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      LINC00844 promotes proliferation and migration of hepatocellular carcinoma by regulating NDRG1 expression

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          Abstract

          Background

          Aberrant expression of long noncoding RNAs are implicated in the pathogenesis of human malignancies. LINC00844 expression is dramatically downregulated in prostate cancer, and functional studies have revealed the association between the aberrant expression of LINC00844 and prostate cancer cell invasion and metastasis. However, the function and mechanism of action of LINC00844 in the pathogenesis of hepatocellular carcinoma (HCC) are poorly understood.

          Methods

          LINC00844 and N-Myc downstream-regulated 1 (NDRG1) expression in HCC tissues and cell lines was detected with real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Correlations between LINC00844 expression level and clinicopathological features were investigated using the original data from The Cancer Genome Atlas (TCGA) database. HepG2 and HCCLM9 cell lines were transfected with Lv-LIN00844 virus to obtain LINC00844-overexpressing cell lines. Cell proliferation and cell invasion and migration were examined with the cell counting kit-8 (CCK-8) and transwell assay, respectively. Furthermore, the correlation between LINC00844 and NDRG1 expression was analysed using Pearson’s correlation analysis.

          Results

          LINC00844 expression was significantly downregulatedin HCC tissues and cell lines, and a statistical correlation was detected between low LINC00844 expression and sex (Female), advanced American Joint Committee on Cancer (AJCC) stage (III + IV), histological grade (G3 + G4), and vascular invasion (Micro and Macro). In vitro experiments showed that LINC00844 overexpression significantly repressed the proliferation, migration, and invasion of HCC cells. NDRG1 expression was higher in HCC tissues and LINC00844 could partly inhibit the expression of NDRG1.

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          Most cited references21

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          Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.

          By analyzing 1,780,295 5'-end sequences of human full-length cDNAs derived from 164 kinds of oligo-cap cDNA libraries, we identified 269,774 independent positions of transcriptional start sites (TSSs) for 14,628 human RefSeq genes. These TSSs were clustered into 30,964 clusters that were separated from each other by more than 500 bp and thus are very likely to constitute mutually distinct alternative promoters. To our surprise, at least 7674 (52%) human RefSeq genes were subject to regulation by putative alternative promoters (PAPs). On average, there were 3.1 PAPs per gene, with the composition of one CpG-island-containing promoter per 2.6 CpG-less promoters. In 17% of the PAP-containing loci, tissue-specific use of the PAPs was observed. The richest tissue sources of the tissue-specific PAPs were testis and brain. It was also intriguing that the PAP-containing promoters were enriched in the genes encoding signal transduction-related proteins and were rarer in the genes encoding extracellular proteins, possibly reflecting the varied functional requirement for and the restricted expression of those categories of genes, respectively. The patterns of the first exons were highly diverse as well. On average, there were 7.7 different splicing types of first exons per locus partly produced by the PAPs, suggesting that a wide variety of transcripts can be achieved by this mechanism. Our findings suggest that use of alternate promoters and consequent alternative use of first exons should play a pivotal role in generating the complexity required for the highly elaborated molecular systems in humans.
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            High-resolution Xist binding maps reveal 2-step spreading during X-inactivation

            The Xist long noncoding RNA (lncRNA) is essential for X-chromosome inactivation (XCI), the process by which mammals compensate for unequal numbers of sex chromosomes 1-3 . During XCI, Xist coats the future inactive X (Xi) 4 and recruits Polycomb Repressive Complex 2 (PRC2) to the X-inactivation center (Xic) 5 . How Xist spreads silencing on a 150 Mb scale is unclear. Here we generate high-resolution maps of Xist binding on the X chromosome across a developmental time course using CHART-seq. In female cells undergoing XCI de novo, Xist follows a two-step mechanism, initially targeting gene-rich islands before spreading to intervening gene-poor domains. Xist is depleted from genes that escape XCI but may concentrate near escapee boundaries. Xist binding is linearly proportional to PRC2 density and H3 lysine 27 trimethylation (H3K27me3), suggesting co-migration of Xist and PRC2. Interestingly, when the Xi is acutely stripped off Xist in post-XCI cells, Xist recovers quickly within both gene-rich and -poor domains on a time-scale of hours instead of days, suggesting a previously primed Xi chromatin state. We conclude that Xist spreading takes distinct stage-specific forms: During initial establishment, Xist follows a two-step mechanism, but during maintenance, Xist spreads rapidly to both gene-rich and -poor regions.
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              Long noncoding RNAs in cancer cells.

              Long noncoding RNA (lncRNA) has recently been investigated as key modulators that regulate many biological processes in human cancers via diverse mechanisms. LncRNAs can interact with macromolecules such as DNA, RNA, or protein to exert cellular effects and to act as either tumor promoters or tumor suppressors in various malignancies. Moreover, the aberrant expression of lncRNAs may be detected in multiple cancer phenotypes by employing the rapidly developing modern gene chip technology and bioinformatics analysis. Herein, we highlight the mechanisms of action of lncRNAs, their functional cellular roles and their involvement in cancer progression. Finally, we provide an overview of recent progress in the lncRNA field and future potential for lncRNAs as cancer diagnostic markers and therapeutics.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                peerj
                peerj
                PeerJ
                PeerJ Inc. (San Diego, USA )
                2167-8359
                28 January 2020
                2020
                : 8
                : e8394
                Affiliations
                [1 ]Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation , Wuhan, China
                [2 ]The 3rd Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology , Changsha, China
                Article
                8394
                10.7717/peerj.8394
                6993750
                32025371
                03d6799b-ffa4-432a-a2d3-eedb2d5f40fe
                ©2020 Zhou et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 13 September 2019
                : 13 December 2019
                Funding
                Funded by: Open Research Fund Program of the State Key Laboratory of Virology of China
                Award ID: 2018KF005
                Funded by: National Natural Science Foundation of China-Xinjiang joint fund
                Award ID: U1403222
                Funded by: Health Commission of Hubei Province scientific research project
                Award ID: 2019H074
                This project was supported by the Open Research Fund Program of the State Key Laboratory of Virology of China (Grant number: 2018KF005), the National Natural Science Foundation of China-Xinjiang joint fund (Grant number: U1403222) and the Health Commission of Hubei Province scientific research project (Grant number: 2019H074). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Bioinformatics
                Genetics
                Genomics
                Nephrology
                Oncology

                hepatocellular carcinoma,linc00844,ndrg1,proliferation,migration,invasion

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