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      Integrative Analysis of Dysregulated lncRNA-Associated ceRNA Network Reveals Functional lncRNAs in Gastric Cancer

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          Abstract

          Mounting evidence suggests that long noncoding RNAs (lncRNAs) play important roles in the regulation of gene expression by acting as competing endogenous RNA (ceRNA). However, the regulatory mechanisms of lncRNA as ceRNA in gastric cancer (GC) are not fully understood. Here, we first constructed a dysregulated lncRNA-associated ceRNA network by integrating analysis of gene expression profiles of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs). Then, we determined three lncRNAs ( RP5-1120P11, DLEU2, and DDX11-AS1) as hub lncRNAs, in which associated ceRNA subnetworks were involved in cell cycle-related processes and cancer-related pathways. Furthermore, we confirmed that the two lncRNAs ( DLEU2 and DDX11-AS1) were significantly upregulated in GC tissues, promote GC cell proliferation, and negatively regulate miRNA expression, respectively. The hub lncRNAs ( DLEU2 and DDX11-AS1) could have oncogenic functions, and act as potential ceRNAs to sponge miRNA. Our findings not only provide novel insights on ceRNA regulation in GC, but can also provide opportunities for the functional characterization of lncRNAs in future studies.

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          Most cited references40

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          A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

          The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs possess a biological role in cancer cells that relies upon their ability to compete for microRNA binding and is independent of their protein-coding function. As a paradigm for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene (PTENP1) and the critical consequences of this interaction. We find that PTENP1 is biologically active as determined by its ability to regulate cellular levels of PTEN, and that it can exert a growth-suppressive role. We also show that PTENP1 locus is selectively lost in human cancer. We extend our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. Further, we demonstrate that the transcripts of protein coding genes such as PTEN are also biologically active. Together, these findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.
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            Cell cycle proteins as promising targets in cancer therapy

            Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells
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              miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database

              MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 nucleotides, which negatively regulate the gene expression at the post-transcriptional level. This study describes an update of the miRTarBase (http://miRTarBase.mbc.nctu.edu.tw/) that provides information about experimentally validated miRNA-target interactions (MTIs). The latest update of the miRTarBase expanded it to identify systematically Argonaute-miRNA-RNA interactions from 138 crosslinking and immunoprecipitation sequencing (CLIP-seq) data sets that were generated by 21 independent studies. The database contains 4966 articles, 7439 strongly validated MTIs (using reporter assays or western blots) and 348 007 MTIs from CLIP-seq. The number of MTIs in the miRTarBase has increased around 7-fold since the 2014 miRTarBase update. The miRNA and gene expression profiles from The Cancer Genome Atlas (TCGA) are integrated to provide an effective overview of this exponential growth in the miRNA experimental data. These improvements make the miRTarBase one of the more comprehensively annotated, experimentally validated miRNA-target interactions databases and motivate additional miRNA research efforts.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                18 June 2018
                June 2018
                : 9
                : 6
                : 303
                Affiliations
                [1 ]College of Computer Science and Technology, Jilin University, Changchun 130012, Jilin, China; liuhaiming0702@ 123456163.com (H.L.); zhangh@ 123456jlu.edu.cn (H.Z.)
                [2 ]Key Laboratory of Symbolic Computation and Knowledge Engineering, Ministry of Education, Jilin University, Changchun 130012, Jilin, China
                [3 ]State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, Shaanxi, China; zz141421@ 123456126.com (Z.Z.); 13119110590@ 123456136.com (N.W.); h.guo@ 123456foxmail.com (H.G.); fandaim@ 123456fmmu.edu.cn (D.F.)
                [4 ]College of Life Sciences, Northwest University, Xi’an 710032, Shaanxi, China
                Author notes
                [* ]Correspondence: liuyn@ 123456jlu.edu.cn (Y.L.); yongznie@ 123456fmmu.edu.cn (Y.N.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-6025-549X
                https://orcid.org/0000-0002-9289-9775
                https://orcid.org/0000-0002-2058-7123
                https://orcid.org/0000-0001-7926-7936
                Article
                genes-09-00303
                10.3390/genes9060303
                6027299
                29912172
                1e462cf7-ddca-4b78-87e6-4c9523db4008
                © 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
                : 03 May 2018
                : 12 June 2018
                Categories
                Article

                competing endogenous rna,long non-coding rna,gastric cancer,network analysis,dleu2,ddx11-as1

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