Nesvick Cody L, Zhang Chao, Edwards Nancy A, Montgomery Blake K, Lee Michaela, Yang Chunzhang, Wang Herui, Zhu Dongwang, Heiss John D, Merrill Marsha J, Ray-Chaudhury Abhik, Zhuang Zhengping
Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.
Department of Neurologic Surgery, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA.
J Neurooncol. 2016 Oct;130(1):111-122. doi: 10.1007/s11060-016-2240-8. Epub 2016 Aug 27.
Transcription factors that induce epithelial-mesenchymal transition (EMT) promote invasion, chemoresistance and a stem-cell phenotype in epithelial tumors, but their roles in central nervous system tumors are not well-understood. We hypothesized these transcription factors have a functional impact in grades II-III gliomas. Using the National Cancer Institute (NCI) Repository for Molecular Brain Neoplasia Data (REMBRANDT) and the Cancer Genome Atlas (TCGA) Lower-Grade Glioma (LGG) data, we determined the impact of EMT-promoting transcription factors (EMT-TFs) on overall survival in grades II-III gliomas, compared their expression across common genetic subtypes and subsequently validated these findings in a set of 31 tumors using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. Increased expression of the gene coding for the transcriptional repressor Zinc Finger E box-binding Homeobox 1 (ZEB1) was associated with a significant increase in overall survival (OS) on Kaplan-Meier analysis. Genetic subtype analysis revealed that ZEB1 expression was relatively increased in IDH1/2-mutant gliomas, and IDH1/2-mutant gliomas expressed significantly lower levels of many ZEB1 transcriptional targets. Similarly, IDH1/2-mutant tumors expressed significantly higher levels of targets of microRNA 200C (MIR200C), a key regulator of ZEB1. In a validation study, ZEB1 mRNA was significantly increased in IDH1-mutant grades II-III gliomas, and ZEB1 protein expression was more pronounced in these tumors. Our findings demonstrate a novel relationship between IDH1/2 mutations and expression of ZEB1 and its transcriptional targets. Therapy targeting ZEB1-associated pathways may represent a novel therapeutic avenue for this class of tumors.
诱导上皮-间质转化（EMT）的转录因子可促进上皮性肿瘤的侵袭、化疗耐药及干细胞表型，但它们在中枢神经系统肿瘤中的作用尚未完全明确。我们推测这些转录因子在II-III级胶质瘤中具有功能性影响。利用美国国立癌症研究所（NCI）分子脑肿瘤数据储存库（REMBRANDT）和癌症基因组图谱（TCGA）低级别胶质瘤（LGG）数据，我们确定了促进EMT的转录因子（EMT-TFs）对II-III级胶质瘤总生存期的影响，比较了它们在常见基因亚型中的表达情况，随后使用定量实时聚合酶链反应（PCR）和免疫组织化学在一组31个肿瘤中验证了这些发现。在Kaplan-Meier分析中，编码转录抑制因子锌指E盒结合同源框1（ZEB1）的基因表达增加与总生存期（OS）显著延长相关。基因亚型分析显示，ZEB1表达在IDH1/2突变型胶质瘤中相对增加，且IDH1/2突变型胶质瘤中许多ZEB1转录靶点的表达水平显著降低。同样，IDH1/2突变型肿瘤中关键的ZEB1调节因子微小RNA 200C（MIR200C）的靶点表达显著更高。在一项验证研究中，IDH1突变的II-III级胶质瘤中ZEB1 mRNA显著增加，且这些肿瘤中ZEB1蛋白表达更明显。我们的研究结果表明IDH1/2突变与ZEB1及其转录靶点的表达之间存在新的关系。靶向ZEB1相关通路的治疗可能代表了这类肿瘤的一种新的治疗途径。
