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1
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Skullcapflavone II, a novel NQO1 inhibitor, alleviates aristolochic acid I-induced liver and kidney injury in mice. Acta Pharmacol Sin 2023:10.1038/s41401-023-01052-3. [PMID: 36697978 PMCID: PMC9876410 DOI: 10.1038/s41401-023-01052-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 01/08/2023] [Indexed: 01/26/2023]
Abstract
Aristolochic acid I (AAI) is a well established nephrotoxin and human carcinogen. Cytosolic NAD(P)H quinone oxidoreductase 1 (NQO1) plays an important role in the nitro reduction of aristolochic acids, leading to production of aristoloactam and AA-DNA adduct. Application of a potent NQO1 inhibitor dicoumarol is limited by its life-threatening side effect as an anticoagulant and the subsequent hemorrhagic complications. As traditional medicines containing AAI remain available in the market, novel NQO1 inhibitors are urgently needed to attenuate the toxicity of AAI exposure. In this study, we employed comprehensive 2D NQO1 biochromatography to screen candidate compounds that could bind with NQO1 protein. Four compounds, i.e., skullcapflavone II (SFII), oroxylin A, wogonin and tectochrysin were screened out from Scutellaria baicalensis. Among them, SFII was the most promising NQO1 inhibitor with a binding affinity (KD = 4.198 μmol/L) and inhibitory activity (IC50 = 2.87 μmol/L). In human normal liver cell line (L02) and human renal proximal tubular epithelial cell line (HK-2), SFII significantly alleviated AAI-induced DNA damage and apoptosis. In adult mice, oral administration of SFII dose-dependently ameliorated AAI-induced renal fibrosis and dysfunction. In infant mice, oral administration of SFII suppressed AAI-induced hepatocellular carcinoma initiation. Moreover, administration of SFII did not affect the coagulation function in short term in adult mice. In conclusion, SFII has been identified as a novel NQO1 inhibitor that might impede the risk of AAI to kidney and liver without obvious side effect.
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2
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Nečasová I, Stojaspal M, Motyčáková E, Brom T, Janovič T, Hofr C. Transcriptional regulators of human oncoviruses: structural and functional implications for anticancer therapy. NAR Cancer 2022; 4:zcac005. [PMID: 35252867 PMCID: PMC8892037 DOI: 10.1093/narcan/zcac005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/04/2022] [Accepted: 02/15/2022] [Indexed: 11/26/2022] Open
Abstract
Transcription is often the first biosynthetic event of viral infection. Viruses produce preferentially viral transcriptional regulators (vTRs) essential for expressing viral genes and regulating essential host cell proteins to enable viral genome replication. As vTRs are unique viral proteins that promote the transcription of viral nucleic acid, vTRs interact with host proteins to suppress detection and immune reactions to viral infection. Thus, vTRs are promising therapeutic targets that are sequentially and structurally distinct from host cell proteins. Here, we review vTRs of three human oncoviruses: HBx of hepatitis B virus, HBZ of human T-lymphotropic virus type 1, and Rta of Epstein-Barr virus. We present three cunningly exciting and dangerous transcription strategies that make viral infections so efficient. We use available structural and functional knowledge to critically examine the potential of vTRs as new antiviral-anticancer therapy targets. For each oncovirus, we describe (i) the strategy of viral genome transcription; (ii) vTRs' structure and binding partners essential for transcription regulation; and (iii) advantages and challenges of vTR targeting in antiviral therapies. We discuss the implications of vTR regulation for oncogenesis and perspectives on developing novel antiviral and anticancer strategies.
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Affiliation(s)
- Ivona Nečasová
- Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, Královopolská 135, Brno 612 65, Czech Republic
| | - Martin Stojaspal
- Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, Královopolská 135, Brno 612 65, Czech Republic
| | - Edita Motyčáková
- Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, Královopolská 135, Brno 612 65, Czech Republic
| | - Tomáš Brom
- LifeB, Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 753/5, Brno 625 00, Czech Republic
| | - Tomáš Janovič
- LifeB, Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 753/5, Brno 625 00, Czech Republic
| | - Ctirad Hofr
- Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, Královopolská 135, Brno 612 65, Czech Republic
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3
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Kai J, Yang X, Wang Z, Wang F, Jia Y, Wang S, Tan S, Chen A, Shao J, Zhang F, Zhang Z, Zheng S. Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease. Free Radic Biol Med 2020; 153:89-102. [PMID: 32289481 DOI: 10.1016/j.freeradbiomed.2020.03.031] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 03/10/2020] [Accepted: 03/30/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND It is well acknowledged that alcoholic liver disease (ALD) is widely prevalent all over the world, characterized by aberrant lipid deposition and excessive oxidative stress in hepatocytes. Recently, pyroptosis, a new type of programmed cell death, has been found in ALD, which provides new ideas for the treatment of ALD. METHODS Male ICR mice were treated with the Lieber-De-Carli diet (Dyets) or isocaloric liquid diet for 8 weeks, and binge alcohol model was also used for ALD. Blood and livers were taken to evaluate the efficacy of oroxylin A. The levels of factors related to hepatocyte pyroptosis were measured via western blot analyses, immunofluorescence analyses and quantitative reverse transcriptase in vitro. RESULT Our study found that oroxylin A suppressed hepatocyte pyroptosis through a NLRP3 inflammasome dependent-canonical caspase-1 pathway. Results illuminated that oroxylin A inhibited NLRP3 inflammasome activation by reducing ROS accumulation. Furthermore, oroxylin A upregulated mitofusin 2 (Mfn2) to resist lipid deposition and mitochondria-derived ROS overproduction. As an upstream mediator of Mfn2, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a major regulator of mitochondria, was found to promote transcription of Mfn2 under oroxylin A treatment. CONCLUSION Our research revealed that oroxylin A could alleviate ALD via PGC-1α/Mfn2 signaling mediated canonical pyroptosis pathway resistance.
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Affiliation(s)
- Jun Kai
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xiang Yang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhimin Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Feixia Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yan Jia
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Shijun Wang
- Shandong University of Traditional Chinese Medicine, Jinan, 250035, China
| | - Shanzhong Tan
- Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Anping Chen
- Department of Pathology, School of Medicine, Saint Louis University, MO, 63104, USA
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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4
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Vescovo T, Pagni B, Piacentini M, Fimia GM, Antonioli M. Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development. Front Cell Dev Biol 2020; 8:47. [PMID: 32181249 PMCID: PMC7059124 DOI: 10.3389/fcell.2020.00047] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/20/2020] [Indexed: 12/14/2022] Open
Abstract
About 20% of total cancer cases are associated to infections. To date, seven human viruses have been directly linked to cancer development: high-risk human papillomaviruses (hrHPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus 1 (HTLV-1). These viruses impact on several molecular mechanisms in the host cells, often resulting in chronic inflammation, uncontrolled proliferation, and cell death inhibition, and mechanisms, which favor viral life cycle but may indirectly promote tumorigenesis. Recently, the ability of oncogenic viruses to alter autophagy, a catabolic process activated during the innate immune response to infections, is emerging as a key event for the onset of human cancers. Here, we summarize the current understanding of the molecular mechanisms by which human oncogenic viruses regulate autophagy and how this negative regulation impacts on cancer development. Finally, we highlight novel autophagy-related candidates for the treatment of virus-related cancers.
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Affiliation(s)
- Tiziana Vescovo
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
| | - Benedetta Pagni
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy.,Department of Biology, University of Rome "Tor Vergata," Rome, Italy
| | - Mauro Piacentini
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy.,Department of Biology, University of Rome "Tor Vergata," Rome, Italy
| | - Gian Maria Fimia
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy.,Department of Molecular Medicine, University of Rome "Sapienza," Rome, Italy
| | - Manuela Antonioli
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
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5
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Down-regulation of GCLC is involved in microcystin-LR-induced malignant transformation of human liver cells. Toxicology 2019; 421:49-58. [DOI: 10.1016/j.tox.2019.03.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 03/04/2019] [Accepted: 03/27/2019] [Indexed: 02/06/2023]
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Hepatitis B virus X protein promotes DNA damage propagation through disruption of liver polyploidization and enhances hepatocellular carcinoma initiation. Oncogene 2018; 38:2645-2657. [PMID: 30538294 DOI: 10.1038/s41388-018-0607-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 10/15/2018] [Accepted: 10/17/2018] [Indexed: 12/19/2022]
Abstract
Hepatitis B virus X protein (HBx) contributes to Hepatitis B virus (HBV)-related liver cancer. However, its impact on hepatocyte proliferation and genomic stability remains elusive. We studied the role of HBx expression on the progression of cell cycle and liver polyploidization during proliferation and liver carcinogenesis. Full-length HBx transgenic mice (FL-HBx) were developed to investigate liver ploidy as well as hepatocyte proliferation, along normal liver maturation and during cancer initiation (chemical carcinogen treatment). Investigation of postnatal liver development in FL-HBx showed an aberrant G1/S and G2/M transitions, triggered (1) a delay of the formation of hepatocytes binucleation, (2) the early synthesis of polyploidy nuclei (≥4n) and (3) DNA damage appearance. Moreover, HBV infection during hepatocytes proliferation in a humanized liver mouse model led, to modifications in polyploidy of hepatocytes. In initiation of hepatocellular carcinoma, FL-HBx protein decreased ChK1 phosphorylation, Mre11 and Rad51 expression, upregulated IL-6 expression and impaired apoptosis. This was related to DNA damage accumulation in FL-HBx mice. At day 75 after initiation of hepatocellular carcinoma, FL-HBx mice revealed significant cell cycle changes related to the increased amount of 4n nuclei and of markers of cancer progenitor cells. Finally, PLK1 upregulation and p38/ERK activation in FL-HBx mice were implicated in aberrant polyploidization favoring DNA damage propagation and hepatocyte transformation. In conclusion, our data indicate that FL-HBx protein increases DNA damage through the hijack of hepatocyte polyploidization. That leads to enhancement of hepatocellular carcinoma initiation in an inflammatory context.
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Meier-Stephenson V, Bremner WTR, Dalton CS, van Marle G, Coffin CS, Patel TR. Comprehensive Analysis of Hepatitis B Virus Promoter Region Mutations. Viruses 2018; 10:E603. [PMID: 30388827 PMCID: PMC6265984 DOI: 10.3390/v10110603] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 10/27/2018] [Accepted: 10/31/2018] [Indexed: 02/06/2023] Open
Abstract
Over 250 million people are infected chronically with hepatitis B virus (HBV), the leading cause of liver cancer worldwide. HBV persists, due, in part, to its compact, stable minichromosome, the covalently-closed, circular DNA (cccDNA), which resides in the hepatocytes' nuclei. Current therapies target downstream replication products, however, a true virological cure will require targeting the cccDNA. Finding targets on such a small, compact genome is challenging. For HBV, to remain replication-competent, it needs to maintain nucleotide fidelity in key regions, such as the promoter regions, to ensure that it can continue to utilize the necessary host proteins. HBVdb (HBV database) is a repository of HBV sequences spanning all genotypes (A⁻H) amplified from clinical samples, and hence implying an extensive collection of replication-competent viruses. Here, we analyzed the HBV sequences from HBVdb using bioinformatics tools to comprehensively assess the HBV core and X promoter regions amongst the nearly 70,000 HBV sequences for highly-conserved nucleotides and variant frequencies. Notably, there is a high degree of nucleotide conservation within specific segments of these promoter regions highlighting their importance in potential host protein-viral interactions and thus the virus' viability. Such findings may have key implications for designing antivirals to target these areas.
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Affiliation(s)
- Vanessa Meier-Stephenson
- Department of Microbiology, Immunology and Infectious Diseases, Cumming, School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
- Alberta RNA Research & Training Institute, Department of Chemistry & Biochemistry, University of Lethbridge, Lethbridge, Alberta, T1K 3M4, Canada.
| | - William T R Bremner
- Department of Ecosystem & Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
| | - Chimone S Dalton
- Department of Ecosystem & Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
| | - Guido van Marle
- Department of Microbiology, Immunology and Infectious Diseases, Cumming, School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
| | - Carla S Coffin
- Department of Microbiology, Immunology and Infectious Diseases, Cumming, School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Calgary, AB T2N 4Z6, Canada.
| | - Trushar R Patel
- Department of Microbiology, Immunology and Infectious Diseases, Cumming, School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
- Alberta RNA Research & Training Institute, Department of Chemistry & Biochemistry, University of Lethbridge, Lethbridge, Alberta, T1K 3M4, Canada.
- DiscoveryLab, Faculty of Medicine & Dentistry, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2H7, Canada.
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8
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Jin H, Lian N, Bian M, Zhang C, Chen X, Shao J, Wu L, Chen A, Guo Q, Zhang F, Zheng S. Oroxylin A inhibits ethanol-induced hepatocyte senescence via YAP pathway. Cell Prolif 2018; 51:e12431. [PMID: 29318697 DOI: 10.1111/cpr.12431] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 12/02/2017] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES Oroxylin A, a natural flavonoid isolated from Scutellaria baicalensis, has been reported to have anti-hepatic injury effects. However, the effects of oroxylin A on alcoholic liver disease (ALD) remains unclear. The aim of this study was to elucidate the effects of oroxylin A on ALD and the potential mechanisms. MATERIALS AND METHODS Male ICR mice and human hepatocyte cell line LO2 were used. Yes-associated protein (YAP) overexpression and knockdown were achieved using plasmid and siRNA technique. Cellular senescence was assessed by analyses of the senescence-associated β-galactosidase (SA-β-gal), senescence marker p16, p21, Hmga1, cell cycle and telomerase activity. RESULTS Oroxylin A alleviated ethanol-induced hepatocyte damage by suppressing activities of supernatant marker enzymes. We found that oroxylin A inhibited ethanol-induced hepatocyte senescence by decreasing the number of SA-β-gal-positive LO2 cells and reducing the expression of senescence markers p16, p21 and Hmga1 in vitro. Moreover, oroxylin A affected the cell cycle and telomerase activity. Of importance, we revealed that YAP pharmacological inhibitor verteporfin or YAP siRNA eliminated the effect of oroxylin A on ethanol-induced hepatocyte senescence in vitro, and this was further supported by the evidence in vivo experiments. CONCLUSION Therefore, these aggregated data suggested that oroxylin A relieved alcoholic liver injury possibly by inhibiting the senescence of hepatocyte, which was dependent on its activation of YAP in hepatocytes.
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Affiliation(s)
- Huanhuan Jin
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Naqi Lian
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mianli Bian
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chenxi Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xingran Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiangjuan Shao
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Li Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Anping Chen
- Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO, USA
| | - Qinglong Guo
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China
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9
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Mui UN, Haley CT, Tyring SK. Viral Oncology: Molecular Biology and Pathogenesis. J Clin Med 2017; 6:E111. [PMID: 29186062 PMCID: PMC5742800 DOI: 10.3390/jcm6120111] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 11/17/2017] [Accepted: 11/22/2017] [Indexed: 02/06/2023] Open
Abstract
Oncoviruses are implicated in approximately 12% of all human cancers. A large number of the world's population harbors at least one of these oncoviruses, but only a small proportion of these individuals go on to develop cancer. The interplay between host and viral factors is a complex process that works together to create a microenvironment conducive to oncogenesis. In this review, the molecular biology and oncogenic pathways of established human oncoviruses will be discussed. Currently, there are seven recognized human oncoviruses, which include Epstein-Barr Virus (EBV), Human Papillomavirus (HPV), Hepatitis B and C viruses (HBV and HCV), Human T-cell lymphotropic virus-1 (HTLV-1), Human Herpesvirus-8 (HHV-8), and Merkel Cell Polyomavirus (MCPyV). Available and emerging therapies for these oncoviruses will be mentioned.
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Affiliation(s)
- Uyen Ngoc Mui
- Center for Clinical Studies, Houston, TX 77004, USA.
| | | | - Stephen K Tyring
- Center for Clinical Studies, Houston, TX 77004, USA.
- Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX 77004, USA.
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10
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Lu C, Xu W, Shao J, Zhang F, Chen A, Zheng S. Blockade of hedgehog pathway is required for the protective effects of magnesium isoglycyrrhizinate against ethanol-induced hepatocyte steatosis and apoptosis. IUBMB Life 2017; 69:540-552. [DOI: 10.1002/iub.1639] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 04/24/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Chunfeng Lu
- Department of Pharmacology, School of Pharmacy; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
| | - Wenxuan Xu
- Department of Pharmacology, School of Pharmacy; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
| | - Jiangjuan Shao
- Department of Pharmacology, School of Pharmacy; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
| | - Feng Zhang
- Department of Pharmacology, School of Pharmacy; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
| | - Anping Chen
- Department of Pathology, School of Medicine; Saint Louis University; St Louis MO USA
| | - Shizhong Zheng
- Department of Pharmacology, School of Pharmacy; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
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11
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Fu S, Zhou RR, Li N, Huang Y, Fan XG. Hepatitis B virus X protein in liver tumor microenvironment. Tumour Biol 2016; 37:15371–15381. [PMID: 27658781 PMCID: PMC5250643 DOI: 10.1007/s13277-016-5406-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 09/13/2016] [Indexed: 12/18/2022] Open
Abstract
Encoded by the hepatitis B virus, hepatitis B virus X protein (HBx) is a multifunctional, potentially oncogenic protein that acts primarily during the progression from chronic hepatitis B to cirrhosis and hepatocellular carcinoma (HCC). In recent decades, it has been established that chronic inflammation generates a tumor-supporting microenvironment. HCC is a typical chronic inflammation-related cancer, and inflammation is the main risk factor for HCC progression. The viral transactivator HBx plays a pivotal role in the initiation and maintenance of hepatic inflammatory processes through interactions with components of the tumor microenvironment including tumor cells and the surrounding peritumoral stroma. The complex interactions between HBx and this microenvironment are thought to regulate tumor growth, progression, invasion, metastasis, and angiogenesis. In this review, we have summarized the current evidence evaluating the function of HBx and its contribution to the inflammatory liver tumor microenvironment.
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Affiliation(s)
- Sha Fu
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan Province, Xiangya Hospital, Central South University, P. O. Box: 410008, Changsha, China
| | - Rong-Rong Zhou
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan Province, Xiangya Hospital, Central South University, P. O. Box: 410008, Changsha, China.
| | - Ning Li
- Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha, China
| | - Yan Huang
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan Province, Xiangya Hospital, Central South University, P. O. Box: 410008, Changsha, China
| | - Xue-Gong Fan
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan Province, Xiangya Hospital, Central South University, P. O. Box: 410008, Changsha, China.
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12
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Lu C, Xu W, Zhang F, Shao J, Zheng S. Nrf2 Knockdown Disrupts the Protective Effect of Curcumin on Alcohol-Induced Hepatocyte Necroptosis. Mol Pharm 2016; 13:4043-4053. [PMID: 27764939 DOI: 10.1021/acs.molpharmaceut.6b00562] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
It has emerged that hepatocyte necroptosis plays a critical role in chronic alcoholic liver disease (ALD). Our previous study has identified that the beneficial therapeutic effect of curcumin on alcohol-caused liver injury might be attributed to activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), whereas the role of curcumin in regulating necroptosis and the underlying mechanism remain to be determined. We first found that chronic alcohol consumption triggered obvious hepatocyte necroptosis, leading to increased expression of receptor-interacting protein 1, receptor-interacting protein 3, high-mobility group box 1, and phosphorylated mixed lineage kinase domain-like in murine livers. Curcumin dose-dependently ameliorated hepatocyte necroptosis and alleviated alcohol-caused decrease in hepatic Nrf2 expression in alcoholic mice. Then Nrf2 shRNA lentivirus was introduced to generate Nrf2-knockdown mice. Our results indicated that Nrf2 knockdown aggravated the effects of alcohol on liver injury and necroptosis and even abrogated the inhibitory effect of curcumin on necroptosis. Further, activated Nrf2 by curcumin inhibited p53 expression in both livers and cultured hepatocytes under alcohol stimulation. The next in vitro experiments, similar to in vivo ones, revealed that although Nrf2 knockdown abolished the suppression of curcumin on necroptosis of hepatocytes exposed to ethanol, p53 siRNA could clearly rescued the relative effect of curcumin. In summary, for the first time, we concluded that curcumin attenuated alcohol-induced hepatocyte necroptosis in a Nrf2/p53-dependent mechanism. These findings make curcumin an excellent candidate for ALD treatment and advance the understanding of ALD mechanisms associated with hepatocyte necroptosis.
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Affiliation(s)
- Chunfeng Lu
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine , Nanjing, Jiangsu, China
| | - Wenxuan Xu
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine , Nanjing, Jiangsu, China
| | - Feng Zhang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine , Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine , Nanjing, Jiangsu, China
| | - Jiangjuan Shao
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine , Nanjing, Jiangsu, China
| | - Shizhong Zheng
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine , Nanjing, Jiangsu, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine , Nanjing, Jiangsu, China
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13
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Deng YT, Liang G, Shi Y, Li HL, Zhang J, Mao XM, Fu QR, Peng WX, Chen QX, Shen DY. Condensed tannins from Ficus altissima leaves: Structural, antioxidant, and antityrosinase properties. Process Biochem 2016. [DOI: 10.1016/j.procbio.2016.04.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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14
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Liu S, Koh SSY, Lee CGL. Hepatitis B Virus X Protein and Hepatocarcinogenesis. Int J Mol Sci 2016; 17:ijms17060940. [PMID: 27314335 PMCID: PMC4926473 DOI: 10.3390/ijms17060940] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 05/18/2016] [Accepted: 05/24/2016] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the most associated factors in hepatocarcinogenesis. HBV is able to integrate into the host genome and encode the multi-functional hepatitis B virus x protein (HBx). Although the mechanism between HBx and carcinogenesis is still elusive, recent studies have shown that HBx was able to influence various signaling pathways, as well as epigenetic and genetic processes. This review will examine and summarize recent literature about HBx’s role in these various processes.
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Affiliation(s)
- Shuaichen Liu
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore.
- Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun 130021, China.
| | - Samantha S Y Koh
- Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 169610 Singapore, Singapore.
| | - Caroline G L Lee
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore.
- Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 169610 Singapore, Singapore.
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 117456 Singapore, Singapore.
- Duke-NUS Graduate Medical School, 169857 Singapore, Singapore.
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15
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Wang Z, Wu S, Liao J, Zhong L, Xing T, Fan J, Peng Z. Interleukin-6 and rs1800796 locus single nucleotide polymorphisms in response to hypoxia/reoxygenation in hepatocytes. Int J Mol Med 2016; 38:192-200. [PMID: 27221654 PMCID: PMC4899033 DOI: 10.3892/ijmm.2016.2595] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 05/10/2016] [Indexed: 02/07/2023] Open
Abstract
Ischemia-reperfusion injury due to hypoxia/reoxygenation (H/R) is one of the main causes of liver damage during liver surgery. Donor interleukin-6 (IL-6) rs1800796 single nucleotide polymorphisms (SNPs) affect the metabolism of tacrolimus following liver transplantation-related hepatic H/R. This study investigated the response of IL-6 and its promoter polymorphisms to hepatic H/R in liver parenchymal cells. The association between IL-6 rs1800796 SNPs and IL‑6 expression was measured in 84 disease-free liver tissues using tissue microarrays and immunohistochemistry. Subsequently, LO2G, LO2C and NC-LO2 cells were successfully constructed via stable lentivirus-mediated transfection. The effects of IL-6 and its SNPs on the biological function of LO2 cells were examined using a cell model of H/R. Our results revealed that IL-6 was mainly expressed in hepatocytes. The intermediate IL-6 expression rate in genotype CC carriers was higher than that in genotype CG/GG carriers (P=0.006), which was subsequently verified at the IL-6 mRNA level (P=0.002). The concentrations of alanine aminotransferase in the LO2G cells were significantly higher than those in the LO2C cells following H/R for 6 h and H/R for 24 h (P<0.05). The viability of the LO2C cells was higher than that of the LO2G cells (P<0.05). Furthermore, the expression of IL-6 and its downstream molecules was significantly increased in the LO2C cells compared with the LO2G cells (P<0.05). Therefore, the sequence variants of rs1800796 SNPs (G→C) exhibit an increased IL-6 transcription efficiency in liver parenchymal cells. In addition, the increased expression of IL-6 protects the hepatocytes following hepatic H/R injury.
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Affiliation(s)
- Zhaowen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Shaohan Wu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Jianhua Liao
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Tonghai Xing
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Junwei Fan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Zhihai Peng
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
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Fu S, Fan XG. Pathophysiological implications of hepatitis B X protein in tumor microenvironment of hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2016; 24:1477-1484. [DOI: 10.11569/wcjd.v24.i10.1477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B X protein (HBx), encoded by hepatitis B virus (HBV), is a multifunctional and potentially oncogenic protein that has significant functions during the progression from chronic hepatitis B to cirrhosis and eventually to hepatocellular carcinoma (HCC). Over the past decades, it has been widely established that chronic inflammation orchestrates a tumor-supporting microenvironment. HCC is a typical chronic inflammation-related cancer and inflammation is the main risk factor for the progression of HCC. As a major viral transactivator, HBx is thought to play a pivotal role in the activation and maintenance of hepatic inflammatory process through interaction with various components of the tumor microenvironment including tumor cell and surrounding peritumoral stroma. Complex interactions between HBx and these cell types in this microenvironment will regulate tumor growth, progression, metastasis, and angiogenesis. In this review, we mainly summarize the current understanding of HBx and its contribution to the inflammatory tumor microenvironment of HBV-related HCC.
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Geng M, Xin X, Bi LQ, Zhou LT, Liu XH. Molecular mechanism of hepatitis B virus X protein function in hepatocarcinogenesis. World J Gastroenterol 2015; 21:10732-10738. [PMID: 26478665 PMCID: PMC4600575 DOI: 10.3748/wjg.v21.i38.10732] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/24/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
Many factors are considered to contribute to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), including products of HBV, HBV integration and mutation, and host susceptibility. HBV X protein (HBx) can interfere with several signaling pathways associated with cell proliferation and invasion, and HBx C-terminal truncation has been suggested to impact the development of HCC. This review focuses on the pathological functions of HBx in HBV-induced hepatocarcinogenesis. As a transactivator, HBx can affect regulatory non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs. HBx is also involved in epigenetic modification and DNA repair. HBx interacts with various signal-transduction pathways, such as the p53, Wnt, and nuclear factor-κB pathways. We conclude that HBx hastens the development of hepatoma.
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Sun Q, Wang R, Luo J, Wang P, Xiong S, Liu M, Cheng B. Notch1 promotes hepatitis B virus X protein-induced hepatocarcinogenesis via Wnt/β-catenin pathway. Int J Oncol 2014; 45:1638-48. [PMID: 25017705 DOI: 10.3892/ijo.2014.2537] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 06/24/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatocellular carcinoma (HCC) via a network of signaling pathways. Notch pathway is a major member of the network. Notch signaling may generate opposing effect in different steps of carcinogenesis, depending on the tumor cell type and the status of other signaling pathways, such as Wnt signaling pathway. Our previous studies have shown that activated Notch1 signaling is required for HBx to promote proliferation and survival of human hepatic cell line L02. However, the exact mechanisms remain vague. Here, we used L02/HBx cell lines as a cell model to study the relationship between Notch and Wnt/β-catenin pathways in promoting proliferation. We observed that activated Notch1 and Wnt/β-catenin signaling pathways and L02 cell malignant transformation were induced by HBx. Inhibition of the Notch1 pathway decreased the activation of Wnt/β-catenin pathway and cell proliferation, while inhibition of the Wnt/β-catenin pathway impaired cell proliferation, but did not significantly affect Notch1 signaling pathway in L02/HBx cells. Furthermore, inhibition of the Wnt/β-catenin pathway overcame the inhibition effect of knockdown Notch1 on proliferation and survival in L02/HBx cells. Additionally, the activity of Wnt/β-catenin signaling appears to be consistent with Fzd10 expression. Therefore, we demonstrate that Wnt signaling is downstream of the Notch pathway in regulating proliferation of L02/HBx cells, and which may be related to Fzd10 instead of Fzd7. These data suggest a new model of HBx-related HCC via cooperation between Wnt and Notch pathways.
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Affiliation(s)
- Qian Sun
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Ronghua Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Jing Luo
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Peng Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Si Xiong
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Man Liu
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Bin Cheng
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
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Bharadwaj M, Roy G, Dutta K, Misbah M, Husain M, Hussain S. Tackling hepatitis B virus-associated hepatocellular carcinoma--the future is now. Cancer Metastasis Rev 2013; 32:229-68. [PMID: 23114844 DOI: 10.1007/s10555-012-9412-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers in many developing countries including India. Among the various etiological factors being implicated in the cause of HCC, the most important cause, however, is hepatitis B virus (HBV) infection. Among all HBV genes, HBx is the most critical carcinogenic component, the molecular mechanisms of which have not been completely elucidated. Despite its clinical significance, there exists a very elemental understanding of the molecular, cellular, and environmental mechanisms that drive disease pathogenesis in HCC infected with HBV. Furthermore, there are only limited therapeutic options, the clinical benefits of which are insignificant. Therefore, the quest for novel and effective therapeutic regimen against HBV-related HCC is of paramount importance. This review attempts to epitomize the current state of knowledge of this most common and dreaded liver neoplasm, highlighting the putative treatment avenues and therapeutic research strategies that need to be implemented with immediate effect for tackling HBV-related HCC that has plagued the medical and scientific fraternity for decades. Additionally, this review proposes a novel "five-point" management algorithm for HBV-related HCC apart from portraying the unmet needs, principal challenges, and scientific perspectives that are relevant to controlling this accelerating global health crisis.
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Affiliation(s)
- Mausumi Bharadwaj
- Division of Molecular Genetics & Biochemistry, Institute of Cytology & Preventive Oncology (ICMR), Noida, India.
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Notch1 is a potential therapeutic target for the treatment of human hepatitis B virus X protein-associated hepatocellular carcinoma. Oncol Rep 2013; 31:933-9. [PMID: 24336972 DOI: 10.3892/or.2013.2917] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 11/27/2013] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal cancer with increasing worldwide incidence, and there are few therapeutics options available for patients with HCC. Thus, novel therapeutic targets for this disease are desperately needed. Chronic infection with hepatitis B virus (HBV) is the major risk factor for the development of HCC, while hepatitis B virus X protein (HBx) is essential for HBV-associated HCC. Based on our previous studies showing that HBx promoted hepatocarcinogenesis of the human non-tumor hepatic cell line L02 and activated Notch1 signaling, Notch1 short hairpin RNA (shRNA) was utilized to inhibit Notch1 mRNA in the present study. We observed that Notch1 shRNA inhibited cell proliferation together with decreased activity of the Notch1 pathway in vitro, and also markedly suppressed tumor formation of L02/HBx cells in a BALB/c nude mouse model in vivo. Furthermore, the blockade of Notch1 was capable of arresting the cell cycle in the G0/G1 phase through the downregulation of CyclinD1, CDK4, E2F1 and the upregulation of p21 and Rb, while all of these factors were involved in the CyclinD1/CDK4 pathway. Inhibition of Notch1 by shRNA markedly promoted the apoptosis of L02/HBx cells via the caspase-9-caspase-3 pathway. These data suggest that inhibition of Notch1 impairs the growth of human HBx-transformed L02 cells, and Notch1 may be a putative therapeutic target for human HBx-associated HCC.
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Luo J, Zhou H, Wang F, Xia X, Sun Q, Wang R, Cheng B. The hepatitis B virus X protein downregulates NF-κB signaling pathways through decreasing the Notch signaling pathway in HBx-transformed L02 cells. Int J Oncol 2013; 42:1636-43. [PMID: 23450368 DOI: 10.3892/ijo.2013.1842] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 02/11/2013] [Indexed: 01/08/2023] Open
Abstract
Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatocellular carcinoma, which has been found to be associated with Notch and NF-κB signaling. This study aimed to investigate the crosstalk between Notch and NF-κB pathways in HBx-related hepatocellular carcinoma. An HBx-transformed non-tumor hepatic cell line L02 (L02/HBx) was previously established. Immunofluorescence assays were performed to visualize HBx and the Notch intracellular domain (NICD) in cell nuclei. Co-immunoprecipitation assays were used to investigate physical interactions between HBx and components of the Notch signaling pathway (NICD and JAG1), NF-κB signaling pathway (p65 and p50) or IκBα. L02/HBx cells were treated with the Notch signal inhibitor DAPT or Notch1 siRNA to inhibit the Notch1 pathway. qRT-PCR was used to quantify the expression of the p65, p50 and IκBα genes. Protein expression changes in cytoplasm and nuclei after treatment with DAPT or Notch1 siRNA were analyzed by western blotting and EMSA assays. We found that HBx directly regulated Notch1 signaling, which cross-talked with the NF-κB pathway. Downregulation of Notch1 decreased the binding of NF-κB p65 to its target gene promoter, reduced NF-κB expression and enhanced IκBα expression. The results suggest that HBx functions through the Notch signaling pathway; Notch contributes to hepatocarcinogenesis partially by regulating the NF-κB pathway. Our findings provide new insights into the role of Notch and NF-κB signaling in the progression of hepatocellular carcinoma related to HBx.
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Affiliation(s)
- Jing Luo
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
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Wang F, Xia X, Wang J, Sun Q, Luo J, Cheng B. Notch1 signaling contributes to the oncogenic effect of HBx on human hepatic cells. Biotechnol Lett 2012; 35:29-37. [PMID: 22986536 DOI: 10.1007/s10529-012-1048-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 09/05/2012] [Indexed: 11/28/2022]
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor and hepatitis B virus X protein (HBx) plays a crucial role in its pathogenesis. The Notch1 signaling pathway is involved in various malignant tumors including liver cancers and down-regulation of Notch-1 may exert anti-tumor effects. Here, we demonstrate that inhibition of Notch1 by plasmid-based shRNA suppresses growth of human hepatic cells transfected with HBx through G0/G1 cell cycle arrest and apoptosis inhibition, possibly linked to the promoted expression of cyclin-dependent kinase inhibitor, P16, and decreased expression of apoptosis inhibitor, Bcl-2. The anti-proliferative and pro-apoptotic effects of Notch1 shRNA in HBx-transformed L02 cell may be partly mediated by down-regulation of nuclear factor-kappaB (NF-κB) binding activities, demonstrating possible cross-talk between Notch-1 and NF-κB signaling pathways. The oncogene HBx may therefore induce malignant transformation of human hepatic cells via Notch1 pathway, indicating that Notch1 plays a crucial role in HBx-related liver cancer and could be an effective therapeutic target for HCC.
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Affiliation(s)
- Fan Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Wei S, Xiong M, Zhan DQ, Liang BY, Wang YY, Gutmann DH, Huang ZY, Chen XP. Ku80 functions as a tumor suppressor in hepatocellular carcinoma by inducing S-phase arrest through a p53-dependent pathway. Carcinogenesis 2012; 33:538-47. [PMID: 22226916 DOI: 10.1093/carcin/bgr319] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Ku80 is a component of the protein complex called DNA-dependent protein kinase, which is involved in DNA double-strand break repair and multiple other functions. Previous studies revealed that Ku80 haplo-insufficient and poly (adenosine diphosphate-ribose) polymerase-null transgenic mice developed hepatocellular carcinoma (HCC) at a high frequency. The role of Ku80 has never been investigated in human HCC. Ku80 expressions in HCC and adjacent liver tissue were investigated by using immunohistochemical staining and western blot. Ku80 was transfected into a Ku80-deficient HCC cell line SMMC7721 cells, and the growth features of the Ku80-expressing cells and vector-transfected cells were studied both in vitro and in vivo. Cell cycle analysis and RNA interference were employed to investigate the mechanisms underlying the growth regulation associated with Ku80 expression. Ku80 was found frequently downregulated in HCC compared with adjacent liver tissue. Ku80 downregulation was significantly correlated with elevated hepatitis B virus-DNA load and severity of liver cirrhosis. Overexpression of Ku80 in SMMC7721 cells significantly suppressed cell proliferation in vitro and in vivo. Ku80 overexpression caused S-phase cell cycle arrest and was associated with upregulation of p53 and p21(CIP1/WAF1), and the inhibition of p53 or p21(CIP1/WAF1) expression by RNA interference overcame the growth suppression and S-phase arrest in the Ku80-expressing cells. A novel mechanism was revealed that Ku80 functions as a tumor suppressor in HCC by inducing S-phase arrest through a p53-dependent pathway.
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Affiliation(s)
- Shuang Wei
- Research Laboratory and Hepatic Surgical Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Da Dao, Wuhan, China
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Abstract
Hepatocellular carcinoma (HCC) ranks as the third most common cause of death from cancer worldwide. Although major risk factors for the development of HCC have been defined, many aspects of the evolution of hepatocellular carcinogenesis and metastasis are still unknown. Suitable animal models are, therefore, essential to promote our understanding of the molecular, cellular and pathophysiological mechanisms of HCC and for the development of new therapeutic strategies. This Review provides an overview of animal models that are relevant to HCC development, metastasis and treatment. For HCC development, this Review focuses on transgenic mouse models of HBV and HCV infection, which provide experimental evidence that viral genes could initiate or promote liver carcinogenesis. Animal models of HCC metastasis provide platforms to elucidate the mechanisms of HCC metastasis, to study the interaction between the microenvironment and HCC invasion and to conduct intervention studies. In addition, animal models have been developed to investigate the effects of new treatment modalities. The criteria for establishing ideal HCC animal models are also discussed.
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Yip WK, Cheng ASL, Zhu R, Lung RWM, Tsang DPF, Lau SSK, Chen Y, Sung JG, Lai PBS, Ng EKO, Yu J, Wong N, To KF, Wong VWS, Sung JJY, Chan HLY. Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in hepatocellular carcinoma development. PLoS One 2011; 6:e22888. [PMID: 21829663 PMCID: PMC3150371 DOI: 10.1371/journal.pone.0022888] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2010] [Accepted: 07/07/2011] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. METHODS Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissues using real-time PCR. RESULTS Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. CONCLUSION Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis.
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Affiliation(s)
- Wing-Kit Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Alfred Sze-Lok Cheng
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ranxu Zhu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Raymond Wai-Ming Lung
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Daisy Pui-Fong Tsang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Suki Shuk-Kei Lau
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yangchao Chen
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jonathan Gabriel Sung
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Paul Bo-San Lai
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Enders Kai-On Ng
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Nathalie Wong
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ka-Fai To
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Joseph Jao-Yiu Sung
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
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Abstract
Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor in hepatocellular carcinoma (HCC), which is one of the most common cancers worldwide. The pathogenesis of HBV-mediated hepatocarcinogenesis is, however, incompletely understood. Evidence suggests that the HBV X protein (HBx) plays a crucial role in HCC development. HBx is a multifunctional regulator that modulates transcription, signal transduction, cell cycle progression, apoptosis, protein degradation pathways, and genetic stability through interaction with host factors. This review describes the current state of knowledge of the molecular pathogenesis of HBV-induced HCC, with a focus on the role of HBx in hepatocarcinogenesis.
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Affiliation(s)
- Sue-Ann Ng
- University of New South Wales, Sydney, Australia.
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Gong Q, He S. Advances in understanding the biological roles of HBx. Shijie Huaren Xiaohua Zazhi 2010; 18:3656-3661. [DOI: 10.11569/wcjd.v18.i34.3656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is the leading cause of liver cancer. Globally, there are over 350 million individuals chronically infected with HBV, and approximately 25% of these individuals will develop hepatocellular carcinoma (HCC). HBV is the prototype virus of the hepadnavirus family. The genome of HBV is circular and contains four open reading frames (ORFs). The HBx protein encoded by the X region of HBV is a multifunctional regulatory protein that possesses a wide transactivation activity and plays critical roles in regulating intracellular signal transduction, viral replication and transcription, cell proliferation and apoptosis, protein degradation, and heredity stability of hepatocytes. Due to its important roles in the development of chronic liver diseases, the research on the HBx protein has become a hot topic in recent years. In this paper, we will summarize the latest advances in understanding the biological roles of the HBx protein.
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Wang F, Zhou H, Xia X, Sun Q, Wang Y, Cheng B. Activated Notch signaling is required for hepatitis B virus X protein to promote proliferation and survival of human hepatic cells. Cancer Lett 2010; 298:64-73. [PMID: 20638778 DOI: 10.1016/j.canlet.2010.06.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2010] [Revised: 06/09/2010] [Accepted: 06/14/2010] [Indexed: 01/13/2023]
Abstract
Hepatitis B virus X protein (HBx) is a multifunctional oncoprotein which plays a crucial role in the pathogenesis of hepatocellular carcinoma (HCC). However, the exact mechanisms remain controversial. Here we show that HBx strongly stimulated cell growth, promoted cell cycle progression and inhibited apoptosis of human non-tumor hepatic cell line L02 cells. It also accelerated tumor formation of L02 cells in BALB/c nude mice. Furthermore, Notch signaling components were upregulated in HBx-expressing L02 cells compared to normal L02 cells. However, blocking Notch signaling with a γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) attenuated cell growth, shortened the S phase of cell cycle and promoted apoptosis of HBx-expressing L02 cell in a dose- and time-dependent manner, but normal L02 cells were not significantly affected by Notch signaling blocking. Therefore, our findings demonstrate that HBx could promote the growth of human non-tumor hepatic cell line L02 cells both in vitro and in vivo, which may require the activation of Notch signaling pathway.
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Affiliation(s)
- Fan Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
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