## 3 miRNAs and Molecular Chaperones in Brain Tumors
### miRNAs in Brain Tumors
MicroRNAs with expression levels different in the tumoral tissues as compared with the normal tissue counterparts were identified for several tumor types, for instance glioblastoma [132; 133; 134]. More than 70 percent of all brain tumors are gliomas that are classified according to the type of the glial cell involved, and include astrocytoma (astrocytoma, anaplastic astrocytoma, and glioblastoma), ependymomas (anplastic ependymoma, myxpopapillary ependymoma, and subependymoma), and oligodendomas (oligodendroglioma, anaplastic oligodendoma, and anaplastic oligoastrocytoma) (Table 2). Microarray studies on miRNAs have shown significant changes of their expression profile in gliomas, both in children and in adults [135; 136] (Table 2). Compared to normal brain tissues, miRNA-155 (miR-155) was found overexpressed in glioma tissues, and its overexpression was associated with poor overall survival rates, suggesting that monitoring its expression levels could be a way to assess prognosis [137]. The positive correlation between miR-155 expression level and glioma malignancy was further established by in vitro and in vivo studies [138]. In vitro, miR-155 promoted tumor cells proliferation, invasion, and migration by downregulating two components of the mitogen-activated protein kinase (MAPK) signaling pathway and, in turn, enhancing secretion of matrix metalloproteinases 2 (MMP2) and MMP9 [138]. Moreover, it competed with miR-185 to induce ANXA2 (annexin A2), which exhibited oncogenic functions in glioblastoma multiforme (GBM) [139]. In vivo studies showed that miR-155 facilitated the progression of glioblastoma and confers drug resistance by modulating Six1 expression [140]. These results confirm the role of miR-155 as oncomiR and suggest its potential use as biomarker and as an anticancer drug target. In fact, its knockdown sensitized glioma cells to temozolomide, a common anticancer drug, through the induction of MAPK13, MAPK14, and Six1, and mediated oxidative stress and apoptosis [138; 140] (Table 2). The other two miRNAs proposed as oncomiRs, and potential prognostic biomarkers, are miR-221 and miR-222, whose high levels of expression are positively correlated with glioma aggressiveness and poor prognosis [141; 142]. Among miR-221 and miR-222 targets that are involved in these protumorigenic effects are the tissue inhibitor of metalloproteinase (TIMP3), which is downregulated concomitantly with miR-221 and miR-222 overexpression, promoting glioma cell invasion [141], and the Akt pathway, which is activated, promoting cancer cell proliferation [143]. Conversely, cosuppression of miR-221 and miR-222 suppresses human glioma-cell growth and proliferation by a mechanism involving the upregulation of the cell cycle inhibitor p27 Kip1 both in vitro and in vivo [144]. Moreover, as reported for the oncomiR-155, downregulation of miR-221 and miR222 sensitizes glioma cells to temozolomide by increasing the expression of proapoptotic factors [145] (Table 2). There are also several examples of miRNAs considered tumor suppressors of malignant gliomas. Low plasma level of miR-185 is a signature of a glioma that correlates with poor survival [146]. Its inhibition after miR-155 overexpression in GBM promoted ANXA2 expression and tumor growth and progression [139]. Similarly, serum miR-205 expression was significantly lower in patients with glioma than in healthy controls, as well as in other brain tumor cohorts, and its serum level appeared inversely correlated with pathological grades and overall survival, since patients with glioma at an advanced pathological grade (grade III or IV) and a higher miR-205 serum level had a longer overall survival than those with a lower miR-205 serum concentration [147]. Thus, miR-185 and miR-205 were identified as tumor suppressors and were proposed as biomarkers with predictive prognostic potential to be used with noninvasive tools for monitoring cancer progression and response to treatment [146; 147; 148; 149] (Table 2).