Ludwig Nicole, Kim Yoo-Jin, Mueller Sabine C, Backes Christina, Werner Tamara V, Galata Valentina, Sartorius Elke, Bohle Rainer M, Keller Andreas, Meese Eckart
Department of Human Genetics Medical School, Saarland University, Homburg/Saar, Germany (N.L., S.C.M., C.B., T.V.W., V.G., E.M.); Institute of Pathology Medical School, Saarland University, Homburg/Saar, Germany (Y.-J.K., E.S., R.M.B.); Chair for Clinical Bioinformatics, Saarland University, University Hospital, Saarbrücken, Germany (S.C.M., C.B., V.G., A.K.).
Neuro Oncol. 2015 Sep;17(9):1250-60. doi: 10.1093/neuonc/nov014. Epub 2015 Feb 13.
Micro (mi)RNAs are key regulators of gene expression and offer themselves as biomarkers for cancer development and progression. Meningioma is one of the most frequent primary intracranial tumors. As of yet, there are limited data on the role of miRNAs in meningioma of different histological subtypes and the affected signaling pathways.
In this study, we compared expression of 1205 miRNAs in different meningioma grades and histological subtypes using microarrays and independently validated deregulation of selected miRNAs with quantitative real-time PCR. Clinical utility of a subset of miRNAs as biomarkers for World Health Organization (WHO) grade II meningioma based on quantitative real-time data was tested. Potential targets of deregulated miRNAs were discovered with an in silico analysis.
We identified 13 miRNAs deregulated between different subtypes of benign meningiomas, and 52 miRNAs deregulated in anaplastic meningioma compared with benign meningiomas. Known and putative target genes of deregulated miRNAs include genes involved in epithelial-to-mesenchymal transition for benign meningiomas, and Wnt, transforming growth factor-β, and vascular endothelial growth factor signaling for higher-grade meningiomas. Furthermore, a 4-miRNA signature (miR-222, -34a*, -136, and -497) shows promise as a biomarker differentiating WHO grade II from grade I meningiomas with an area under the curve of 0.75.
Our data provide novel insights into the contribution of miRNAs to the phenotypic spectrum in benign meningiomas. By deregulating translation of genes belonging to signaling pathways known to be important for meningioma genesis and progression, miRNAs provide a second in line amplification of growth promoting cellular signals. MiRNAs as biomarkers for diagnosis of aggressive meningiomas might prove useful and should be explored further in a prospective manner.
微小(mi)RNA是基因表达的关键调节因子,有望成为癌症发生和发展的生物标志物。脑膜瘤是最常见的原发性颅内肿瘤之一。迄今为止,关于miRNA在不同组织学亚型脑膜瘤中的作用以及受影响的信号通路的数据有限。
在本研究中,我们使用微阵列比较了1205种miRNA在不同级别和组织学亚型脑膜瘤中的表达,并通过定量实时PCR独立验证了所选miRNA的失调情况。基于定量实时数据,测试了一组miRNA作为世界卫生组织(WHO)II级脑膜瘤生物标志物的临床效用。通过计算机分析发现失调miRNA的潜在靶标。
我们鉴定出13种在良性脑膜瘤不同亚型之间失调的miRNA,与良性脑膜瘤相比,52种在间变性脑膜瘤中失调的miRNA。失调miRNA的已知和推定靶基因包括参与良性脑膜瘤上皮-间质转化的基因,以及高级别脑膜瘤中的Wnt、转化生长因子-β和血管内皮生长因子信号通路相关基因。此外,一个4-miRNA特征(miR-222、-34a*、-136和-497)有望作为区分WHO II级和I级脑膜瘤的生物标志物,曲线下面积为0.75。
我们的数据为miRNA对良性脑膜瘤表型谱的贡献提供了新的见解。通过调节已知对脑膜瘤发生和发展重要的信号通路中基因的翻译,miRNA提供了促进生长的细胞信号的二级放大。miRNA作为侵袭性脑膜瘤诊断的生物标志物可能有用,应进一步前瞻性探索。