Posttranscriptional deregulation of signaling pathways in meningioma subtypes by differential expression of miRNAs

Micro (mi)RNAs are short, noncoding RNAs that downregulate gene expression by binding to specific sequences in the 3′ untranslated regions of their target genes and thereby either inhibiting the binding of the translation machinery or leading to degradation of the corresponding mRNAs.1 Recent research has attributed key roles to miRNAs in cancer initiation, progression, and metastasis as key regulators of gene expression, whose deregulation affects multiple cellular pathways, including angiogenesis, epithelial-to-mesenchymal transition (EMT), and signaling pathways crucial for proliferation.2 Meningiomas account for about 35% of all primary brain tumors and are classified into 3 malignancy grades and 15 histological subtypes.3 About 80% of meningiomas (World Health Organization [WHO] grade I) are slow-growing benign tumors, with most common histological subtypes being meningothelial, fibroblastic, and transitional meningioma. Meningiomas of WHO grades II and III represent 18%–20% and 1%–2%, respectively, of all meningiomas and are characterized by a more aggressive growth with increased recurrence rates and shorter disease-specific survival.4 Cytogenetic aberrations in meningioma include partial or complete loss of chromosome 22 and loss of chromosomes 1p, 6q, 9p, 10, 14q, and 18q and gains on chromosomes 1q, 9q, 12q, 15q, 17q, and 20q in high-grade meningiomas (reviewed by Perry et al5). Loss of expression of neurofibromatosis 2, a gene located on 22q, is more frequent in fibroblastic than in meningothelial meningioma, suggesting different drivers for tumorigenesis in the mesenchymal (fibroblastic) and epithelial (meningothelial) lineages of benign meningioma.6 Deregulated signaling pathways associated with meningioma include Wnt, hedgehog, transforming growth factor–β (TGFB), mitogen-activated protein kinase (MAPK)/phosphatidylinositol-3 kinase (PI3K), and vascular endothelial growth factor (VEGF) pathways,7 and a role for EMT in meningioma genesis has been recently proposed.8 Despite their undisputed importance in various cancer types, only a few miRNAs have been associated with meningiomas, including miR-200a, -145, -190, -29c-3p, and -219-5p.9–12 MiR-200a was found downregulated in benign meningioma, and its overexpression inhibited meningioma cell growth in vitro and in vivo. Targets of miR-200a include β-catenin, a major component of the Wnt signaling pathway frequently involved in meningioma genesis, and nonmuscle heavy chain IIb, a protein involved in cell migration and divison.10,12 Another study provided evidence that a combination of high expression of miR-190 and low expression of miR-29c-3p and miR-219-5p significantly correlates with increased recurrence rates in meningiomas.11 The only study on differential miRNA expression between low-grade and high-grade meningiomas focused on 5 known cancer-related miRNAs, showing that miR-145 is significantly downregulated in WHO grades II and III meningiomas.9 When reexpressed in higher-grade meningioma cell lines in vitro, miR-145 expression led to decreased proliferation and migratory potential and an increased sensitivity for apoptosis, suggesting an important antimigratory and antiproliferative role for miR-145 in higher-grade meningiomas. In the present study we aim at deepening the knowledge of miRNA deregulation in meningiomas of different histological subtypes and grades and exploring the clinical usability of miRNAs for prediction of higher-grade meningioma. Additionally, we try to link deregulated miRNAs to signaling pathways associated with meningioma initiation and progression using their validated and potential targets derived from an in silico analysis.