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      Targeting the Epigenetic Non-Coding RNA MALAT1/Wnt Signaling Axis as a Therapeutic Approach to Suppress Stemness and Metastasis in Hepatocellular Carcinoma

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          Abstract

          Background: With recorded under-performance of current standard therapeutic strategies as highlighted by high rates of post-treatment (resection or local ablation) recurrence, resistance to chemotherapy, poor overall survival, and an increasing global incidence, hepatocellular carcinoma (HCC) constitutes a medical challenge. Accumulating evidence implicates the presence of HCC stem cells (HCC-SCs) in HCC development, drug-resistance, recurrence, and progression. Therefore, treatment strategies targeting both HCC-SCs and non-CSCs are essential. Methods: Recently, there has been an increasing suggestion of MALAT1 oncogenic activity in HCC; however, its role in HCC stemness remains unexplored. Herein, we investigated the probable role of MALAT1 in the SCs-like phenotype of HCC and explored likely molecular mechanisms by which MALAT1 modulates HCC-SCs-like and metastatic phenotypes. Results: We showed that relative to normal, cirrhotic, or dysplastic liver conditions, MALAT1 was aberrantly expressed in HCC, similar to its overexpression in Huh7, Mahlavu, and SK-Hep1 HCC cells lines, compared to the normal liver cell line THLE-2. We also demonstrated a positive correlation between MALAT1 expression and poor cell differentiation status in HCC using RNAscope. Interestingly, we demonstrated that shRNA-mediated silencing of MALAT1 concomitantly downregulated the expression levels of β-catenin, Stat3, c-Myc, CK19, vimentin, and Twist1 proteins, inhibited HCC oncogenicity, and significantly suppressed the HCC-SCs-related dye-effluxing potential of HCC cells and reduced their ALDH-1 activity, partially due to inhibited MALAT1-β-catenin interaction. Additionally, using TOP/FOP (TCL/LEF-Firefly luciferase) Flash, RT-PCR, and western blot assays, we showed that silencing MALAT1 downregulates β-catenin expression, dysregulates the canonical Wnt signaling pathway, and consequently attenuates HCC tumorsphere formation efficiency, with concurrent reduction in CD133+ and CD90+ HCC cell population, and inhibits tumor growth in SK-Hep1-bearing mice. Conclusions: Taken together, our data indicate that MALAT1/Wnt is a targetable molecular candidate, and the therapeutic targeting of MALAT1/Wnt may constitute a novel promising anticancer strategy for HCC treatment.

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          Resveratrol Inhibits Invasion and Metastasis of Colorectal Cancer Cells via MALAT1 Mediated Wnt/β-Catenin Signal Pathway

          Resveratrol, extracted from Chinese herbal medicine Polygonum cuspidatum, is known to inhibit invasion and metastasis of human colorectal cancer (CRC), in which long non-coding Metastasis Associated Lung Adenocarcinoma Transcript 1 (RNA-MALAT1) also plays an important role. Using MALAT1 lentiviral shRNA and over-expression constructs in CRC derived cell lines, LoVo and HCT116, we demonstrated that the anti-tumor effects of resveratrol on CRC are through inhibiting Wnt/β-catenin signaling, thus the expression of its target genes such as c-Myc, MMP-7, as well as the expression of MALAT1. In detail, resveratrol down-regulates MALAT1, resulting in decreased nuclear localization of β-catenin thus attenuated Wnt/β-catenin signaling, which leads to the inhibition of CRC invasion and metastasis. This finding of ours surely provides important pre-clinical evidence supporting future use of resveratrol in prevention and treatment of CRC.
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            Mortality assessment of patients with hepatocellular carcinoma according to underlying disease and treatment modalities

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              Rapid evolutionary turnover underlies conserved lncRNA–genome interactions

              In this study, Quinn et. al. used an integrative strategy based on matching focal and repeated RNA secondary structures and other RNA features that uncovers novel lncRNA orthologs despite limited sequence similarity. This method was applied to Drosophilia roX1 and roX2 RNAs, and 47 new roX RNAs across ∼40 million years of evolution were discovered.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                20 April 2020
                April 2020
                : 9
                : 4
                : 1020
                Affiliations
                [1 ]Department of General Surgery, En Chu Kong Hospital, New Taipei City 237, Taiwan; changhl0321@ 123456gmail.com
                [2 ]Department of Health Care Management, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
                [3 ]Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan; dr_bamodu@ 123456yahoo.com (O.A.B.); ctyeh@ 123456s.tmu.edu.tw (C.-T.Y.)
                [4 ]Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan
                [5 ]Department of Emergency Medicine, School of Medicine, Taipei Medical University, Taipei 110, Taiwan; 12642@ 123456s.tmu.edu.tw
                [6 ]Department of Emergency Medicine, Shuang-Ho Hospital-Taipei Medical University, New Taipei City 235, Taiwan
                [7 ]Department of Pathology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan; whlpath97616@ 123456s.tmu.edu.tw
                [8 ]Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
                [9 ]Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
                [10 ]Department of Radiation Oncology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan
                [11 ]Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan
                Author notes
                [* ]Correspondence: 10576@ 123456s.tmu.edu.tw or kitty10576@ 123456gmail.com ; Tel.: +886-(2)-2490088 (ext. 8885); Fax: +886-2-2248-0900
                [†]

                Contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-8229-0408
                https://orcid.org/0000-0003-0932-3191
                https://orcid.org/0000-0001-5189-9755
                Article
                cells-09-01020
                10.3390/cells9041020
                7226390
                32326045
                b4ac8df4-c315-4b1f-9810-74d5638d32fc
                © 2020 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
                : 25 January 2020
                : 15 April 2020
                Categories
                Article

                lncrna malat1,hcc-scs,tumorspheres,drug resistance,cancer recurrence

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