## 3 miRNAs and Molecular Chaperones in Brain Tumors
### Molecular Chaperones in Brain Tumors
This concept has played a key role in alerting physicians and pathologists to the fact that chaperones may be determinant pathogenic factors and should be looked upon as tumor biomarkers and targets for treatment, with negative chaperotherapy being the modality of choice most often, which consists of inhibiting, blocking, or eliminating the \"mistaken\" chaperone. Molecular chaperones can confer resistance against chemo- and radiotherapies, and support glial tumor growth and invasion, i.e., the typical role of \"mistaken\" chaperones that characterize the chaperopathies by mistake, underpinning carcinogenic mechanisms in certain types of tumors [13; 204; 205; 206; 207; 208] (Table 3). A positive correlation between Hsp27 expression level and the growth rate of different types of high-grade astrocytoma, including glioblastoma, has been reported, suggesting its involvement in promoting tumor growth [209; 210]. Hsp27 is an important regulator of F-actin polymerization and it was shown that p38 MAPK activation, followed by Hsp27 phosphorylation, was required for Phorbol 12-myristate 13-acetate (PMA)-induced migration of glioblastoma cells, suggesting that this chaperone is a potential target of negative chaperotherapy to inhibit cancer invasion and progression [211]. This hypothesis was further supported by findings showing that Hsp27 downregulation synergizes the anticancer effects of different drugs and treatments, reducing GBM cell proliferation and promoting caspase 3-mediated apoptosis [212; 213; 214]. Another Hsp involved in glioblastoma tumorigenesis is Hsp47. Hsp47 was found overexpressed in glioma tissues and cell lines and associated with glioma tumor grade [215]. Moreover, its expression level was positively correlated with tumor vascularization, since its silencing consistently decreased VEGF expression in glioma cells, and reduced glioma vasculature [215]. Hsp47 knockdown also inhibited glioma cell growth, migration, and invasion in vitro and in vivo [216]. Contrarily, in vivo Hsp47 overexpression promoted primary glioma cell tumor formation and stemlike properties maintenance, as well as tumor invasion and angiogenesis, thanks to the upregulation of extracellular matrix related genes, such as CD44, LAMC1m COLA42, ITGB1, FN1, and MMP9, through the TGF-\(\beta\) pathway [217]. These data indicate a key role of Hsp47 in glioma angiogenesis, suggesting its potential use as therapeutic target to treat glioma tumors (Table 3). In addition, the involvement of the mitochondrial chaperonin Hsp60 in glioblastoma tumorigenesis and progression has been studied. The Hsp60 expression level was found higher in glioblastoma patients and cell lines, with an antiapoptotic and a prosurvival role [218; 219]. Hsp60 through its interaction with cyclophilin D, Hsp90, and other cofactors, modulates tumor growth and prevents apoptosis in vivo [218]. Moreover, the chaperonin downregulation in glioblastoma cells leads to epithelial-mesenchymal transition and increases production of reactive oxygen species (ROS), ultimately suppressing cell growth and proliferation through the ROS/AMPK/mTOR pathway [219]. The protumorigenic role of Hsp60 was suggested also by immunohistochemical analysis on a subset of human brain neoplasms by comparing the levels of Hsp60 and Hsp70, another Hsp commonly implicated in carcinogenesis [220; 221; 222]. The results showed a significant difference between Hsp60 and Hsp70 levels in neuroepithelial tumors, while levels of both molecules did not differ among each other in meningeal neoplasms. It was suggested that Hsp60 is not increased by a passive phenomenon, but may play an active role in tumor progression, although other studies are needed to fully understand this issue [220; 223; 224]. Hsp70 is another chaperone that is thought to play a role in carcinogenesis, since it was found abundantly expressed in malignant cells, and with different roles [225].