Chromodomain Helicase DNA-Binding Protein 7 Is Suppressed in the Perinecrotic/Ischemic Microenvironment and Is a Novel Regulator of Glioblastoma Angiogenesis
Chromodomain Helicase DNA-Binding Protein 7 Is Suppressed in the Perinecrotic/Ischemic Microenvironment and Is a Novel Regulator of Glioblastoma Angiogenesis
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DOI：
10.1002/stem.2969
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发表时间：
2019-04-01
期刊：
影响因子：
5.2
通讯作者：
Hjelmeland, Anita B.
中科院分区：
文献类型：
--
作者：
Boyd, Nathaniel H.;Walker, Kiera;Hjelmeland, Anita B.
致瘤性和非肿瘤性组织损伤是通过缺血微环境发生的，这种微环境是由血液供应障碍导致的低氧、pH和营养物质所定义的。缺血性情况存在于假性乳样坏死区域，胶质母细胞瘤（GBM）的病理标志，成人中最常见的原发性恶性脑肿瘤。为了概括GBM肿瘤和组织损伤的生理微环境，我们建立了一个体外缺血模型，并确定了染色质结构域解旋酶dna结合蛋白7 （CHD7）是一个新的缺血调节基因。CHD7基因的点突变是导致CHARGE综合征（一种导致结肠瘤、心脏缺陷、先天性闭锁、生长迟缓以及生殖器和耳朵异常的发育障碍）的原因，并中断CHD7调节神经干细胞维持和发育的表观遗传功能。在我们的缺血系统中，我们观察到微环境介导的CHD7在脑肿瘤启动细胞和神经干细胞中的表达降低。验证我们的方法，CHD7在GBM患者和异种移植切片的会阴生态位中被抑制，并且对患者基因表达数据集的调查确定了低CHD7与胶质瘤级别增加和患者预后恶化的相关性。按分子亚型分离的GBM揭示了一个新的观察，CHD7表达在原膜与间质GBM中升高。CHD7的基因靶向和随后RNA测序数据的基因本体论分析表明，血管生成是受CHD7表达变化影响的主要生物学功能。我们在原位GBM模型的管形成实验和血管形成中验证了这一发现。总之，我们的数据提供了对缺血的分子反应和CHD7在肿瘤和非肿瘤系统中调节血管生成的新功能的进一步理解。茎Cells2019;37:453 - 462
Tumorigenic and non-neoplastic tissue injury occurs via the ischemic microenvironment defined by low oxygen, pH, and nutrients due to blood supply malfunction. Ischemic conditions exist within regions of pseudopalisading necrosis, a pathological hallmark of glioblastoma (GBM), the most common primary malignant brain tumor in adults. To recapitulate the physiologic microenvironment found in GBM tumors and tissue injury, we developed an in vitro ischemic model and identified chromodomain helicase DNA-binding protein 7 (CHD7) as a novel ischemia-regulated gene. Point mutations in the CHD7 gene are causal in CHARGE syndrome (a developmental disorder causing coloboma, heart defects, atresia choanae, retardation of growth, and genital and ear anomalies) and interrupt the epigenetic functions of CHD7 in regulating neural stem cell maintenance and development. Using our ischemic system, we observed microenvironment-mediated decreases in CHD7 expression in brain tumor-initiating cells and neural stem cells. Validating our approach, CHD7 was suppressed in the perinecrotic niche of GBM patient and xenograft sections, and an interrogation of patient gene expression datasets determined correlations of low CHD7 with increasing glioma grade and worse patient outcomes. Segregation of GBM by molecular subtype revealed a novel observation that CHD7 expression is elevated in proneural versus mesenchymal GBM. Genetic targeting of CHD7 and subsequent gene ontology analysis of RNA sequencing data indicated angiogenesis as a primary biological function affected by CHD7 expression changes. We validated this finding in tube-formation assays and vessel formation in orthotopic GBM models. Together, our data provide further understanding of molecular responses to ischemia and a novel function of CHD7 in regulating angiogenesis in both neoplastic and non-neoplastic systems. Stem Cells2019;37:453-462