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      Long noncoding RNA MALAT1 inhibits the apoptosis and autophagy of hepatocellular carcinoma cell by targeting the microRNA-146a/PI3K/Akt/mTOR axis

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          Abstract

          Background

          Increased long noncoding RNA (lncRNA) expression is characteristic to hepatocellular carcinoma (HCC) and several other neoplasms. The present study aimed to identify the mechanism underlying modulation of HCC development by the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1).

          Methods

          Quantitative real-time polymerase chain reaction was used to determine MALAT1 and microRNA (miR)-146a expression in HCC tissues and cell lines. Western blotting was performed to measure PI3K, Akt, and mTOR levels. Dual-luciferase reporter assay was used to validate the direct targeting and negative regulatory interaction between miR-146a and MALAT1. Cell viability, proliferation, and apoptosis were analyzed using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, colony formation assay, and flow cytometry, respectively; autophagy was detected based on LC3B expression.

          Results

          MALAT1 expression was higher in HCC tissues than in normal tissues. MALAT1 upregulation promoted HCC cell proliferation, whereas MALAT1 downregulation promoted HCC apoptosis and autophagy. Moreover, effects of MALAT1 downregulation on HCC cells were abolished by miR-146a inhibition. miR-146a directly targeted the 3′-untranslated region of PI3K, and PI3K protein level was clearly decreased upon miR-146a mimic transfection.

          Conclusions

          MALAT1 may modulate HCC cell proliferation, apoptosis, and autophagy via sponging miR-146a, which regulates HCC progression.

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          Most cited references33

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          Management of hepatocellular carcinoma.

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            Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.

            Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.
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              Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth.

              Hepatocellular carcinoma (HCC) is characterized by a propensity for multifocality, growth by local spread, and dysregulation of multiple signaling pathways. These features may be determined by the tumoral microenvironment. The potential of tumor cells to modulate HCC growth and behavior by secreted proteins has been extensively studied. In contrast, the potential for genetic modulation is poorly understood. We investigated the role and involvement of tumor-derived nanovesicles capable of altering gene expression and characterized their ability to modulate cell signaling and biological effects in other cells. We show that HCC cells can produce nanovesicles and exosomes that differ in both RNA and protein content from their cells of origin. These can be taken up and internalized by other cells and can transmit a functional transgene. The microRNA (miRNA) content of these exosomes was examined, and a subset highly enriched within exosomes was identified. A combinatorial approach to identify potential targets identified transforming growth factor β activated kinase-1 (TAK1) as the most likely candidate pathway that could be modulated by these miRNAs. Loss of TAK1 has been implicated in hepatocarcinogenesis and is a biologically plausible target for intercellular modulation. We show that HCC cell-derived exosomes can modulate TAK1 expression and associated signaling and enhance transformed cell growth in recipient cells. Exosome-mediated miRNA transfer is an important mechanism of intercellular communication in HCC cells. These observations identify a unique intercellular mechanism that could potentially contribute to local spread, intrahepatic metastases, or multifocal growth in HCC. Copyright © 2011 American Association for the Study of Liver Diseases.
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                Author and article information

                Contributors
                vziwaw@163.com
                abxhlh@163.com
                pmgvhy@163.com
                khoiyp@163.com
                fjbnyp@163.com
                kvfatt@163.com
                hk9ml1k4@163.com
                Journal
                Cancer Cell Int
                Cancer Cell Int
                Cancer Cell International
                BioMed Central (London )
                1475-2867
                13 May 2020
                13 May 2020
                2020
                : 20
                : 165
                Affiliations
                [1 ]GRID grid.256607.0, ISNI 0000 0004 1798 2653, Department of Hepatobiliary Surgery, , Guangxi Medical University Cancer Hospital, ; No. 71, Hedi Road, Qingxiu District, Nanning, 530021 Guangxi China
                [2 ]GRID grid.256607.0, ISNI 0000 0004 1798 2653, Department of Clinical Nutrition, , Guangxi Medical University Cancer Hospital, ; Nanning, 530021 Guangxi China
                Author information
                http://orcid.org/0000-0001-8683-4978
                Article
                1231
                10.1186/s12935-020-01231-w
                7222315
                32435156
                8fe800a3-80a0-4f48-a1dd-8978474d205f
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 17 January 2020
                : 23 April 2020
                Funding
                Funded by: the National Natural Science Foundation of China
                Award ID: 81560460/H1602
                Funded by: the Self-Raised Scientific Research Fund of the Ministry of Health in Guangxi Province
                Award ID: Z2016479
                Categories
                Primary Research
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                hcc,lncrna,mir,pi3k,apoptosis,autophagy
                Oncology & Radiotherapy
                hcc, lncrna, mir, pi3k, apoptosis, autophagy

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