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      Long noncoding RNA MSC‐AS1 promotes hepatocellular carcinoma oncogenesis via inducing the expression of phosphoglycerate kinase 1

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          Abstract

          Background and Objectives

          Increasing studies report that lncRNAs are dysregulated in hepatocellular carcinoma (HCC), which might function as significant diagnostic biomarkers of HCC. LncRNA MSC‐AS1 has been newly discovered in several cancers. However, its biological effect in HCC remains to be clearly elucidated. The aim of our work was to test MSC‐AS1 expression level and assess its function in HCC progression.

          Methods

          Expression levels of MSC‐AS1 and PGK1 in HCC were tested by qRT‐PCR in HCC cells including HUH‐7, BEL‐7404, SNU449, HepG2, QGY‐7701, and human normal liver cells (HL‐7702 cells). Association of MSC‐AS1 expression with various clinicopathological features and patients’ survival were analyzed by chi‐squared test and Kaplan‐Meier, respectively. The functions of MSC‐AS1 in HCC cells were investigated using EdU assay, colony formation, flow cytometry, would healing assay, and Transwell matrigel invasion assays. The correlation between MSC‐AS1 and PGK1 was confirmed using a RIP assay. Protein expression of PGK1 was evaluated using a western blot assay.

          Results

          MSC‐AS1 was obviously upregulated in HCC tissues and HCC cells. Knockdown of MSC‐AS1 repressed HepG2 and BEL‐7404 cell proliferation, colony formation capacity, and triggered cell apoptosis. HepG2 and BEL‐7404 cell cycle was blocked in G1 phase and cell migration/invasion was remarkably depressed. Downregulation of MSC‐AS1 in HCC cells reduced PGK1 expression. In vivo data demonstrated that silence of MSC‐AS1 suppressed HCC development via activating PGK1.

          Conclusions

          Taken these together, we indicated that MSC‐AS1 promoted HCC oncogenesis via inducing the expression of PGK1.

          Abstract

          MSC‐AS1 manifested an oncogenic role in HCC. MSC‐AS1 could contribute to HCC progression through activating PGK1 in HCC.

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          Most cited references17

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          LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

          While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis 1 yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repertoire of genes central to the identity and behavior of prostate cancer cells 2 , and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy 3 . Here, we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 and PCGEM1, bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the C-terminally acetylated AR on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the DOT1L-mediated methylated AR N-terminus. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited Pygopus2 PHD domain proves to enhance selective looping of AR-bound enhancers to target gene promoters in these cells. In “resistant” prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally-expressed short hairpin RNA (shRNA) targeting of these lncRNAs in castration-resistant prostate cancer (CRPC) cell lines strongly suppressed tumor xenograft growth in vivo. Together, these results suggest that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumors.
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            The long noncoding RNA Malat1: Its physiological and pathophysiological functions.

            Recent studies suggest that in humans, DNA sequences responsible for protein coding regions comprise only 2% of the total genome. The rest of the transcripts result in RNA transcripts without protein-coding ability, including long noncoding RNAs (lncRNAs). Different from most members in the lncRNA family, the metastasis-associated lung adenocarcinoma transcript 1 (Malat1) is abundantly expressed and evolutionarily conserved throughout various mammalian species. Malat1 is one of the first identified lncRNAs associated with human disease, and cumulative studies have indicated that Malat1 plays critical roles in the development and progression of various cancers. Malat1 is also actively involved in various physiologic processes, including alternative splicing, epigenetic modification of gene expression, synapse formation, and myogenesis. Furthermore, extensive evidences show that Malat1 plays pivotal roles in multiple pathological conditions as well. In this review, we will summarize latest findings related to the physiologic and pathophysiological processes of Malat1 and discuss its therapeutic potentials.
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              Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis.

              It is unclear how the Warburg effect that exemplifies enhanced glycolysis in the cytosol is coordinated with suppressed mitochondrial pyruvate metabolism. We demonstrate here that hypoxia, EGFR activation, and expression of K-Ras G12V and B-Raf V600E induce mitochondrial translocation of phosphoglycerate kinase 1 (PGK1); this is mediated by ERK-dependent PGK1 S203 phosphorylation and subsequent PIN1-mediated cis-trans isomerization. Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex. This reduces mitochondrial pyruvate utilization, suppresses reactive oxygen species production, increases lactate production, and promotes brain tumorigenesis. Furthermore, PGK1 S203 and PDHK1 T338 phosphorylation levels correlate with PDH S293 inactivating phosphorylation levels and poor prognosis in glioblastoma patients. This work highlights that PGK1 acts as a protein kinase in coordinating glycolysis and the tricarboxylic acid (TCA) cycle, which is instrumental in cancer metabolism and tumorigenesis.
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                Author and article information

                Contributors
                weihua686@163.com
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                02 June 2020
                July 2020
                : 9
                : 14 ( doiID: 10.1002/cam4.v9.14 )
                : 5174-5184
                Affiliations
                [ 1 ] Department of General Practice The Affiliated Hospital of Youjiang Medical University for Nationalities Baise Guangxi Province China
                [ 2 ] Nursing Department The Affiliated Hospital of Youjiang Medical University for Nationalities Baise Guangxi Province China
                [ 3 ] Department of Ultrasonics The Affiliated Hospital of Youjiang Medical University for Nationalities Baise Guangxi Province China
                Author notes
                [*] [* ] Correspondence

                Hua Wei, Department of General Practice, The Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18, Zhongshan Second Road, Youjiang District, Baise, Guangxi Province, China.

                Email: weihua686@ 123456163.com .

                Lianxin Meng, Department of Ultrasonics, The Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18, Zhongshan Second Road, Youjiang District, Baise, 533000, Guangxi Province, China.

                Email: mlx89303@ 123456163.com .

                Author information
                https://orcid.org/0000-0002-4328-8863
                Article
                CAM43080
                10.1002/cam4.3080
                7367619
                32489020
                6826a7f6-4ad8-4033-bd1f-70615899f334
                © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 October 2019
                : 10 March 2020
                : 17 March 2020
                Page count
                Figures: 6, Tables: 1, Pages: 11, Words: 4390
                Funding
                Funded by: Young and middle-aged teachers' basic scientific research ability improvement project in Guangxi colleges and universities
                Award ID: 2020KY13020
                Funded by: Innovation Project of Guangxi Graduate Education
                Award ID: JGY2020166
                Categories
                Original Research
                Clinical Cancer Research
                Original Research
                Custom metadata
                2.0
                July 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:17.07.2020

                Oncology & Radiotherapy
                cell viability,hepatocellular carcinoma,invasion,msc‐as1,pgk1
                Oncology & Radiotherapy
                cell viability, hepatocellular carcinoma, invasion, msc‐as1, pgk1

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