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      miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC

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          Abstract

          Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.

          Abstract

          TUSC3 resides on chromosome 8p which is frequently deleted in advanced stage tumors. Here, the authors show that TUSC3 loss mediated by miR-224/-520c promotes NSCLC metastasis where it enhances ATF-6α-dependent UPR and HRD-1 dependent ERAD, which in turn suppress p53-NM23H1/2 tumor suppressor pathway.

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          Most cited references43

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          Tumor metastasis: molecular insights and evolving paradigms.

          Metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by the acquisition of genetic and/or epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. Recent advances provide provocative insights into these cell-biological and molecular changes, which have implications regarding the steps of the invasion-metastasis cascade that appear amenable to therapeutic targeting. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors.

            When unfolded proteins accumulate in the endoplasmic reticulum (ER), transcription of glucose-regulated proteins (GRPs) representing ER-resident molecular chaperones is markedly induced via the unfolded protein response (UPR) pathway. In contrast to recent progress in the analysis of yeast UPR, both cis-acting elements and transactivators responsible for mammalian UPR have remained obscure. Here, we analyzed the promoter regions of human GRP78, GRP94, and calreticulin genes and identified a novel element designated the ER stress response element (ERSE). ERSE, with a consensus of CCAATN9CCACG, was shown to be necessary and sufficient for induction of these GRPs. Using yeast one-hybrid screening, we isolated a human cDNA encoding a basic leucine zipper (bZIP) protein, ATF6, as a putative ERSE-binding protein. When overexpressed in HeLa cells, ATF6 enhanced transcription of GRP genes in an ERSE-dependent manner, whereas CREB-RP, another bZIP protein closely related to ATF6, specifically inhibited GRP induction. Endogenous ATF6 constitutively expressed as a 90-kDa protein was converted to a 50-kDa protein in ER-stressed cells, which appeared to be important for the cellular response to ER stress. These results suggest that, as in yeast, bZIP proteins are involved in mammalian UPR, acting through newly defined ERSE.
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              Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders.

              GRP78/BiP is a major endoplasmic reticulum (ER) chaperone protein critical for protein quality control of the ER, as well as controlling the activation of the ER-transmembrane signaling molecules. Through creation of mouse models targeting the Grp78 allele, the function of GRP78 in development and disease has been investigated. These led to the discovery that GRP78 function is obligatory for early embryonic development. However, in adult animals, GRP78 is preferably required for cancer cell survival under pathologic conditions such as tumor progression and drug resistance. The discovery of surface localization of GRP78 in cancer cells reveals potential novel function, interaction with cell-surface receptors, and possible therapeutic implications. Mouse models also reveal that GRP78 controls maturation and secretion of neuronal factors for proper neural migration and offers neuroprotection.
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                Author and article information

                Contributors
                ri.cui@osumc.edu
                carlo.croce@osumc.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                30 November 2018
                30 November 2018
                2018
                : 9
                : 5110
                Affiliations
                [1 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, Comprehensive Cancer Center, , The Ohio State University, ; Columbus, OH 43210 USA
                [2 ]ISNI 0000000419368956, GRID grid.168010.e, Stanford Cancer Institute, , Stanford University School of Medicine, ; Stanford, CA 94305 USA
                [3 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Biology, , Stanford University, ; Stanford, CA 94305 USA
                [4 ]ISNI 0000 0004 1936 9924, GRID grid.89336.37, Institute for Cellular and Molecular Biology, Center for Systems and Synthetic Biology, , The University of Texas at Austin, ; Austin, TX 78712 USA
                [5 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Pathology, , Stanford University, ; Stanford, CA 94305 USA
                [6 ]ISNI 0000 0000 9628 9654, GRID grid.411815.8, Department of Biosciences, , Mokpo National University, ; Muan, 58554 South Korea
                [7 ]ISNI 0000000419368710, GRID grid.47100.32, Departments of Immunobiology, , Yale University School of Medicine, ; New Haven, CT 06520 USA
                [8 ]ISNI 0000 0001 0356 9399, GRID grid.14005.30, Department of Animal Science, College of Agriculture and Life Sciences, , Chonnam National University, ; Gwangju, 61186 Korea
                [9 ]ISNI 0000 0000 9149 5707, GRID grid.410885.0, Gwangju Center, , Korea Basic Science Institute, ; Gwangju, 61186 Korea
                [10 ]Department of Life System, Sookmyung Woman’s University, Seoul, 140-742 Republic of Korea
                [11 ]ISNI 0000 0001 0807 1581, GRID grid.13291.38, Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, , Sichuan University, and Collaborative Innovation Center for Biotherapy, ; 610041 Chengdu, China
                [12 ]ISNI 0000000121662407, GRID grid.5379.8, Transcriptional Networks in Lung Cancer Group, Cancer Research United Kingdom Manchester Institute, , University of Manchester, ; Manchester, M20 4BX United Kingdom
                [13 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, Department of Cancer Biology and Genetics, , The Ohio State University, ; Columbus, OH 43210 USA
                [14 ]ISNI 0000 0001 0348 3990, GRID grid.268099.c, School of Pharmaceutical Sciences, , Wenzhou Medical University, Wenzhou, ; 325035 Zhejiang, China
                [15 ]ISNI 0000000106344187, GRID grid.265892.2, Department of Neurosurgery UAB Comprehensive Cancer Center, , University of Alabama at Birmingham, ; Birmingham, AL 35294 USA
                [16 ]ISNI 0000000419368710, GRID grid.47100.32, Departments of Immunobiology, Howard Hughes Medical Institute, , Yale University School of Medicine, ; New Haven, CT 06520 USA
                [17 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Medical Oncology, , The Ohio State University, ; Columbus, OH 43210 USA
                Author information
                http://orcid.org/0000-0002-7202-009X
                http://orcid.org/0000-0002-7642-4016
                http://orcid.org/0000-0001-8574-4938
                Article
                7561
                10.1038/s41467-018-07561-8
                6269493
                30504895
                bb93c610-e3c2-4b5c-baeb-ce341d9a7063
                © The Author(s) 2018

                Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 17 May 2018
                : 9 November 2018
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