Investigating the Link between Molecular Subtypes of Glioblastoma, Epithelial-Mesenchymal Transition, and CD133 Cell Surface Protein

In this manuscript, we use genetic data to provide a three-faceted analysis on the links between molecular subclasses of glioblastoma, epithelial-to-mesenchymal transition (EMT) and CD133 cell surface protein. The contribution of this paper is three-fold: First, we use a newly identified signature for epithelial-to-mesenchymal transition in human mammary epithelial cells, and demonstrate that genes in this signature have significant overlap with genes differentially expressed in all known GBM subtypes. However, the overlap between genes up regulated in the mesenchymal subtype of GBM and in the EMT signature was more significant than other GBM subtypes. Second, we provide evidence that there is a negative correlation between the genetic signature of EMT and that of CD133 cell surface protein, a putative marker for neural stem cells. Third, we study the correlation between GBM molecular subtypes and the genetic signature of CD133 cell surface protein. We demonstrate that the mesenchymal and neural subtypes of GBM have the strongest correlations with the CD133 genetic signature. While the mesenchymal subtype of GBM displays similarity with the signatures of both EMT and CD133, it also exhibits some differences with each of these signatures that are partly due to the fact that the signatures of EMT and CD133 are inversely related to each other. Taken together these data shed light on the role of the mesenchymal transition and neural stem cells, and their mutual interaction, in molecular subtypes of glioblastoma multiforme.本研究利用遗传数据，针对胶质母细胞瘤（glioblastoma multiforme, GBM）分子亚型、上皮间质转化（epithelial-to-mesenchymal transition, EMT）以及CD133细胞表面蛋白（CD133 cell surface protein）三者之间的关联开展三维度分析。本研究的核心贡献包含三点： 其一，我们采用在人类乳腺上皮细胞中全新鉴定得到的上皮间质转化特征基因集，证实该特征基因集内的基因与所有已知GBM亚型中的差异表达基因存在显著重叠；其中，GBM间质亚型中上调表达的基因与该EMT特征基因集的重叠程度，显著高于其余GBM亚型。 其二，我们提供证据表明，上皮间质转化的遗传特征基因集与CD133细胞表面蛋白的遗传特征基因集之间存在负相关关系——CD133是神经干细胞（neural stem cells）的推定标志物。 其三，我们分析了GBM分子亚型与CD133细胞表面蛋白遗传特征基因集的相关性，证实GBM的间质亚型与神经亚型与CD133遗传特征基因集的相关性最为显著。 尽管GBM间质亚型同时与EMT特征基因集及CD133特征基因集存在相似性，但该亚型与这两类特征基因集各自均存在一定差异，这一现象部分源于EMT特征基因集与CD133特征基因集本身呈负相关关系。 综上，本研究数据阐明了上皮间质转化与神经干细胞在多形性胶质母细胞瘤分子亚型形成中的作用，以及二者之间的相互调控关系。