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      LncRNA GMDS‐AS1 inhibits lung adenocarcinoma development by regulating miR‐96‐5p/CYLD signaling

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          Abstract

          According to the global cancer statistic, lung cancer is one of the most dangerous tumors, which poses a serious threat to human health. Exploration the mechanism of lung cancer and new targeted therapeutic measures is always the hot topic. Long noncoding RNA (lncRNA) is an important factor affecting the development of tumors. However, the research on the mechanism of lncRNA in the progress of lung cancer needs to be further expanded. In this study, we found that the expression of lncRNA GMDS‐AS1 was significantly reduced in lung adenocarcinoma (LUAD) tissues and cells. Upregulated GMDS‐AS1 can significantly inhibit the proliferation of LUAD cells and promote cell apoptosis in vitro and in vivo. The results indicate that GMDS‐AS1 acts as a tumor suppressor gene to affect the development of LUAD. Further studies revealed that GMDS‐AS1 is a target gene of miR‐96‐5p, and GMDS‐AS1 regulates proliferation and apoptosis of LUAD cells in association with miR‐96‐5p. In addition, we also confirmed that CYLD lysine 63 deubiquitinase (CYLD) is also a target gene of miR‐96‐5p. Through various validations, we confirmed that GMDS‐AS1 can act as a ceRNA to upregulate the expression of CYLD by sponging miR‐96‐5p. Moreover, the intervention of GMDS‐AS1/miR‐96‐5p/CYLD network can regulate the proliferation and apoptosis of LUAD cells. In this study, we revealed that the GMDS‐AS1/miR‐96‐5p/CYLD network based on ceRNA mechanism plays an important role in the development of LUAD and provides a new direction and theoretical basis for targeted therapy of LUAD.

          Abstract

          GMDS‐AS1/miR‐96‐5p/CYLD network based on ceRNA mechanism plays an important role in the development of lung cancer and provides a new direction and theoretical basis for targeted therapy of lung cancer.

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          Most cited references20

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          LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

          While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis 1 yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repertoire of genes central to the identity and behavior of prostate cancer cells 2 , and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy 3 . Here, we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 and PCGEM1, bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the C-terminally acetylated AR on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the DOT1L-mediated methylated AR N-terminus. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited Pygopus2 PHD domain proves to enhance selective looping of AR-bound enhancers to target gene promoters in these cells. In “resistant” prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally-expressed short hairpin RNA (shRNA) targeting of these lncRNAs in castration-resistant prostate cancer (CRPC) cell lines strongly suppressed tumor xenograft growth in vivo. Together, these results suggest that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumors.
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            The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator.

            The identification of ultraconserved noncoding sequences in vertebrates has been associated with developmental regulators and DNA-binding proteins. One of the first of these was identified in the intergenic region between the Dlx-5 and Dlx-6 genes, members of the Dlx/dll homeodomain-containing protein family. In previous experiments, we showed that Sonic hedgehog treatment of forebrain neural explants results in the activation of Dlx-2 and the novel noncoding RNA (ncRNA), Evf-1. In this report, we show that the Dlx-5/6 ultraconserved region is transcribed to generate an alternatively spliced form of Evf-1, the ncRNA Evf-2. Evf-2 specifically cooperates with Dlx-2 to increase the transcriptional activity of the Dlx-5/6 enhancer in a target and homeodomain-specific manner. A stable complex containing the Evf-2 ncRNA and the Dlx-2 protein forms in vivo, suggesting that the Evf-2 ncRNA activates transcriptional activity by directly influencing Dlx-2 activity. These experiments identify a novel mechanism whereby transcription is controlled by the cooperative actions of an ncRNA and a homeodomain protein. The possibility that a subset of vertebrate ultraconserved regions may function at both the DNA and RNA level to control key developmental regulators may explain why ultraconserved sequences exhibit 90% or more conservation even after 450 million years of vertebrate evolution.
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              The long noncoding RNA Malat1: Its physiological and pathophysiological functions.

              Recent studies suggest that in humans, DNA sequences responsible for protein coding regions comprise only 2% of the total genome. The rest of the transcripts result in RNA transcripts without protein-coding ability, including long noncoding RNAs (lncRNAs). Different from most members in the lncRNA family, the metastasis-associated lung adenocarcinoma transcript 1 (Malat1) is abundantly expressed and evolutionarily conserved throughout various mammalian species. Malat1 is one of the first identified lncRNAs associated with human disease, and cumulative studies have indicated that Malat1 plays critical roles in the development and progression of various cancers. Malat1 is also actively involved in various physiologic processes, including alternative splicing, epigenetic modification of gene expression, synapse formation, and myogenesis. Furthermore, extensive evidences show that Malat1 plays pivotal roles in multiple pathological conditions as well. In this review, we will summarize latest findings related to the physiologic and pathophysiological processes of Malat1 and discuss its therapeutic potentials.
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                Author and article information

                Contributors
                bairoushui@163.com
                yong_song6310@yahoo.com
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                20 December 2019
                February 2020
                : 9
                : 3 ( doiID: 10.1002/cam4.v9.3 )
                : 1196-1208
                Affiliations
                [ 1 ] Department of Respiratory Medicine Jinling Hospital, Second Military Medical University Nanjing China
                Author notes
                [*] [* ] Correspondence

                Tang‐Feng Lv and Yong Song, Department of Respiratory Medicine, JinLing Hospital, Second Military Medical University, 305 Zhongshan East Road, Nanjing 210002, China.

                Email: bairoushui@ 123456163.com ; yong_song6310@ 123456yahoo.com

                Author information
                https://orcid.org/0000-0002-2871-1408
                https://orcid.org/0000-0003-4979-4131
                Article
                CAM42776
                10.1002/cam4.2776
                6997056
                31860169
                797e7e40-4359-456d-a9f8-3cafe30079fb
                © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 September 2019
                : 18 November 2019
                : 28 November 2019
                Page count
                Figures: 7, Tables: 1, Pages: 13, Words: 6166
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81772500
                Categories
                Original Research
                Cancer Biology
                Original Research
                Custom metadata
                2.0
                February 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:03.02.2020

                Oncology & Radiotherapy
                cyld,lncrna gmds‐as1,lung adenocarcinoma,mir‐96‐5p
                Oncology & Radiotherapy
                cyld, lncrna gmds‐as1, lung adenocarcinoma, mir‐96‐5p

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