤抑制基因缺失后变得更易发生。为了提供IDH1对PDGFB驱动的胶质瘤发展产生相反作用的直接证据，我们从单个转录本中探索了这两种分子的串联表达，以排除对表达的选择。我们的结果表明当与致癌性PDGFB并列时，即使在富含谷氨酸的微环境中，IDH1也能克服致癌活性，消除神经球形成和胶质瘤发生。因此我们提出IDH1本质上抑制胶质瘤的起始和生长，但这种肿瘤抑制活性会被富含谷氨酸的大脑皮层削弱，从而为IDH1在胶质瘤起始和生长中令人困惑的作用提供了一个统一的假设。
