A developmental taxonomy of glioblastoma defined and maintained by MicroRNAs.
A developmental taxonomy of glioblastoma defined and maintained by MicroRNAs.
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DOI：
10.1158/0008-5472.can-10-4117
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发表时间：
2011-05-01
期刊：
影响因子：
11.2
通讯作者：
Johnson MD
中科院分区：
文献类型：
--
作者：
Kim TM;Huang W;Park R;Park PJ;Johnson MD
mRNA表达谱表明存在多个胶质母细胞瘤亚类，但它们的数量和特征在研究中各不相同，其发展的病因尚不清楚。在这项研究中，我们分析了来自癌症基因组图谱（TCGA）的261个microRNA表达谱，确定了5个临床和遗传上不同的胶质母细胞瘤亚类，每个亚类与不同的神经前体细胞类型相关。这些基于microRNA的胶质母细胞瘤亚类显示出类似于放射状胶质细胞、寡神经元前体、神经元前体、神经上皮/神经嵴前体或星形胶质细胞前体的microRNA和mRNA表达特征。根据患者种族、年龄、治疗反应和生存率方面的显著差异，确定每个亚类在遗传上是不同的。我们还鉴定了几种microRNA作为胶质母细胞瘤中亚类特异性基因表达网络的有效调节因子。其中最重要的是miR-9，其通过下调JAK激酶的表达和抑制STAT 3的活化来抑制胶质母细胞瘤中的间充质分化。我们的研究结果表明，microRNA是胶质母细胞瘤亚类的重要决定因素，通过它们的能力，以调节发育生长和分化程序在几个转化的神经前体细胞类型。总之，我们的研究结果定义了发育microRNA表达特征，这些特征表征并有助于胶质母细胞瘤亚类的表型多样性，从而为理解人类神经发育背景下胶质母细胞瘤的发病机制提供了一个扩展的框架。
mRNA expression profiling has suggested the existence of multiple glioblastoma subclasses, but their number and characteristics vary among studies and the etiology underlying their development is unclear. In this study, we analyzed 261 microRNA expression profiles from the Cancer Genome Atlas (TCGA), identifying five clinically and genetically distinct subclasses of glioblastoma that each related to a different neural precursor cell type. These microRNA-based glioblastoma subclasses displayed microRNA and mRNA expression signatures resembling those of radial glia, oligoneuronal precursors, neuronal precursors, neuroepithelial/neural crest precursors or astrocyte precursors. Each subclass was determined to be genetically distinct, based on the significant differences they displayed in terms of patient race, age, treatment response and survival. We also identified several microRNAs as potent regulators of subclass-specific gene expression networks in glioblastoma. Foremost among these is miR-9, which suppresses mesenchymal differentiation in glioblastoma by downregulating expression of JAK kinases and inhibiting activation of STAT3. Our findings suggest that microRNAs are important determinants of glioblastoma subclasses through their ability to regulate developmental growth and differentiation programs in several transformed neural precursor cell types. Taken together, our results define developmental microRNA expression signatures that both characterize and contribute to the phenotypic diversity of glioblastoma subclasses, thereby providing an expanded framework for understanding the pathogenesis of glioblastoma in a human neurodevelopmental context.