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      miR-20b and miR-451a Are Involved in Gastric Carcinogenesis through the PI3K/AKT/mTOR Signaling Pathway: Data from Gastric Cancer Patients, Cell Lines and Ins-Gas Mouse Model

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          Abstract

          Gastric cancer (GC) is one of the most common and lethal gastrointestinal malignancies worldwide. Many studies have shown that development of GC and other malignancies is mainly driven by alterations of cellular signaling pathways. MicroRNAs (miRNAs) are small noncoding molecules that function as tumor-suppressors or oncogenes, playing an essential role in a variety of fundamental biological processes. In order to understand the functional relevance of miRNA dysregulation, studies analyzing their target genes are of major importance. Here, we chose to analyze two miRNAs, miR-20b and miR-451a, shown to be deregulated in many different malignancies, including GC. Deregulated expression of miR-20b and miR-451a was determined in GC cell lines and the INS-GAS mouse model. Using Western Blot and luciferase reporter assay we determined that miR-20b directly regulates expression of PTEN and TXNIP, and miR-451a: CAV1 and TSC1. Loss-of-function experiments revealed that down-regulation of miR-20b and up-regulation of miR-451a expression exhibits an anti-tumor effect in vitro (miR-20b: reduced viability, colony formation, increased apoptosis rate, and miR-451a: reduced colony forming ability). To summarize, the present study identified that expression of miR-20b and miR-451a are deregulated in vitro and in vivo and have a tumor suppressive role in GC through regulation of the PI3K/AKT/mTOR signaling pathway.

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          Most cited references41

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          MicroRNAs in human cancer.

          Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23-nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the translation and stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and invasion. miRNA targeting is initiated through specific base-pairing interactions between the 5' end ("seed" region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR lead to more effective mRNA destabilization. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. To provide a critical overview of miRNA dysregulation in cancer, we first discuss the methods currently available for studying the role of miRNAs in cancer and then review miRNA genomic organization, biogenesis, and mechanism of target recognition, examining how these processes are altered in tumorigenesis. Given the critical role miRNAs play in tumorigenesis processes and their disease specific expression, they hold potential as therapeutic targets and novel biomarkers.
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            Molecular evolution of a microRNA cluster.

            Many of the known microRNAs are encoded in polycistronic transcripts. Here, we reconstruct the evolutionary history of the mir17 microRNA clusters which consist of miR-17, miR-18, miR-19a, miR-19b, miR-20, miR-25, miR-92, miR-93, miR-106a, and miR-106b. The history of this cluster is governed by an initial phase of local (tandem) duplications, a series of duplications of entire clusters and subsequent loss of individual microRNAs from the resulting paralogous clusters. The complex history of the mir17 microRNA family appears to be closely linked to the early evolution of the vertebrate lineage.
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              The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo.

              Activated oncogenic signaling is central to the development of nearly all forms of cancer, including the most common class of primary brain tumor, glioma. Research over the last two decades has revealed the particular importance of the Akt pathway, and its molecular antagonist PTEN (phosphatase and tensin homolog), in the process of gliomagenesis. Recent studies have also demonstrated that microRNAs (miRNAs) may be responsible for the modulation of cancer-implicated genes in tumors. Here we report the identification miR-26a as a direct regulator of PTEN expression. We also show that miR-26a is frequently amplified at the DNA level in human glioma, most often in association with monoallelic PTEN loss. Finally, we demonstrate that miR-26a-mediated PTEN repression in a murine glioma model both enhances de novo tumor formation and precludes loss of heterozygosity and the PTEN locus. Our results document a new epigenetic mechanism for PTEN regulation in glioma and further highlight dysregulation of Akt signaling as crucial to the development of these tumors.
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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
                29 January 2020
                February 2020
                : 21
                : 3
                : 877
                Affiliations
                [1 ]Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; greta.streleckiene@ 123456lsmuni.lt (G.S.); ruta.inciuraite@ 123456lsmuni.lt (R.I.); simonas.juzenas@ 123456lsmuni.lt (S.J.); violeta.salteniene@ 123456lsmuni.lt (V.S.); ruta.steponaitiene@ 123456lsmuni.lt (R.S.); ugne.gyvyte@ 123456lsmuni.lt (U.G.); gediminaskiudelis@ 123456gmail.com (G.K.); j_kupcinskas@ 123456yahoo.com (J.K.)
                [2 ]Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany
                [3 ]Institute for Clinical and Preventive Medicine, University of Latvia, Riga LV-1586, Latvia; marcis.leja@ 123456lu.lv
                [4 ]Faculty of Medicine, University of Latvia, Riga LV-1586, Latvia
                [5 ]Department of Research, Riga East University Hospital, Riga LV-1038, Latvia
                [6 ]Digestive Diseases Centre GASTRO, Riga LV-1079, Latvia
                [7 ]Biophysical Research Group, Faculty of Natural Sciences, Vytautas Magnus University, Kaunas LT-44404, Lithuania; paulius.ruzgys@ 123456vdu.lt (P.R.); saulius.satkauskas@ 123456vdu.lt (S.S.)
                [8 ]Department of Biology, Faculty of Nature Sciences, Vytautas Magnus University, Kaunas LT-44404, Lithuania; eugenija.kupcinskiene@ 123456vdu.lt
                [9 ]Institute of Pathology, Otto-von-Guericke University, 39120 Magdeburg, Germany; sabine.franke@ 123456med.ovgu.de
                [10 ]Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39120 Magdeburg, Germany; cosima.thon@ 123456med.ovgu.de (C.T.); alexander.link@ 123456med.ovgu.de (A.L.)
                [11 ]Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
                Author notes
                [* ]Correspondence: jurgita.skieceviciene@ 123456lsmuni.lt ; Tel.: +370-37-327236
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-4501-4073
                https://orcid.org/0000-0002-9001-7767
                https://orcid.org/0000-0002-9514-4562
                Article
                ijms-21-00877
                10.3390/ijms21030877
                7038213
                32013265
                370e3446-d2b6-43f6-ba69-f343d20e2315
                © 2020 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
                : 09 January 2020
                : 28 January 2020
                Categories
                Article

                Molecular biology
                micrornas,mir-20b,mir-451a,pi3k/akt/mtor signaling pathway,gastric cancer
                Molecular biology
                micrornas, mir-20b, mir-451a, pi3k/akt/mtor signaling pathway, gastric cancer

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