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      Ubiquitin-specific protease 3 promotes cell migration and invasion by interacting with and deubiquitinating SUZ12 in gastric cancer

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          Abstract

          Background

          The deubiquitinating enzyme ubiquitin-specific protease 3 (USP3) plays a crucial role in numerous biological processes. The aberrant expression of USP3 may have an important role in tumor development. However, the mechanism by which USP3 promotes gastric cancer (GC) metastasis remains largely unknown.

          Methods

          Effects of USP3 on the progression of GC in vivo and in vitro and the potential underlying mechanisms have been investigated utilizing proteomics, RT-PCR, western blotting, immunohistochemistry, immunofluorescence, cell invasion and migration assays and xenograft tumor models.

          Results

          USP3 expression was upregulated in GC compared with matched normal tissues and was predictive of poor survival. USP3 also promoted migration and epithelial-to-mesenchymal transition (EMT) in GC cells. Moreover, TGF-β1 induced USP3 expression, and USP3 knockdown inhibited TGF-β1-induced EMT. Furthermore, we utilized Isobaric Tag for Relative and Absolute Quantitation (iTRAQ) to identify differentially expressed proteins in USP3-overexpressing cells compared with control cells. Importantly, we found that SUZ12 is indispensable for USP3-mediated oncogenic activity in GC. We observed that USP3 interacted with and stabilized SUZ12 via deubiquitination. SUZ12 knockdown inhibited USP3-induced migration and invasion, as well as EMT in GC cells. Examination of clinical samples confirmed that USP3 expression was positively correlated with SUZ12 protein expression and that the levels of USP3 or SUZ12 protein were negatively correlated with the levels of E-cadherin protein.

          Conclusions

          These findings identify USP3 as a critical regulator. The USP3-SUZ12 axis might promote tumor progression and could be a potential therapeutic candidate for human GC.

          Electronic supplementary material

          The online version of this article (10.1186/s13046-019-1270-4) contains supplementary material, which is available to authorized users.

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          Most cited references36

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          Changing Trends in Stomach Cancer Throughout the World.

          The paper aims to discuss the global trends in gastric cancer incidence in relation to important factors involved in the pathogenesis of gastric cancer.
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            USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors.

            Lysine 63 (K63)-linked ubiquitination of RIG-I plays a critical role in the activation of type I interferon pathway, yet the molecular mechanism responsible for its deubiquitination is still poorly understood. Here we report that the deubiquitination enzyme ubiquitin-specific protease 3 (USP3) negatively regulates the activation of type I interferon signaling by targeting RIG-I. Knockdown of USP3 specifically enhanced K63-linked ubiquitination of RIG-I, upregulated the phosphorylation of IRF3 and augmented the production of type I interferon cytokines and antiviral immunity. We further show that there is no interaction between USP3 and RIG-I-like receptors (RLRs) in unstimulated or uninfected cells, but upon viral infection or ligand stimulation, USP3 binds to the caspase activation recruitment domain of RLRs and then cleaves polyubiquitin chains through cooperation of its zinc-finger Ub-binding domain and USP catalytic domains. Mutation analysis reveals that binding of USP3 to polyubiquitin chains on RIG-I is a prerequisite step for its cleavage of polyubiquitin chains. Our findings identify a previously unrecognized role of USP3 in RIG-I activation and provide insights into the mechanisms by which USP3 inhibits RIG-I signaling and antiviral immunity.
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              Activation of EZH2 and SUZ12 Regulated by E2F1 Predicts the Disease Progression and Aggressive Characteristics of Bladder Cancer.

              Previous study identified E2F1 as a key mediator of non-muscle-invasive bladder cancer (NMIBC) progression. The aim of this study was to identify the E2F1-related genes associated with poor prognosis and aggressive characteristics of bladder cancer.
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                Author and article information

                Contributors
                wuxiaosheng92@163.com
                1151005330@qq.com
                huiqueenzhu@163.com
                jingw2225@163.com
                dd_weiyu@163.com
                kikoli1994@163.com
                785747472@qq.com
                tangwm208@163.com
                yizhixiao77@163.com
                linjeana@126.com
                wenjing_zhang1@163.com
                465335749@qq.com
                13533787871@163.com
                593739165@qq.com
                gzliguoxin@163.com
                lam0725@163.com
                86-020-61645169 , shellyxiang@sina.com
                86-020-61645169 , liuside@163.com
                86-020-61645169 , jidewang55@163.com
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                24 June 2019
                24 June 2019
                2019
                : 38
                Affiliations
                [1 ]GRID grid.416466.7, Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, , Nanfang Hospital, Southern Medical University, ; Guangzhou, 510515 China
                [2 ]Department of Clinical Laboratory, General Hospital of Southern Theatre Command, Guangzhou, 510010 China
                [3 ]Department of Gastroenterology, Longgang District People’s Hospital, Shenzhen, 518172 China
                [4 ]GRID grid.414918.1, Department of Medical Oncology, , the First people’s Hospital of Yunnan Province, Medical School of Kunming University of Science and Technology, ; Kunming, 650032 China
                [5 ]ISNI 0000 0004 1758 4591, GRID grid.417009.b, Department of Gastroenterology, , The third affiliated Hospital of Guangzhou Medical University, ; Guangzhou, 510150 China
                [6 ]GRID grid.416466.7, Department of General Surgery, , Nanfang Hospital, Southern Medical University, ; Guangzhou, 510515 China
                [7 ]GRID grid.416466.7, Department of Digestive Medicine, , Nanfang Hospital, Southern Medical University, ; Guangzhou, 510515 Guangdong Province China
                Article
                1270
                10.1186/s13046-019-1270-4
                6591922
                31234902
                727029b7-0ff5-4904-bd8c-bb690a9982d4
                © The Author(s). 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 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.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81672875
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                usp3,suz12,gastric cancer,emt,itraq
                Oncology & Radiotherapy
                usp3, suz12, gastric cancer, emt, itraq

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