## 3 miRNAs and Molecular Chaperones in Brain Tumors
### miRNAs in Brain Tumors
Glioblastoma multiforme (WHO grade IV astrocytoma) is characterized by poorly differentiated glial cells with polymorphism, nuclear atypia, and high mitotic activity, and is the most common malignant primary brain tumor, with an incidence of 3.19 cases per 100,000 person/year and a remarkably poor prognosis due to the still limited therapeutic options [150]. Therefore, the identification of new diagnostic and prognostic biomarkers is necessary to develop novel and personalized therapeutic treatments. Also, in this case, great interest was elicited by miRNAs, which often show an altered expression level in GMB patients compared to healthy controls, as already discussed for miR-155 and miR-185. It was observed that the serum level of miR-203 is decreased in GBM patients compared with low grade glioma (LGG) patients and healthy controls, and it positively correlates with poor overall survival [151]. These results confirm the tumor-suppressor activity of miR-203 in GMB, whose low expression level in two human GBM cell lines was previously shown to induce their epithelial-mesenchymal transition and confer them chemoresistance [152] (Table 2). Similarly, miR-605 has a reduced expression level in GMB tissues and cell lines, and this was correlated with patients' poor survival [153]. Conversely, increased levels of miR-605 inhibited cancer cell proliferation and growth in vitro and in vivo, by directly targeting SOX9 (SRY-box 9) and by inhibiting the activation of the PI3K (phosphatidylinositol 3-kinase)/Akt (protein kinase B) pathway [153] (Table 2). Compared to GBM, much less is known about circulating miRNAs as useful indicators for diagnosis and prognosis of meningiomas. In addition, for these tumors, miRNAs have been identified that act as oncogenes or tumor suppressors. For instance, miR-200a has been implicated in the pathogenesis of meningiomas and was found downregulated in sporadic benign human meningioma tumors (WHO grade I), compared to the arachnoid tissues from which these tumors arise [154]. This miRNA functions as a potential tumor suppressor since its upregulation inhibits Wnt/\(\beta\)-catenin signaling, involved in cell proliferation, through two complementary mechanisms: a) direct targeting of the \(\beta\)-catenin mRNA, which reduces the levels of \(\beta\)-catenin, acting as the main activator of the Wnt signaling; and b) targeting the mRNAs for ZEB1 (Zinc Finger E-Box Binding Homeobox 1) and SIP1 (Smad Interacting Protein 1), which negatively regulate the expression of the E-cadherin gene, with a consequent upregulation of E-cadherin levels and sequestration of \(\beta\)-catenin [154]. Another mir-200a target is the nonmuscle myosin heavy chain IIb (NMHCIIb), involved in regulation of cells motility. NMHCIIb downregulation concomitantly with miR-200a overexpression in malignant meningioma cells significantly reduced the rate of cancer cells migration, and thus tumor invasiveness [155]. The expression level of miR-145 appears significantly reduced in atypical and anaplastic tumors as compared with benign meningiomas [156]. In vitro, the overexpression of miR-145 reduced meningioma cells proliferation and motility, thanks to the associated downregulation of collagen type V alpha (COL5A1) and induced apoptotic cell death [156]. These effects translated into a decreased growth of an orthotopic tumor in a nude mice model, with reduction in tumor cell infiltration upon overexpression of miR-145 [156] (Table 2). The microRNA miR-335 is overexpressed in meningiomas and acts as an oncomiR. It has been shown that elevated levels of miR-335 in vitro increased tumor cell growth by directly targeting the signaling pathway of the tumor suppressor Rb1, whereas reduction of the miR-335 levels had the opposite effect on tumor growth and progression, leading to cell cycle arrest in the G0/G1 phase [157].