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      Long Noncoding RNA MEG3 Inhibits Cell Proliferation and Metastasis in Chronic Myeloid Leukemia via Targeting miR-184

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          Abstract

          Maternally expressed gene 3 (MEG3), a long noncoding RNA, has been reported to be associated with the pathogenesis of multiple malignancies. However, little is known regarding the role of MEG3 in leukemia. In this study, we found that the expression of MEG3 was decreased in leukemia patients and cell lines and has potential to be considered as a biomarker for leukemia. In addition, overexpression of MEG3 inhibited cell proliferation and invasion in vitro and in vivo. Moreover, a potential bonding site between miR-184 and MEG3 was predicted, and low expression of miR-184 was found in leukemia patients and cell lines. In vitro loss and gain of function showed that overexpression of MEG3 significantly decreased the expression of miR-184, and MEG3 knockdown markedly increased it. Furthermore, our results showed that MEG3 interacted with miR-184 and subsequently mitigated the proliferation and invasion of leukemia cells by downregulating related proteins. In conclusion, our study has identified a novel pathway through which MEG3 acts as a tumor suppressor in leukemia at the level of miRNAs and provided a molecular basis for potential applications of MEG3 in the prognosis and treatment of leukemia.

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          Most cited references32

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          A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells.

          Human pituitary adenomas are the most common intracranial neoplasm. Typically monoclonal in origin, a somatic mutation is a prerequisite event in tumor development. To identify underlying pathogenetic mechanisms in tumor formation, we compared the difference in gene expression between normal human pituitary tissue and clinically nonfunctioning pituitary adenomas by cDNA-representational difference analysis. We cloned a cDNA, the expression of which was absent in these tumors, that represents a novel transcript from the previously described MEG3, a maternal imprinting gene with unknown function. It was expressed in normal human gonadotrophs, from which clinically nonfunctioning pituitary adenomas are derived. Additional investigation by Northern blot and RT-PCR demonstrated that this gene was also not expressed in functioning pituitary tumors as well as many human cancer cell lines. Moreover, ectopic expression of this gene inhibits growth in human cancer cells including HeLa, MCF-7, and H4. Genomic analysis revealed that MEG3 is located on chromosome 14q32.3, a site that has been predicted to contain a tumor suppressor gene involved in the pathogenesis of meningiomas. Taken together, our data suggest that MEG3 may represent a novel growth suppressor, which may play an important role in the development of human pituitary adenomas.
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            Overexpression of the long non-coding RNA MEG3 impairs in vitro glioma cell proliferation.

            Gliomas are the most common type of primary brain tumor in the central nervous system of adults. Maternally Expressed Gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes a non-coding RNA (ncRNA) associated with tumorigenesis. However, little is known about whether and how MEG3 regulates glioma development. In the present study we assayed the expression of MEG3 in glioma tissue samples by real-time polymerase chain reaction assay, and defined the biological functions and target genes by CCK-8 assay, flow cytometry, and RNA immunoprecipitation. We first demonstrated that MEG3 expression was markedly decreased in glioma tissues compared with adjacent normal tissues. Moreover, ectopic expression of MEG3 inhibited cell proliferation and promoted cell apoptosis in U251 and U87 MG human glioma cell lines. We further verified that MEG3 was associated with p53 and that this association was required for p53 activation. These data suggest an important role of MEG3 in the molecular etiology of glioma and implicate the potential application of MEG3 in glioma therapy. Copyright © 2012 Wiley Periodicals, Inc.
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              Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions.

              Maternally expressed gene 3 (MEG3) is an imprinted gene highly expressed in the human pituitary. However, MEG3 expression is lost in human gonadotroph-derived pituitary adenomas and most human tumor cell lines. Expression of MEG3 in tumor cells results in growth suppression, p53 protein increase, and activation of p53 downstream targets. The MEG3 gene encodes a noncoding RNA of approximately 1700 nucleotides. There are 12 different MEG3 gene transcripts, generated by alternative splicing. They contain the common exons 1-3 and exons 8-10, but each uses one or more exons 4-7 in a different combination in the middle. MEG3 isoform expression patterns are tissue and cell type specific. Functionally, each isoform stimulates p53-mediated transactivation and suppresses tumor cell growth. We analyzed the secondary RNA folding structure of each MEG3 isoform, using the computer program mfold. All MEG3 RNA isoforms contain three distinct secondary folding motifs M1, M2, and M3. Deletion analysis showed that motifs M2 and M3 are important for p53 activation. Furthermore, a hybrid MEG3 RNA, containing a piece of artificially synthesized sequence different from the wild type but folding into a similar secondary structure, retained the functions of both p53 activation and growth suppression. These results support the hypothesis that a proper folding structure of the MEG3 RNA molecule is critical for its biological functions. This study establishes for the first time the structure-function relationship of a large noncoding RNA and provides a first look into the molecular mechanisms of the biological functions of a large noncoding RNA.
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                Author and article information

                Journal
                Oncol Res
                Oncol Res
                OR
                Oncology Research
                Cognizant Communication Corporation (Elmsford, NY )
                0965-0407
                1555-3906
                2018
                05 March 2018
                : 26
                : 2
                : 297-305
                Affiliations
                [1] Department of Hematology, the First Affiliated Hospital of Xinxiang Medical University , Xinxiang, P.R. China
                Author notes
                Address correspondence to Jingdong Li, Department of Hematology, the First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui County, Xinxiang, Henan 453100, P.R. China. Tel: (+86) 0373-4403432; E-mail: Jingdong_Lee@ 123456163.com
                Article
                OR1139
                10.3727/096504017X14980882803151
                7844682
                28653609
                8a551983-5dcd-4207-9914-b9768b66af65
                Copyright © 2018 Cognizant, LLC.

                This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.

                History
                Page count
                Figures: 4, Tables: 0, References: 32, Pages: 9
                Categories
                Article

                long noncoding rnas (lncrnas),maternally expressed gene 3 (meg3),mir-184,leukemia

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