Euskirchen Philipp, Radke Josefine, Schmidt Marc Sören, Schulze Heuling Eva, Kadikowski Eric, Maricos Meron, Knab Felix, Grittner Ulrike, Zerbe Norman, Czabanka Marcus, Dieterich Christoph, Miletic Hrvoje, Mørk Sverre, Koch Arend, Endres Matthias, Harms Christoph
Dept. of Neurology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
Dept. of Experimental Neurology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
PLoS One. 2017 Sep 25;12(9):e0185376. doi: 10.1371/journal.pone.0185376. eCollection 2017.
The transcription factor ZEB1 has gained attention in tumor biology of epithelial cancers because of its function in epithelial-mesenchymal transition, DNA repair, stem cell biology and tumor-induced immunosuppression, but its role in gliomas with respect to invasion and prognostic value is controversial. We characterized ZEB1 expression at single cell level in 266 primary brain tumors and present a comprehensive dataset of high grade gliomas with Ki67, p53, IDH1, and EGFR immunohistochemistry, as well as EGFR FISH. ZEB1 protein expression in glioma stem cell lines was compared to their parental tumors with respect to gene expression subtypes based on RNA-seq transcriptomic profiles. ZEB1 is widely expressed in glial tumors, but in a highly variable fraction of cells. In glioblastoma, ZEB1 labeling index is higher in tumors with EGFR amplification or IDH1 mutation. Co-labeling studies showed that tumor cells and reactive astroglia, but not immune cells contribute to the ZEB1 positive population. In contrast, glioma cell lines constitutively express ZEB1 irrespective of gene expression subtype. In conclusion, our data indicate that immune infiltration likely contributes to differential labelling of ZEB1 and confounds interpretation of bulk ZEB1 expression data.
转录因子ZEB1因其在上皮-间质转化、DNA修复、干细胞生物学和肿瘤诱导的免疫抑制中的作用，在上皮性癌的肿瘤生物学中受到关注，但其在胶质瘤侵袭和预后价值方面的作用存在争议。我们在266例原发性脑肿瘤中对ZEB1表达进行了单细胞水平的表征，并提供了一个包含高级别胶质瘤的综合数据集，该数据集包含Ki67、p53、IDH1和EGFR免疫组化以及EGFR荧光原位杂交（FISH）数据。基于RNA测序转录组谱，将胶质瘤干细胞系中的ZEB1蛋白表达与其亲本肿瘤的基因表达亚型进行了比较。ZEB1在胶质肿瘤中广泛表达，但在细胞中的比例变化很大。在胶质母细胞瘤中，EGFR扩增或IDH1突变的肿瘤中ZEB1标记指数更高。共标记研究表明，肿瘤细胞和反应性星形胶质细胞而非免疫细胞构成了ZEB1阳性群体。相比之下，胶质瘤细胞系无论基因表达亚型如何都组成性表达ZEB1。总之，我们的数据表明免疫浸润可能导致ZEB1标记差异，并混淆对整体ZEB1表达数据的解释。
