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      Pan-cancer analysis of long non-coding RNA NEAT1 in various cancers

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          Abstract

          Changes in the abundance and activity of long non-coding RNAs (lncRNAs) have an important impact on the development of cancer. The nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be overexpressed in many types of cancer since its discovery. However, inconsistencies exist as NEAT1 can also function as a tumor suppressor in certain types of cancer, such as acute promyelocytic leukemia. Here we systematically describe our current understanding of NEAT1 in tumor initiation and progression. First, we analyzed the expression patterns of NEAT1 in various normal tissues and malignant cancers using data from public data portals, the Genotype-Tissue Expression Project (GTEx) and the Cancer Genome Atlas (TCGA), together with recent progress in the study of NEAT1 in various types of cancer. Second, we discussed the functions and mechanisms of NEAT1 in modulating tumor activity. Then, the upstream transcription factors and downstream microRNA targets of NEAT1 in the transcription cascade of cancers were also summarized. These data highlight the emerging role of NEAT1 in tumorigenesis, and present promising targetable pathways and clinical opportunities for tumor prevention and classifications.

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          Recurrent and functional regulatory mutations in breast cancer

          High-depth sequencing of targeted regions in primary breast cancer identifies mutated promoter elements with recurrent mutations at specific and/or nearby bases, suggesting selection of certain non-coding events.
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            NEAT1: A novel cancer-related long non-coding RNA.

            Aberrant overexpression of the long non-coding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) has been documented in different types of solid tumours, such as lung cancer, oesophageal cancer, colorectal cancer and hepatocellular carcinoma, in which its high levels are associated with poor prognosis. In contrast, NEAT1 is downregulated in acute promyelocytic leukaemia where it promotes leucocyte differentiation. In this review, we provide an overview of current evidence concerning the oncogenic role and potential clinical utilities of NEAT1. Further investigations are warranted to elucidate the upstream and downstream mechanisms of NEAT1 overexpression.
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              Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression

              Background Oct4, a key stemness transcription factor, is overexpressed in lung cancer. Here, we reveal a novel transcription regulation of long non-coding RNAs (lncRNAs) by Oct4. LncRNAs have emerged as important players in cancer progression. Methods Oct4 chromatin-immunoprecipitation (ChIP)-sequencing and several lncRNA databases with literature annotation were integrated to identify Oct4-regulated lncRNAs. Luciferase activity, qRT-PCR and ChIP-PCR assays were conducted to examine transcription regulation of lncRNAs by Oct4. Reconstitution experiments of Oct4 and downstream lncRNAs in cell proliferation, migration and invasion assays were performed to confirm the Oct4-lncRNAs signaling axes in promoting lung cancer cell growth and motility. The expression correlations between Oct4 and lncRNAs were investigated in 124 lung cancer patients using qRT-PCR analysis. The clinical significance of Oct4/lncRNAs signaling axes were further evaluated using multivariate Cox regression and Kaplan-Meier analyses. Results We confirmed that seven lncRNAs were upregulated by direct binding of Oct4. Among them, nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and urothelial carcinoma-associated 1 (UCA1) were validated as Oct4 transcriptional targets through promoter or enhancer activation. We showed that lung cancer cells overexpressing NEAT1 or MALAT1 and the Oct4-silenced cells reconstituted with NEAT1 or MALAT1 promoted cell proliferation, migration and invasion. In addition, knockdown of NEAT1 or MALAT1 abolished Oct4-mediated lung cancer cell growth and motility. These cell-based results suggested that Oct4/NEAT1 or Oct4/MALAT1 axis promoted oncogenesis. Clinically, Oct4/NEAT1/MALAT1 co-overexpression was an independent factor for prediction of poor outcome in 124 lung cancer patients. Conclusions Our study reveals a novel mechanism by which Oct4 transcriptionally activates NEAT1 via promoter and MALAT1 via enhancer binding to promote cell proliferation and motility, and led to lung tumorigenesis and poor prognosis. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0674-z) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                21 November 2017
                March 2018
                21 November 2017
                : 5
                : 1
                : 27-35
                Affiliations
                [a ]State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
                [b ]McMaster University, Hamilton, Ontario, Canada
                Author notes
                []Corresponding author. State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, 197 Ruijin Er Rd, Shanghai 200025, China. Fax: +86 21 64743206. kankanwang@ 123456shsmu.edu.cn
                Article
                S2352-3042(17)30084-3
                10.1016/j.gendis.2017.11.003
                6146416
                30258932
                421bc450-5d44-438b-ad4a-1ee648d14db5
                © 2017 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 13 October 2017
                : 10 November 2017
                Categories
                Article

                cancer,long non-coding rna,neat1,pan-cancer analysis,regulation

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