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      E2-Induced Activation of the NLRP3 Inflammasome Triggers Pyroptosis and Inhibits Autophagy in HCC Cells

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          Abstract

          Emerging evidence suggests that 17β-estradiol (E2) and estrogen receptor (ER) signaling are protective against hepatocellular carcinoma (HCC). In our previous study, we showed that E2 suppressed the carcinogenesis and progression of HCC by targeting NLRP3 inflammasome activation, whereas the molecular mechanism by which the NLRP3 inflammasome initiated cancer cell death was not elucidated. The present study aimed to investigate the effect of NLRP3 inflammasome activation on cell death pathways and autophagy of HCC cells. First, we observed an increasing mortality in E2-treated HCC cells, and then apoptotic and pyroptotic cell death were both detected. The mortality of HCC cells was largely reversed by the caspase 1 antagonist, YVAD-cmk, suggesting that E2-induced cell death was associated with caspase 1-dependent pyroptosis. Second, the key role of the NLRP3 inflammasome in autophagy of HCC cells was assessed by E2-induced activation of the NLRP3 inflammasome, and we demonstrated that autophagy was inhibited by the NLRP3 inflammasome via the E2/ERβ/AMPK/mTOR pathway. Last, the interaction of pyroptosis and autophagy was confirmed by flow cytometry methods. We observed that E2-induced pyroptosis was dramatically increased by 3-methyladenine (3-MA) treatment, which was abolished by YVAD-cmk treatment, suggesting that caspase 1-dependent pyroptosis was negatively regulated by autophagy. In conclusion, E2-induced activation of the NLRP3 inflammasome may serve as a suppressor in HCC progression, as it triggers pyroptotic cell death and inhibits protective autophagy.

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          Most cited references28

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          Pro-inflammatory programmed cell death.

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            Epidemiology of viral hepatitis and hepatocellular carcinoma.

            Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Regulation of inflammasome activation.

              Inflammasome biology is one of the most exciting and rapidly growing areas in immunology. Over the past 10 years, inflammasomes have been recognized for their roles in the host defense against invading pathogens and in the development of cancer, auto-inflammatory, metabolic, and neurodegenerative diseases. Assembly of an inflammasome complex requires cytosolic sensing of pathogen-associated molecular patterns or danger-associated molecular patterns by a nucleotide-binding domain and leucine-rich repeat receptor (NLR) or absent in melanoma 2 (AIM2)-like receptors (ALR). NLRs and ALRs engage caspase-1, in most cases requiring the adapter protein apoptosis-associated speck-like protein containing a CARD (ASC), to catalyze proteolytic cleavage of pro-interleukin-1β (pro-IL-1β) and pro-IL-18 and drive pyroptosis. Recent studies indicate that caspase-8, caspase-11, IL-1R-associated kinases (IRAK), and receptor-interacting protein (RIP) kinases contribute to inflammasome functions. In addition, post-translational modifications, including ubiquitination, deubiquitination, phosphorylation, and degradation control almost every aspect of inflammasome activities. Genetic studies indicate that mutations in NLRP1, NLRP3, NLRC4, and AIM2 are linked with the development of auto-inflammatory diseases, enterocolitis, and cancer. Overall, these findings transform our understanding of the basic biology and clinical relevance of inflammasomes. In this review, we provide an overview of the latest development of inflammasome research and discuss how inflammasome activities govern health and disease.
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                Author and article information

                Journal
                Oncol Res
                Oncol Res
                OR
                Oncology Research
                Cognizant Communication Corporation (Elmsford, NY )
                0965-0407
                1555-3906
                2019
                12 July 2019
                : 27
                : 7
                : 827-834
                Affiliations
                [1] Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University , Shanghai, P.R. China
                Author notes

                1These authors provided equal contribution to this work.

                Address correspondence to Min Li, Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 160 Pujian Road, Pudong New District, Shanghai 200127, P.R. China. Tel: +86 021 3450 6261; E-mail: ruth_limin@ 123456126.com
                Article
                OR1370
                10.3727/096504018X15462920753012
                7848400
                30940293
                7a7bfcc2-d3c5-432c-b2f0-66b168b0914e
                Copyright © 2019 Cognizant, LLC.

                This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.

                History
                Page count
                Figures: 5, Tables: 0, References: 28, Pages: 8
                Categories
                Article

                hepatocellular carcinoma (hcc),nlrp3 inflammasome,pyroptosis,autophagy

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