Meningiomas are tumours arising from the membranous layers that surround the central nervous system. These tumours are mostly benign and asymptomatic although a small proportion (about 3%) present as malignant. The latter form has a poor prognosis with a median survival after diagnosis of <2 years. This is usually associated with metastatic dissemination that can either be intra-cranial or to distant organs,1,2 making the management of the disease difficult. Hence, the identification of regulators of meningioma cell migration and invasion is essential if we intend to improve the prognosis of patients with this disease. In this issue, using a proteomic approach, Senol et al. identify a target of the microRNA, miR200a, that regulates the ability of meningioma cells to migrate. The authors had previously involved miR200a in the pathogenicity of meningioma following a microRNA profiling study and demonstrated that it influences the growth of this tumour type through the direct targeting of β-catenin mRNA and interfering with the Wnt signalling pathway.3

In the present study, the authors identify 130 differentially expressed proteins in response to miR200a overexpression in immortalised human primary meningioma cells. Among these 130 targets, four proteins: complement C4-A precursor (C4-A), myosin X (NMHCIIb), polyadenylate-binding protein 4 (PABPC4) and ester hydrolase C11orf54 (C11orf54), were predicted by computational algorithms to contain binding sites for miR200a in their 3′UTRs. The authors decided to further focus their study on the role of NMHCIIb, a component of the actomyosin cytoskeleton. Indeed, this protein is reported to be involved in processes related to cell migration and metastasis4,5 as it participates in filopodia formation.6 Comparative analysis revealed that the levels for miR200a were decreased in meningioma cell lines as compared to arachnoidal cells and this correlated with a significant increase in NMHCIIb mRNA. Conversely, overexpression of miR200a in immortalised human primary meningioma cells decreased levels of NMHCIIb at both the mRNA and protein levels, suggesting that it could be a direct target of miR200a. These changes correlated with a significant decrease in the ability of the transfected cells to migrate, an effect that could be partially corrected by the overexpression of NMHCIIb. Independent confirmation of the role of this protein in the migration of meningioma cells was provided by the reduction in the migration rate of cells where NMHCIIb had been silenced using siRNAs. In addition to modulating cell migration, NMHCIIb silencing decreased the viability of transfected cells as well as their ability to grow tumours in mice. Moreover, linking the present study to the authors’ previously published work,3 overexpression of miR200a similarly inhibited tumour growth in vivo, an effect partially rescued by the overexpression of NMHCIIb. This is significant in view of the fact that the expression levels for NMHCIIb were found to be elevated in meningioma compared to dura mater tissues, while those of miR200a were decreased.

This manuscript is the second published in Oncogene on the role of microRNAs in the regulation of invasion and motility of meningioma cells. Indeed, in 2013 the Journal published a manuscript by Kliese et al.7 reporting the role of miR145 in this disease. This microRNA appeared significantly downregulated in anaplastic tumours as compared to benign meningiomas. Overexpression of miR145 not only reduced the cell proliferation of meningioma cells and sensitised these to apoptotic cell death in vitro, but it also reduced the ability of the cells to migrate in wound-healing assays. These effects translated into the decreased growth of orthotopic tumour in a nude mice model of the disease with reduction in tumour cell infiltration upon overexpression of miR145 as compared to that of a non-targeting microRNA control. Here again, as in the work by Senol et al., the targeting of a structural protein, collagen type V alpha (COL5A1) was suggested to be involved in the observed effects. Indeed, COL5A1 expression levels significantly increased with tumour grade while those for miR145 decreased.

In contrast to the case of miR200a and miR145 where the levels of these microRNAs are downregulated in the disease, another study by Shi et al.8 revealed that miR335 is over-expressed in human meningioma. Overexpression of this MicroRNA led to increased cell growth and inhibition of G0/G1 phase cell cycle arrest in vitro. Conversely, reduction of miR335 levels in primary meningioma cells lead to cell cycle arrest. These effects were mediated through the ability of miR335 to inhibit the Rb1 signalling pathway. Indeed, the authors demonstrated through the use of a luciferase reporter assay that this microRNA directly targeted the 3’UTR of Rb1’s mRNA, leading to its degradation. Hence, increased expression of miR335 may in itself explain the reduced levels of this tumour suppressor found in meningioma.

While these studies provide a deeper mechanistic understanding of the pathogenesis of the disease (see Figure 1), it is not obvious at this point how to translate this information into novel therapeutic strategies for anaplastic meningioma. Indeed, the targets identified in the above three studies are not easily (if at all) druggable. However, a better understanding about the involvement of microRNAs in this pathology may indirectly guide clinical practice based on the predictive value of the targets modulated or the selective expression pattern of the microRNAs themselves. In agreement with this notion, a comparative profiling study of the expression of 200 miRNAs in 110 meningioma and 35 normal adjacent tissues revealed a 14-miRNA signature that predicts recurrence in this disease.9 Among the included microRNAs, downregulation of miR29c-3p and miR219-5p was associated with advanced clinical stages of the disease. Also, high expression of miR190a and low expression of miR29c-3p and miR219-5p significantly correlated with higher recurrence rates. In particular, miR190a expression levels were found to be an independent prognostic predictor in multivariate analysis. Incidentally, miR200a, miR335 or miR145 was not among the 14 microRNAs identified by Zhi et al., but it is not clear whether these particular microRNAs were among those profiled by the authors. Conversely, while Senol et al. indicate that the expression of NMHCIIb did not increase and that of miR200a did not decrease with tumour grade, this may have been confounded by the reduced number of samples analysed (20 Grade I, 6 Grade II and 4 Grade III), and assessment of these markers in a larger cohort similar to that used in the manuscript of Zhi et al. may be required to reveal significant trends.

Figure 1
figure 1

Three microRNAs involved in meningioma cell migration and growth: Through preventing Myosin X translation, miR200a is likely to inhibit filopodia formation as Myosin X hotspots at the tip of these structures have been suggested to promote actin polymerisation. In parallel, miR145 modulates the composition of the extracellular matrix by inhibiting the production of Collagen Vα. By increasing actin polymerisation and collagen deposition, the decreased levels of both these miRNAs in meningioma are expected to favour tumour dissemination. On the other hand, increased levels of miR335 promote cell cycle progression through the inhibition of the tumour suppressor Rb1

In short, while much remains to be done to understand the biology of meningioma and how this disease becomes anaplastic, the manuscript by Senol et al. brings us one step closer to unravelling the molecular mechanisms on which future therapeutic strategies and more efficient management for this disease may be based.