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      NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells

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          Abstract

          Background

          This study was performed to investigate the role of nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) in regulating hepatocellular carcinoma (HCC) progression.

          Methods

          Expression levels of NLRX1 in clinical specimens and cell lines were determined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB). Transwell assays were conducted to evaluate the effect of NLRX1 on cell invasion, and flow cytometry was used to assess apoptosis. Expression patterns of key molecules in the phosphoinositide 3-kinase (PI3K)-AKT pathways were determined via WB. The effect of NLRX1 on cell senescence was evaluated with β-galactosidase assays. Kaplan-Meier analyses and Cox regression models were used for prognostic evaluation.

          Results

          NLRX1 was downregulated in tumor tissue compared with adjacent normal liver tissue. Low tumor NLRX1 expression was identified as an independent indicator for HCC prognosis (recurrence: hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26–2.76, overall survival [OS] 2.26, 95% CI 1.44–3.56). NLRX1 over-expression (OE) significantly inhibited invasiveness ability and induced apoptosis in HCC cells. In vivo experiments showed that NLRX1 knock-down (KD) significantly promoted HCC growth. Mechanistically, NLRX1 exhibited a suppressor function by decreasing phosphorylation of AKT and thus downregulating Snail1 expression, which inhibited epithelial-mesenchymal-transition (EMT) in HCC cells. Moreover, NLRX1 OE could induce cell senescence via an AKT-P21-dependent manner.

          Conclusions

          NLRX1 acted as a tumor suppressor in HCC by inducing apoptosis, promoting senescence, and decreasing invasiveness by repressing PI3K-AKT signaling pathway. Future investigations will focus on restoring expression of NLRX1 to provide new insights into HCC treatment.

          Electronic supplementary material

          The online version of this article (10.1186/s13045-018-0573-9) contains supplementary material, which is available to authorized users.

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          Most cited references25

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          Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

          (2017)
          Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1 , EEF1A1 , SF3B1 , and SMARCA4 . Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming ( ALB , APOB , and CPS1 ) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1. Multiplex molecular profiling of human hepatocellular carcinoma patients provides insight into subtype characteristics and points toward key pathways to target therapeutically.
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            NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-κB signaling pathways.

            The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well defined. We showed that Nlrx1(-/-) mice exhibited increased expression of antiviral signaling molecules IFN-β, STAT2, OAS1, and IL-6 after influenza virus infection. Consistent with increased inflammation, Nlrx1(-/-) mice exhibited marked morbidity and histopathology. Infection of these mice with an influenza strain that carries a mutated NS-1 protein, which normally prevents IFN induction by interaction with RNA and the intracellular RNA sensor RIG-I, further exacerbated IL-6 and type I IFN signaling. NLRX1 also weakened cytokine responses to the 2009 H1N1 pandemic influenza virus in human cells. Mechanistically, Nlrx1 deletion led to constitutive interaction of MAVS and RIG-I. Additionally, an inhibitory function is identified for NLRX1 during LPS activation of macrophages where the MAVS-RIG-I pathway was not involved. NLRX1 interacts with TRAF6 and inhibits NF-κB activation. Thus, NLRX1 functions as a checkpoint of overzealous inflammation. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Therapies for advanced stage hepatocellular carcinoma with macrovascular invasion or metastatic disease: A systematic review and meta-analysis

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                Author and article information

                Contributors
                bohu1120@hotmail.com
                ding.guangyu@zs-hospital.sh.cn
                fpy_luck@foxmail.com
                zhuxiaodong@gmail.com
                ji.yuan@zs-hospital.sh.cn
                shi.guoming@zs-hospital.sh.cn
                shen.yinghao@zs-hospital.sh.cn
                cai.jiabin@zs-hospital.sh.cn
                yangzhen@picb.ac.cn
                zhou.jian@zs-hospital.sh.cn
                fan.jia@zs-hospital.sh.cn
                sun.huichuan@zs-hospital.sh.cn
                0086-20-8733-2200 , kuangm@mail.sysu.edu.cn
                0086-21-6403-7181 , huang.cheng@zs-hospital.sh.cn
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                26 February 2018
                26 February 2018
                2018
                : 11
                : 28
                Affiliations
                [1 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, , Fudan University, ; 136 Yi Xue Yuan Rd, Shanghai, 200032 China
                [2 ]ISNI 0000 0004 0369 313X, GRID grid.419897.a, Key Laboratory for Carcinogenesis and Cancer Invasion, , Chinese Ministry of Education, ; Shanghai, China
                [3 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Department of Pathology, Zhongshan Hospital, , Fudan University, ; Shanghai, China
                [4 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Department of Liver Surgery, The First Affiliated Hospital, , Sun Yat-sen University, ; 58 Zhong Shan Rd 2, Guangzhou, 510080 China
                [5 ]ISNI 0000 0004 0626 5181, GRID grid.464656.3, Key Laboratory of Computational Biology, , CAS-MPG Partner Institute for Computational Biology, ; 320 Yue Yang Road, Shanghai, 200031 China
                Article
                573
                10.1186/s13045-018-0573-9
                5828065
                29482578
                912ba45d-6699-4858-b3aa-385b1e578c1e
                © The Author(s). 2018

                Open AccessThis 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.

                History
                : 27 December 2017
                : 11 February 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81572298
                Award ID: 81502006
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                hepatocellular carcinoma,nlrx1,epithelial-mesenchymal-transition,tumor suppressor,senescence,transition

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