Schliesser Maximilian Georg, Claus Rainer, Hielscher Thomas, Grimm Christiane, Weichenhan Dieter, Blaes Jonas, Wiestler Benedikt, Hau Peter, Schramm Johannes, Sahm Felix, Weiß Elisa K, Weiler Markus, Baer Constance, Schmidt-Graf Friederike, Schackert Gabriele, Westphal Manfred, Hertenstein Anne, Roth Patrick, Galldiks Norbert, Hartmann Christian, Pietsch Torsten, Felsberg Joerg, Reifenberger Guido, Sabel Michael Christoph, Winkler Frank, von Deimling Andreas, Meisner Christoph, Vajkoczy Peter, Platten Michael, Weller Michael, Plass Christoph, Wick Wolfgang
Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.
Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Oncotarget. 2016 Dec 13;7(50):82028-82045. doi: 10.18632/oncotarget.13452.
The outcome of patients with anaplastic gliomas varies considerably depending on single molecular markers, such as mutations of the isocitrate dehydrogenase (IDH) genes, as well as molecular classifications based on epigenetic or genetic profiles. Remarkably, 98% of the RNA within a cell is not translated into proteins. Of those, especially microRNAs (miRNAs) have been shown not only to have a major influence on physiologic processes but also to be deregulated and prognostic in malignancies.To find novel survival markers and treatment options we performed unbiased DNA methylation screens that revealed 12 putative miRNA promoter regions with differential DNA methylation in anaplastic gliomas. Methylation of these candidate regions was validated in different independent patient cohorts revealing a set of miRNA promoter regions with prognostic relevance across data sets. Of those, miR-155 promoter methylation and miR-155 expression were negatively correlated and especially the methylation showed superior correlation with patient survival compared to established biomarkers.Functional examinations in malignant glioma cells further cemented the relevance of miR-155 for tumor cell viability with transient and stable modifications indicating an onco-miRNA activity. MiR-155 also conferred resistance towards alkylating temozolomide and radiotherapy as consequence of nuclear factor (NF)κB activation.Preconditioning glioma cells with an NFκB inhibitor reduced therapy resistance of miR-155 overexpressing cells. These cells resembled tumors with a low methylation of the miR-155 promoter and thus mir-155 or NFκB inhibition may provide treatment options with a special focus on patients with IDH wild type tumors.
间变性胶质瘤患者的预后差异很大，这取决于单个分子标志物，如异柠檬酸脱氢酶（IDH）基因突变，以及基于表观遗传或基因图谱的分子分类。值得注意的是，细胞内98%的RNA不会被翻译成蛋白质。其中，尤其是微小RNA（miRNA）不仅对生理过程有重大影响，而且在恶性肿瘤中存在失调并具有预后价值。为了寻找新的生存标志物和治疗方案，我们进行了无偏倚的DNA甲基化筛选，结果显示在间变性胶质瘤中有12个推定的miRNA启动子区域存在差异DNA甲基化。这些候选区域的甲基化在不同的独立患者队列中得到验证，揭示了一组在不同数据集中具有预后相关性的miRNA启动子区域。其中，miR-155启动子甲基化与miR-155表达呈负相关，特别是与已确立的生物标志物相比，甲基化与患者生存的相关性更强。在恶性胶质瘤细胞中的功能研究进一步证实了miR-155对肿瘤细胞活力的相关性，短暂和稳定的修饰表明其具有致癌miRNA活性。由于核因子（NF）κB激活，miR-155还赋予了对烷化剂替莫唑胺和放疗的抗性。用NFκB抑制剂预处理胶质瘤细胞可降低miR-155过表达细胞的治疗抗性。这些细胞类似于miR-155启动子低甲基化的肿瘤，因此抑制miR-155或NFκB可能为IDH野生型肿瘤患者提供特别关注的治疗选择。
