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      Exosomal Chaperones and miRNAs in Gliomagenesis: State-of-Art and Theranostics Perspectives

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          Abstract

          Gliomas have poor prognosis no matter the treatment applied, remaining an unmet clinical need. As background for a substantial change in this situation, this review will focus on the following points: (i) the steady progress in establishing the role of molecular chaperones in carcinogenesis; (ii) the recent advances in the knowledge of miRNAs in regulating gene expression, including genes involved in carcinogenesis and genes encoding chaperones; and (iii) the findings about exosomes and their cargo released by tumor cells. We would like to trigger a discussion about the involvement of exosomal chaperones and miRNAs in gliomagenesis. Chaperones may be either targets for therapy, due to their tumor-promoting activity, or therapeutic agents, due to their antitumor growth activity. Thus, chaperones may well represent a Janus-faced approach against tumors. This review focuses on extracellular chaperones as part of exosomes’ cargo, because of their potential as a new tool for the diagnosis and management of gliomas. Moreover, since exosomes transport chaperones and miRNAs (the latter possibly related to chaperone gene expression in the recipient cell), and probably deliver their cargo in the recipient cells, a new area of investigation is now open, which is bound to generate significant advances in the understanding and treatment of gliomas.

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          Most cited references115

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          Identification of mammalian microRNA host genes and transcription units.

          To derive a global perspective on the transcription of microRNAs (miRNAs) in mammals, we annotated the genomic position and context of this class of noncoding RNAs (ncRNAs) in the human and mouse genomes. Of the 232 known mammalian miRNAs, we found that 161 overlap with 123 defined transcription units (TUs). We identified miRNAs within introns of 90 protein-coding genes with a broad spectrum of molecular functions, and in both introns and exons of 66 mRNA-like noncoding RNAs (mlncRNAs). In addition, novel families of miRNAs based on host gene identity were identified. The transcription patterns of all miRNA host genes were curated from a variety of sources illustrating spatial, temporal, and physiological regulation of miRNA expression. These findings strongly suggest that miRNAs are transcribed in parallel with their host transcripts, and that the two different transcription classes of miRNAs ('exonic' and 'intronic') identified here may require slightly different mechanisms of biogenesis.
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            The transcriptional network for mesenchymal transformation of brain tumors

            Inference of transcriptional networks that regulate transitions into physiologic or pathologic cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumor aggressiveness in human malignant glioma but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here, we show that reverse-engineering and unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPβ and Stat3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ and Stat3 reprograms neural stem cells along the aberrant mesenchymal lineage whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumor aggressiveness. In human glioma, expression of C/EBPβ and Stat3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results reveal that activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.
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              The heat-shock response.

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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                05 September 2018
                September 2018
                : 19
                : 9
                : 2626
                Affiliations
                [1 ]Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy; celestebavisotto@ 123456gmail.com (C.C.B.); francyrappa@ 123456hotmail.com (F.R.); antonella.marino@ 123456hotmail.it (A.M.G.); fabiobuk@ 123456hotmail.com (F.B.); francapp@ 123456hotmail.com (F.C.)
                [2 ]Euro-Mediterranean Institute of Science and Technology (IEMEST), 90136 Palermo, Italy; ajlmacario@ 123456som.umaryland.edu
                [3 ]Institute of Biophysics, National Research Council, 90143 Palermo, Italy
                [4 ]Department of Experimental Biomedicine and Clinical Neuroscience, Section of Neurosurgery, University of Palermo, 90127 Palermo, Italy; francesca.graziano03@ 123456unipa.it (F.G.); rosario.maugeri1977@ 123456gmail.com (R.M.); gerardo.iacopino@ 123456gmail.com (D.G.I.)
                [5 ]Department of Oncology and Molecular Medicine, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy; mariantonia.logozzi@ 123456iss.it (M.L.); stefano.fais@ 123456iss.it (S.F.)
                [6 ]Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA; econwaydemacario@ 123456som.umaryland.edu
                Author notes
                [* ]Correspondence: claudia.campanella@ 123456unipa.it or claudiettacam@ 123456hotmail.com ; Tel.: +39-091-655-3508
                Author information
                https://orcid.org/0000-0001-8260-8471
                https://orcid.org/0000-0002-6181-2876
                Article
                ijms-19-02626
                10.3390/ijms19092626
                6164348
                30189598
                18242f88-0ece-4471-bba0-91e622b7fef5
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 25 July 2018
                : 31 August 2018
                Categories
                Review

                Molecular biology
                gliomas,molecular chaperones,hsps (heat shock proteins),hsp60,mirna,exosomes,extracellular vesicles,theranostic tools

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