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Jia C, Wu H, Yang A, Chen A, Wang X, Ding S, Fan B, Zhou G, Li Z, Chen J. Mechanism Research of QingReJieDu Formula for Treating Hepatitis B Virus Based on Network Pharmacology. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:155915. [PMID: 39550917 DOI: 10.1016/j.phymed.2024.155915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 05/27/2024] [Accepted: 07/25/2024] [Indexed: 11/19/2024]
Abstract
BACKGROUND Hepatitis B virus (HBV) is a DNA virus known to induce hepatitis and liver dysfunction, and is one of the main causes of liver cirrhosis and liver cancer. At present, there lacks a satisfactory optimal treatment plan for HBV in clinical practice, promoting the development of a novel Chinese formula, QingReJieDu Formula (QRJDF), as a potential solution. PURPOSE This study aims to explore the underlying mechanisms of QRJDF in the treatment of Hepatitis B virus (HBV) through a combination of network pharmacology and experimental validation. METHODS/STUDY DESIGN HepG2.2.15 cells were used to study the efficacy of QRJDF against HBV in vitro. Entecavir (ETV) was used as a positive control. Additionally, HBV transgenic mice served as subjects to study the in vivo efficacy of QRJDF against HBV, with serum and tissue samples analyzed post-euthanasia at 12 weeks to observe relevant indicators. UPLC-Q-TOF-MS technology was utilized to obtain the main ingredients in QRJDF. Network pharmacology was used to explore the potential ingredients and targets of QRJDF against HBV. Transcriptome sequencing was used to further explore the potential targets of QRJDF against HBV. Finally, integration of network pharmacology and transcriptomics results facilitated the screening of potential key targets and identification of potential pathways. RESULTS QRJDF demonstrated anti-HBV effects in HepG2.2.15 cells, compared to ETV control, QRJDF was more efficient in inhibiting HBV antigen levels, although it was less efficient in inhibiting HBV DNA level. In addition, the antiviral effect was verified in HBV transgenic mice. Network pharmacology results found three major active anti-HBV ingredients from QRJDF. Network pharmacology and transcriptomics revealed that QRJDF could act on the TGFβ1/Smad4 signaling pathway. CONCLUSION The study comprehensively evaluated the efficacy in vivo and in vitro, and fully confirmed that QRJDF was a potential therapeutic agent for HBV. In addition, the transcriptome technology was verified, and the key targets and approaches of QRJDF against hepatitis B were screened in combination with network pharmacology, which provided research ideas for the follow-up research of antiviral Chinese medicine.
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Affiliation(s)
- Caixia Jia
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Hongxing Wu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Aiqing Yang
- State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, P.R. 100850, China
| | - Aiping Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xueting Wang
- State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, P.R. 100850, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Key Laboratory of Analytical Science and Technology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, Hebei, China
| | - Shuqin Ding
- State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, P.R. 100850, China; College of Life Sciences, Anhui Medical University, Hefei 230032, China
| | - Baofeng Fan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Gangqiao Zhou
- State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, P.R. 100850, China.
| | - Zhihong Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China; Dongzhimen Hospital, Beijing university of Chinese Medicine, No.5 Haiyuncang Hutong, Dongcheng district, Beijing 100700, China.
| | - Jianxin Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
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Li X, Kong D, Hu W, Zheng K, You H, Tang R, Kong F. Insight into the mechanisms regulating liver cancer stem cells by hepatitis B virus X protein. Infect Agent Cancer 2024; 19:56. [PMID: 39529119 PMCID: PMC11555838 DOI: 10.1186/s13027-024-00618-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous disease with high recurrence and mortality. It is well known that a large proportion of HCCs are caused by hepatitis B virus (HBV) infection. In particular, the HBV X protein (HBX), a multifunctional molecule produced by the virus, plays a leading role in hepatocarcinogenesis. However, the molecular mechanisms underlying HBX-mediated HCC remain not fully elucidated. Recently, liver cancer stem cells (LCSCs), a unique heterogeneous subpopulation of the malignancy, have received particular attention owing to their close association with tumorigenesis. Especially, the modulation of LCSCs by HBX by upregulating CD133, CD44, EpCAM, and CD90 plays a significant role in HBV-related HCC development. More importantly, not only multiple signaling pathways, including Wnt/β-catenin signaling, transforming growth factor-β (TGF-β) signaling, phosphatidylinositol-3-kinase (PI-3 K)/AKT signaling, and STAT3 signaling pathways, but also epigenetic regulation, such as DNA and histone methylation, and noncoding RNAs, including lncRNA and microRNA, are discovered to participate in regulating LCSCs mediated by HBX. Here, we summarized the mechanisms underlying different signaling pathways and epigenetic alterations that contribute to the modulation of HBX-induced LCSCs to facilitate hepatocarcinogenesis. Because LCSCs are important in hepatic carcinogenesis, understanding the regulatory factors controlled by HBX might open new avenues for HBV-associated liver cancer treatment.
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Affiliation(s)
- Xiaocui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Delong Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Experimental Animal Center, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wei Hu
- NanJing Drum Tower Hospital Group Suqian Hospital, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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Bayat M, Golestani S, Motlaghzadeh S, Bannazadeh Baghi H, Lalehzadeh A, Sadri Nahand J. War or peace: Viruses and metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189179. [PMID: 39299491 DOI: 10.1016/j.bbcan.2024.189179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 09/04/2024] [Accepted: 09/07/2024] [Indexed: 09/22/2024]
Abstract
Metastasis, the dissemination of malignant cells from a primary tumor to secondary sites, poses a catastrophic burden to cancer treatment and is the predominant cause of mortality in cancer patients. Metastasis as one of the main aspects of cancer progression could be strongly under the influence of viral infections. In fact, viruses have been central to modern cancer research and are associated with a great number of cancer cases. Viral-encoded elements are involved in modulating essential pathways or specific targets that are implicated in different stages of metastasis. Considering the continuous emergence of new viruses and the establishment of their contribution to cancer progression, the warfare between viruses and cancer appears to be endless. Here we aimed to review the critical mechanism and pathways involved in cancer metastasis and the influence of viral machinery and various routes that viruses adopt to manipulate those pathways for their benefit.
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Affiliation(s)
- Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahin Golestani
- Department of ophthalmology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Motlaghzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aidin Lalehzadeh
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Michler T, Zillinger J, Hagen P, Cheng F, Festag J, Kosinska A, Protzer U. The lack of HBsAg secretion does neither facilitate induction of antiviral T cell responses nor Hepatitis B Virus clearance in mice. Antiviral Res 2024; 226:105896. [PMID: 38679167 DOI: 10.1016/j.antiviral.2024.105896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/09/2024] [Accepted: 04/23/2024] [Indexed: 05/01/2024]
Abstract
Immune tolerance to the hepatitis B virus (HBV) is crucial for developing chronic hepatitis B, and the HBV surface antigen (HBsAg) produced and secreted in high amounts is regarded as a key contributor. HBsAg is expressed in HBV-infected hepatocytes and those carrying an HBV integration. Whether either HBsAg secretion or the high antigen amount expressed in the liver determines its immunomodulatory properties, however, remains unclear. We, therefore, developed a novel HBV animal model that allowed us to study the role of secreted HBsAg. We introduced a previously described HBs mutation, C65S, abolishing HBsAg secretion into a replication-competent 1.3-overlength HBV genome and used adeno-associated virus vectors to deliver it to the mouse liver. The AAV-HBV established a carrier state of wildtype and C65S mutant HBV, respectively. We investigated antiviral B- and T-cell immunity in the HBV-carrier mice after therapeutic vaccination. Moreover, we compared the effect of a lacking HBsAg secretion with that of an antiviral siRNA. While missing HBsAg secretion allowed for higher levels of detectable anti-HBs antibodies after therapeutic vaccination, it did neither affect antiviral T-cell responses nor intrahepatic HBV gene expression, irrespective of the starting level. A treatment with HBV siRNA restricting viral antigen expression within hepatocytes, however, improved the antiviral efficacy of therapeutic vaccination, irrespective of the ability of HBV to secrete HBsAg. Our data indicate that clearing HBsAg from blood cannot significantly impact HBV persistence or T-cell immunity. This indicates that a restriction of hepatic viral antigen expression will be required to break HBV immunotolerance.
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Affiliation(s)
- Thomas Michler
- Institute of Virology, School of Medicine and Health, Technical University of Munich / Helmholtz Munich, Germany; Institute of Laboratory Medicine, LMU University Hospital, LMU Munich, Germany
| | - Jakob Zillinger
- Institute of Virology, School of Medicine and Health, Technical University of Munich / Helmholtz Munich, Germany
| | - Philipp Hagen
- Institute of Virology, School of Medicine and Health, Technical University of Munich / Helmholtz Munich, Germany
| | - Fuwang Cheng
- Institute of Virology, School of Medicine and Health, Technical University of Munich / Helmholtz Munich, Germany
| | - Julia Festag
- Institute of Virology, School of Medicine and Health, Technical University of Munich / Helmholtz Munich, Germany; German Center for Infection Research (DZIF), Munich Partner Site, Germany
| | - Anna Kosinska
- Institute of Virology, School of Medicine and Health, Technical University of Munich / Helmholtz Munich, Germany; German Center for Infection Research (DZIF), Munich Partner Site, Germany
| | - Ulrike Protzer
- Institute of Virology, School of Medicine and Health, Technical University of Munich / Helmholtz Munich, Germany; German Center for Infection Research (DZIF), Munich Partner Site, Germany.
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Sabourirad S, Dimitriadis E, Mantamadiotis T. Viruses exploit growth factor mechanisms to achieve augmented pathogenicity and promote tumorigenesis. Arch Microbiol 2024; 206:193. [PMID: 38526562 PMCID: PMC10963461 DOI: 10.1007/s00203-024-03855-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/13/2024] [Accepted: 01/20/2024] [Indexed: 03/26/2024]
Abstract
Cellular homeostasis is regulated by growth factors (GFs) which orchestrate various cellular processes including proliferation, survival, differentiation, motility, inflammation and angiogenesis. Dysregulation of GFs in microbial infections and malignancies have been reported previously. Viral pathogens exemplify the exploitation of host cell GFs and their signalling pathways contributing to viral entry, virulence, and evasion of anti-viral immune responses. Viruses can also perturb cellular metabolism and the cell cycle by manipulation of GF signaling. In some cases, this disturbance may promote oncogenesis. Viral pathogens can encode viral GF homologues and induce the endogenous biosynthesis of GFs and their corresponding receptors or manipulate their activity to infect the host cells. Close investigation of how viral strategies exploit and regulate GFs, a will shed light on how to improve anti-viral therapy and cancer treatment. In this review, we discuss and provide insights on how various viral pathogens exploit different GFs to promote viral survival and oncogenic transformation, and how this knowledge can be leveraged toward the design of more efficient therapeutics or novel drug delivery systems in the treatment of both viral infections and malignancies.
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Affiliation(s)
- Sarvenaz Sabourirad
- Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia.
| | - Evdokia Dimitriadis
- Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia
- Gynaecology Research Centre, Royal Women's Hospital, Parkville, VIC, Australia
- Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Theo Mantamadiotis
- Department of Surgery RMH, The University of Melbourne, Parkville, Australia
- Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia
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Ding S, Liu H, Liu L, Ma L, Chen Z, Zhu M, Liu L, Zhang X, Hao H, Zuo L, Yang J, Wu X, Zhou P, Huang F, Zhu F, Guan W. Epigenetic addition of m 5C to HBV transcripts promotes viral replication and evasion of innate antiviral responses. Cell Death Dis 2024; 15:39. [PMID: 38216565 PMCID: PMC10786922 DOI: 10.1038/s41419-023-06412-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 12/17/2023] [Accepted: 12/21/2023] [Indexed: 01/14/2024]
Abstract
Eukaryotic five-methylcytosine (m5C) is an important regulator of viral RNA splicing, stability, and translation. However, its role in HBV replication remains largely unknown. In this study, functional m5C sites are identified in hepatitis B virus (HBV) mRNA. The m5C modification at nt 1291 is not only indispensable for Aly/REF export factor (ALYREF) recognition to promote viral mRNA export and HBx translation but also for the inhibition of RIG-I binding to suppress interferon-β (IFN-β) production. Moreover, NOP2/Sun RNA methyltransferase 2 (NSUN2) catalyzes the addition of m5C to HBV mRNA and is transcriptionally downregulated by the viral protein HBx, which suppresses the binding of EGR1 to the NSUN2 promoter. Additionally, NSUN2 expression correlates with m5C modification of type I IFN mRNA in host cells, thus, positively regulating IFN expression. Hence, the delicate regulation of NSUN2 expression induces m5C modification of HBV mRNA while decreasing the levels of m5C in host IFN mRNA, making it a vital component of the HBV life cycle. These findings provide new molecular insights into the mechanism of HBV-mediated IFN inhibition and may inform the development of new IFN-α based therapies.
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Affiliation(s)
- Shuang Ding
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, 430071, China
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China
| | - Haibin Liu
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China
- Hubei JiangXia Laboratory, Wuhan, Hubei, 430200, China
| | - Lijuan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, 430071, China
| | - Li Ma
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China
| | - Zhen Chen
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China
| | - Miao Zhu
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China
| | - Lishi Liu
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China
| | - Xueyan Zhang
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China
| | - Haojie Hao
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China
| | - Li Zuo
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China
| | - Jingwen Yang
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China
| | - Xiulin Wu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, 430071, China
| | - Ping Zhou
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, 430071, China
| | - Fang Huang
- Hubei JiangXia Laboratory, Wuhan, Hubei, 430200, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, 430071, China.
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan, Hubei, 430071, China.
| | - Wuxiang Guan
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430207, China.
- Hubei JiangXia Laboratory, Wuhan, Hubei, 430200, China.
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Shen L, Yin H, Sun L, Zhang Z, Jin Y, Cao S, Fu Q, Fan C, Bao C, Lu L, Zhan Y, Xu X, Chen X, Yan Q. Iguratimod attenuated fibrosis in systemic sclerosis via targeting early growth response 1 expression. Arthritis Res Ther 2023; 25:151. [PMID: 37596660 PMCID: PMC10439582 DOI: 10.1186/s13075-023-03135-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 08/02/2023] [Indexed: 08/20/2023] Open
Abstract
BACKGROUND The early growth response 1 (EGR1) is a central transcription factor involved in systemic sclerosis (SSc) pathogenesis. Iguratimod is a synthesized anti-rheumatic disease-modifying drug, which shows drastic inhibition to EGR1 expression in B cells. This study is aiming to investigate the anti-fibrotic effect of iguratimod in SSc. METHODS EGR1 was detected by immunofluorescence staining real-time PCR or western blot. Iguratimod was applied in EGR1 overexpressed or knockdown human dermal fibroblast, bleomycin pre-treated mice, tight skin 1 mice, and SSc skin xenografts. RNA sequencing was performed in cultured fibroblast and xenografts to identify the iguratimod regulated genes. RESULTS EGR1 overexpressed predominantly in non-immune cells of SSc patients. Iguratimod reduced EGR1 expression in fibroblasts and neutralized changes of EGR1 response genes regulated by TGFβ. The extracellular matrix (ECM) production and activation of fibroblasts were attenuated by iguratimod while EGR1 overexpression reversed this effect of iguratimod. Iguratimod ameliorated the skin fibrosis induced by bleomycin and hypodermal fibrosis in TSK-1 mice. Decreasing in the collagen content as well as the density of EGR1 or TGFβ positive fibroblasts of skin xenografts from naïve SSc patients was observed after local treatment of iguratimod. CONCLUSION Targeting EGR1 expression is a probable underlying mechanism for the anti-fibrotic effect of iguratimod.
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Affiliation(s)
- Lichong Shen
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Hanlin Yin
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Li Sun
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhiliang Zhang
- Department of Plastic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Yuyang Jin
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Shan Cao
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Qiong Fu
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Chaofan Fan
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Chunde Bao
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Liangjing Lu
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Yifan Zhan
- Department of Drug Discovery, Shanghai Huaota Biopharm, Shanghai, 201203, China
| | - Xiaojiang Xu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
| | - Xiaoxiang Chen
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
- Department of Rheumatology, Nantong First People's Hospital, Affiliated Hospital 2 of Nantong Universuty, Nantong Hospital of Renji Hospital Affiliated to Shanghai Jiao Tong Universuty School of Medicine, Nantong, 226006, China.
| | - Qingran Yan
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
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Korbecki J, Bosiacki M, Barczak K, Łagocka R, Chlubek D, Baranowska-Bosiacka I. The Clinical Significance and Role of CXCL1 Chemokine in Gastrointestinal Cancers. Cells 2023; 12:1406. [PMID: 37408240 DOI: 10.3390/cells12101406] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/09/2023] [Accepted: 05/15/2023] [Indexed: 07/07/2023] Open
Abstract
One area of cancer research is the interaction between cancer cells and immune cells, in which chemokines play a vital role. Despite this, a comprehensive summary of the involvement of C-X-C motif ligand 1 (CXCL1) chemokine (also known as growth-regulated gene-α (GRO-α), melanoma growth-stimulatory activity (MGSA)) in cancer processes is lacking. To address this gap, this review provides a detailed analysis of CXCL1's role in gastrointestinal cancers, including head and neck cancer, esophageal cancer, gastric cancer, liver cancer (hepatocellular carcinoma (HCC)), cholangiocarcinoma, pancreatic cancer (pancreatic ductal adenocarcinoma), and colorectal cancer (colon cancer and rectal cancer). This paper presents the impact of CXCL1 on various molecular cancer processes, such as cancer cell proliferation, migration, and invasion, lymph node metastasis, angiogenesis, recruitment to the tumor microenvironment, and its effect on immune system cells, such as tumor-associated neutrophils (TAN), regulatory T (Treg) cells, myeloid-derived suppressor cells (MDSCs), and macrophages. Furthermore, this review discusses the association of CXCL1 with clinical aspects of gastrointestinal cancers, including its correlation with tumor size, cancer grade, tumor-node-metastasis (TNM) stage, and patient prognosis. This paper concludes by exploring CXCL1's potential as a therapeutic target in anticancer therapy.
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Affiliation(s)
- Jan Korbecki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
- Department of Anatomy and Histology, Collegium Medicum, University of Zielona Góra, Zyty 28 St., 65-046 Zielona Góra, Poland
| | - Mateusz Bosiacki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
- Department of Functional Diagnostics and Physical Medicine, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, Żołnierska 54 Str., 71-210 Szczecin, Poland
| | - Katarzyna Barczak
- Department of Conservative Dentistry and Endodontics, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Ryta Łagocka
- Department of Conservative Dentistry and Endodontics, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
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You H, Wang X, Ma L, Zhang F, Zhang H, Wang Y, Pan X, Zheng K, Kong F, Tang R. Insights into the impact of hepatitis B virus on hepatic stellate cell activation. Cell Commun Signal 2023; 21:70. [PMID: 37041599 PMCID: PMC10088164 DOI: 10.1186/s12964-023-01091-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/26/2023] [Indexed: 04/13/2023] Open
Abstract
During chronic hepatitis B virus (HBV) infection, hepatic fibrosis is a serious pathological condition caused by virus-induced liver damage. The activation of hepatic stellate cells (HSCs) is a central event in the occurrence and progression of liver fibrosis. Although accumulating evidence has shown that HBV directly stimulates HSC activation, whether the virus infects and replicates in HSCs remains controversial. Inflammation is one of the obvious characteristics of chronic HBV infection, and it has been demonstrated that persistent inflammation has a predominant role in triggering and maintaining liver fibrosis. In particular, the regulation of HSC activation by HBV-related hepatocytes via various inflammatory modulators, including TGF-β and CTGF, in a paracrine manner has been reported. In addition to these inflammation-related molecules, several inflammatory cells are essential for the progression of HBV-associated liver fibrosis. Monocytes, macrophages, Th17 cells, NK cells, as well as NKT cells, participate in the modulation of HBV-related liver fibrosis by interacting with HSCs. This review summarizes current findings on the effects of HBV and the relevant molecular mechanisms involved in HSC activation. Because HSC activation is essential for liver fibrosis, targeting HSCs is an attractive therapeutic strategy to prevent and reverse hepatic fibrosis induced by HBV infection. Video abstract.
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Affiliation(s)
- Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xing Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Lihong Ma
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fulong Zhang
- Imaging Department, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Huanyang Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yuxin Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiucheng Pan
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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Wei Q, Liu S, Huang X, Xin H, Ding J. Immunologically effective biomaterials-enhanced vaccines against infection of pathogenic microorganisms. BIOSAFETY AND HEALTH 2023; 5:45-61. [PMID: 40078604 PMCID: PMC11894984 DOI: 10.1016/j.bsheal.2022.11.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 11/27/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022] Open
Abstract
Infectious diseases are severe public health events that threaten global health. Prophylactic vaccines have been considered as the most effective strategy to train the immune system to recognize and clear pathogenic infections. However, the existing vaccines against infectious diseases have several limitations, such as difficulties in mass manufacturing and storage, weak immunogenicity, and low efficiency of available adjuvants. Biomaterials, especially functional polymers, are expected to break through these bottlenecks based on the advantages of biocompatibility, degradability, controlled synthesis, easy modification, precise targeting, and immune modulation, which are excellent carriers and adjuvants of vaccines. This review mainly summarizes the application of immunologically effective polymers-enhanced vaccines against viruses- and bacteria-related infectious diseases and predicted their potential improvements.
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Affiliation(s)
- Qi Wei
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China
| | - Shixian Liu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China
| | - Xu Huang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
| | - Hua Xin
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
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11
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The Importance of CXCL1 in the Physiological State and in Noncancer Diseases of the Oral Cavity and Abdominal Organs. Int J Mol Sci 2022; 23:ijms23137151. [PMID: 35806156 PMCID: PMC9266754 DOI: 10.3390/ijms23137151] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/23/2022] [Accepted: 06/25/2022] [Indexed: 02/06/2023] Open
Abstract
CXCL1 is a CXC chemokine, CXCR2 ligand and chemotactic factor for neutrophils. In this paper, we present a review of the role of the chemokine CXCL1 in physiology and in selected major non-cancer diseases of the oral cavity and abdominal organs (gingiva, salivary glands, stomach, liver, pancreas, intestines, and kidneys). We focus on the importance of CXCL1 on implantation and placentation as well as on human pluripotent stem cells. We also show the significance of CXCL1 in selected diseases of the abdominal organs, including the gastrointestinal tract and oral cavity (periodontal diseases, periodontitis, Sjögren syndrome, Helicobacter pylori infection, diabetes, liver cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), HBV and HCV infection, liver ischemia and reperfusion injury, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), obesity and overweight, kidney transplantation and ischemic-reperfusion injury, endometriosis and adenomyosis).
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12
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Transforming growth factor-β: An early predictor of a functional cure in chronic hepatitis B treated with interferon. Virus Res 2021; 309:198657. [PMID: 34919970 DOI: 10.1016/j.virusres.2021.198657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/07/2021] [Accepted: 12/11/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND The relationship between the serum transforming growth factor (TGF)-β level and HBsAg loss has not been clearly elaborated in patients with chronic hepatitis B (CHB). METHODS Two cohorts of patients with CHB were studied. Cohort A: A total of 207 hepatitis B e antigen (HBeAg)-negative CHB patients who finished ≥1 year nucleos(t)ide analogue monotherapy and sequentially received PEGylated interferon treatment for less than 96 weeks were included. Cohort B: Forty HBeAg-positive patients who initially received entecavir therapy for at least 96 weeks were included. Their viral markers and serum TGF-β levels were measured at different time points during therapy. RESULTS The levels of serum TGF-β and HBsAg (0-24 W) were significantly lower in the patients who had HBsAg< 0.05 IU/mL at 48 weeks than in patients who did not in cohort A. We got the same results when we further divided the patients into subgroups according to the initial HBsAg cut-off values (1000 IU/mL, 100 IU/mL, 50 IU/mL) in cohort A. However, HBeAg seroconversion did not lead to the downregulation of TGF-β levels. The levels of serum TGF-β were significantly correlated with HBsAg quantitation in cohort A (12-24 W) but not in cohort B (0-48 W). The levels of TGF-β at week 12 could be used as an early index to predict a functional cure (AUC=0.818) as well as the levels of HBsAg itself (AUC=0.882) in HBeAg-negative chronic hepatitis B patients treated with PEGylated interferon. CONCLUSIONS The levels of serum TGF-β were significantly associated with HBsAg loss but not with HBeAg seroconversion and could be used as an early index to predict a functional cure in CHB patients treated with PEGylated interferon.
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13
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DTNA promotes HBV-induced hepatocellular carcinoma progression by activating STAT3 and regulating TGFβ1 and P53 signaling. Life Sci 2020; 258:118029. [PMID: 32619495 DOI: 10.1016/j.lfs.2020.118029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/16/2020] [Accepted: 06/26/2020] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Hepatitis B virus (HBV) infection causes liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) development, but the underlying mechanism remains poorly understood. This study aimed to investigate the roles and molecular mechanisms of Dystrobrevin-α (DTNA) in HBV-induced liver cirrhosis and HCC pathogenesis. METHODS DTNA expression was bioinformatically analyzed using the GEO database. DTNA expression was silenced by transfection with shRNAs. Cell proliferation and apoptosis were evaluated by MTT and flow cytometry respectively. The expression of genes in mRNA or protein levels was assessed by quantitative RT-PCR and western blotting. The interaction between proteins was predicted with the String and GCBI online softwares, and then confirmed by co-immunoprecipitation. Animal models were established by injecting nude mice with AVV8-HBV1.3 vector. RESULTS Bioinformatics analysis showed a significantly increase in DTNA expression in HBV-positive liver cirrhosis and HCC patients. HBV infection caused a significantly increase in DTNA expression in HCC cell lines HepAD38 and HepG2.2.15. DTNA knockdown suppressed proliferation and promoted apoptosis of HBV-infected HepAD38 and HepG2.2.15 cells. HBV induced elevated expression of fibrosis-related genes Collagen II and TGFβ1 in LO-2 cells, which were suppressed by DTNA knockdown. DTNA directly binded with STAT3 protein to promote STAT3 phosphorylation and TGFβ1 expression and repress P53 expression in HBV-infected HepAD38 and LO-2 cells. The DTNA/STAT3 axis was activated during HBV-induced fibrosis, cirrhosis and HCC development in mouse model. CONCLUSION DTNA binds with and further activates STAT3 to induce TGFβ1 expression and repress P53 expression, thus promoting HBV-induced liver fibrosis, cirrhosis and hepatocellular carcinoma progression.
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14
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Gowripalan A, Abbott CR, McKenzie C, Chan WS, Karupiah G, Levy L, Newsome TP. Cell-to-cell spread of vaccinia virus is promoted by TGF-β-independent Smad4 signalling. Cell Microbiol 2020; 22:e13206. [PMID: 32237038 DOI: 10.1111/cmi.13206] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 02/02/2020] [Accepted: 02/19/2020] [Indexed: 12/19/2022]
Abstract
The induction of Smad signalling by the extracellular ligand TGF-β promotes tissue plasticity and cell migration in developmental and pathological contexts. Here, we show that vaccinia virus (VACV) stimulates the activity of Smad transcription factors and expression of TGF-β/Smad-responsive genes at the transcript and protein levels. Accordingly, infected cells share characteristics to those undergoing TGF-β/Smad-mediated epithelial-to-mesenchymal transition (EMT). Depletion of the Smad4 protein, a common mediator of TGF-β signalling, results in an attenuation of viral cell-to-cell spread and reduced motility of infected cells. VACV induction of TGF-β/Smad-responsive gene expression does not require the TGF-β ligand or type I and type II TGF-β receptors, suggesting a novel, non-canonical Smad signalling pathway. Additionally, the spread of ectromelia virus, a related orthopoxvirus that does not activate a TGF-β/Smad response, is enhanced by the addition of exogenous TGF-β. Together, our results indicate that VACV orchestrates a TGF-β-like response via a unique activation mechanism to enhance cell migration and promote virus spread.
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Affiliation(s)
- Anjali Gowripalan
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia
| | - Caitlin R Abbott
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia
| | - Christopher McKenzie
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia
| | - Weng S Chan
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia
| | - Gunasegaran Karupiah
- Tasmanian School of Medicine, The University of Tasmania, Hobart, Tasmania, Australia
| | - Laurence Levy
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France
| | - Timothy P Newsome
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia
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15
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Dong KS, Chen Y, Yang G, Liao ZB, Zhang HW, Liang HF, Chen XP, Dong HH. TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p. Oncogene 2019; 39:1807-1820. [PMID: 31740785 PMCID: PMC7033045 DOI: 10.1038/s41388-019-1107-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 10/29/2019] [Accepted: 11/06/2019] [Indexed: 12/25/2022]
Abstract
Increasing evidence has suggested that liver cancer arises partially from transformed hepatic progenitor cells (HPCs). However, the detailed mechanisms underlying HPC transformation are poorly understood. In this study, we provide evidence linking the coexistence of hepatitis B virus X protein (HBx) and transforming growth factor beta 1 (TGF-β1) with miR-199a-3p in the malignant transformation of HPCs. The examination of liver cancer specimens demonstrated that HBx and TGF-β1 expression was positively correlated with epithelial cell adhesion molecule (EpCAM) and cluster of differentiation 90 (CD90). Importantly, EpCAM and CD90 expression was much higher in the specimens expressing both high HBx and high TGF-β1 than in those with high HBx or high TGF-β1 and the double-low-expression group. HBx and TGF-β1 double-high expression was significantly associated with poor prognosis in primary liver cancer. We also found that HBx and TGF-β1 induced the transformation of HPCs into hepatic cancer stem cells and promoted epithelial–mesenchymal transformation, which was further enhanced by concomitant HBx and TGF-β1 exposure. Moreover, activation of the c-Jun N-terminal kinase (JNK)/c-Jun pathway was involved in the malignant transformation of HPCs. miR-199a-3p was identified as a significantly upregulated microRNA in HPCs upon HBx and TGF-β1 exposure, which were shown to promote miR-199a-3p expression via c-Jun-mediated activation. Finally, we found that miR-199a-3p was responsible for the malignant transformation of HPCs. In conclusion, our results provide evidence that TGF-β1 cooperates with HBx to promote the malignant transformation of HPCs through a JNK/c-Jun/miR-199a-3p-dependent pathway. This may open new avenues for therapeutic interventions targeting the malignant transformation of HPCs in treating liver cancer.
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Affiliation(s)
- Ke-Shuai Dong
- Hepatic Surgery Center, Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Hepatobiliary and Laparoscopic Surgery, Renmin Hospital, Wuhan University, Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Yan Chen
- Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guang Yang
- Hepatic Surgery Center, Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi-Bin Liao
- Hepatic Surgery Center, Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong-Wei Zhang
- Hepatic Surgery Center, Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui-Fang Liang
- Hepatic Surgery Center, Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han-Hua Dong
- Hepatic Surgery Center, Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Mirzaei H, Faghihloo E. Viruses as key modulators of the TGF-β pathway; a double-edged sword involved in cancer. Rev Med Virol 2018; 28:e1967. [PMID: 29345394 PMCID: PMC7169117 DOI: 10.1002/rmv.1967] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 12/11/2017] [Accepted: 12/12/2017] [Indexed: 12/12/2022]
Abstract
Transforming growth factor-β (TGF-β) signaling pathway is a key network in cell signaling that controls vital processes such as proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and migration, thus acting as a double-edged sword in normal development and diseases, in particular organ fibrosis, vascular disorders, and cancer. Early in tumorigenesis, the pathway exerts anti-tumor effects through suppressing cell cycle and inducing apoptosis, while during late stages, it functions as a tumor promoter by enhancing tumor invasiveness and metastasis. This signaling pathway can be perturbed by environmental and genetic factors such as microbial interference and mutation, respectively. In this way, the present review describes the modulation of the TGF-β pathway by oncogenic human viral pathogens and other viruses. The main mechanisms by which viruses interferes with TGF-β signaling seems to be through (1) the alteration of either TGF-β protein expression or activation, (2) the modulation of the TGF-β receptors or SMADs factors (by interfering with their levels and functions), (3) the alteration of none-SMAD pathways, and (4) indirect interaction with the pathway by the modulation of transcriptional co-activator/repressor and regulators of the pathway. Given the axial role of this pathway in tumorigenesis, it can be regarded as an attractive target for cancer therapy. Hence, further investigations on this subject may represent molecular targets among either TGF-β signaling molecules or viral factors for the treatment and management of viral infection consequences such as cancer.
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Affiliation(s)
- Habibollah Mirzaei
- Department of Virology, School of MedicineAhvaz Jundishapur University of Medical SciencesAhvazIran
- Hepatitis Research CenterLorestan University of Medical SciencesKhorramabadIRIran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
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17
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Liver regeneration microenvironment of hepatocellular carcinoma for prevention and therapy. Oncotarget 2018; 8:1805-1813. [PMID: 27655683 PMCID: PMC5352100 DOI: 10.18632/oncotarget.12101] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 09/12/2016] [Indexed: 02/06/2023] Open
Abstract
Research on liver cancer prevention and treatment has mainly focused on the liver cancer cells themselves. Currently, liver cancers are no longer viewed as only collections of genetically altered cells but as aberrant organs with a plastic stroma, matrix, and vasculature. Improving the microenvironment of the liver to promote liver regeneration and repair by affecting immune function, inflammation and vasculature can regulate the dynamic imbalance between normal liver regeneration and repair and abnormal liver regeneration, thus improving the microenvironment of liver regeneration for the prevention and treatment of liver cancer. This review addresses the basic theory of the liver regeneration microenvironment, including the latest findings on immunity, inflammation and vasculature. Attention is given to the potential design of molecular targets in the microenvironment of hepatocellular carcinoma (HCC). In an effort to improve the liver regeneration microenvironment of HCC, researchers have extensively utilized the enhancement of immunity, anti-inflammation and the vasculature niche, which are discussed in detail in this review. In addition, the authors summarize the latest pro-fibrotic transition characteristics of the vascular niche and review potential cell therapies for liver disease.
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18
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Pan X, Zhu F, Li G, Cao H, Liu J. HBx induces expression of CTGF in the transfected hepatoma cell line HepG2. Future Virol 2018. [DOI: 10.2217/fvl-2017-0095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: To investigate the effect of HBx on CTGF expression by hepatocytes. Materials & methods: HepG2 cells were transfected with the full-length gene of HBV, HBV protein-expressing plasmids, rhTGFβ1, LY2109761 or Smad2 siRNA, respectively, using Lipofectamine 3000. CTGF expression was detected by real-time PCR, ELISA, respectively. Then the effect of IL-32 on CTGF promoter was assayed by the Dual Luciferase® Reporter Assay System. Results: We found that HBx could induce CTGF expression by HepG2 cells in a concentration-dependent manner. CTGF expression induced by HBx employed the activation of TGFβ1-Smad2 signal pathway. Inhibition of TGFβ1 or Smad2 decreased CTGF expression induced by HBx. Conclusion: HBV might be involved in the pathogenesis of liver fibrosis through the HBx-induced CTGF expression.
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Affiliation(s)
- Xingfei Pan
- Department of Infectious Diseases, the 3rd Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Fengqin Zhu
- Department of Gastroenterology, the Affiliated Hospital of Jining Medical University, Jining 272000, China
| | - Gang Li
- Department of Infectious Diseases, the 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
| | - Hong Cao
- Department of Gastroenterology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Jing Liu
- Department of Gastroenterology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
- Hubei Provincial Key Laboratory of Bowel Disease, Wuhan 430071, China
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19
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Teng CF, Wu HC, Shyu WC, Jeng LB, Su IJ. Pre-S2 Mutant-Induced Mammalian Target of Rapamycin Signal Pathways as Potential Therapeutic Targets for Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cell Transplant 2017; 26:429-438. [PMID: 28195035 PMCID: PMC5657708 DOI: 10.3727/096368916x694382] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/06/2017] [Indexed: 12/15/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Pre-S2 mutant represents an HBV oncoprotein that is accumulated in the endoplasmic reticulum (ER) and manifests as type II ground glass hepatocytes (GGHs). Pre-S2 mutant can induce ER stress and initiate multiple ER stress-dependent or -independent cellular signal pathways, leading to growth advantage of type II GGH. Importantly, the mammalian target of rapamycin (mTOR) signal pathways are consistently activated throughout the liver tumorigenesis in pre-S2 mutant transgenic mice and in human HCC tissues, leading to hepatocyte proliferation, metabolic disorders, and HCC tumorigenesis. In this review, we summarize the pre-S2 mutant-induced mTOR signal pathways and its implications in HBV-related HCC tumorigenesis. Clinically, the presence of pre-S2 mutant exhibits a high resistance to antiviral treatment and carries a high risk of HCC development in patients with chronic HBV infection. Targeting at pre-S2 mutant-induced mTOR signal pathways may thus provide potential strategies for the prevention or therapy of HBV-associated HCC.
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Affiliation(s)
- Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan
| | - Han-Chieh Wu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan
| | - Woei-Cherng Shyu
- Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
| | - Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan
| | - Ih-Jen Su
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
- Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan
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20
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Chen S, Dong Z, Yang P, Wang X, Jin G, Yu H, Chen L, Li L, Tang L, Bai S, Yan H, Shen F, Cong W, Wen W, Wang H. Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis. Cancer Lett 2017; 394:22-32. [PMID: 28216372 DOI: 10.1016/j.canlet.2017.02.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2016] [Revised: 01/17/2017] [Accepted: 02/10/2017] [Indexed: 12/20/2022]
Abstract
Hepatitis B virus X protein (HBx) plays an important role in the progression of hepatocellular carcinoma. Here we reported that overexpression of HBx in hepatocellular carcinoma (HCC) cells could induce the secretion of high-mobility group box 1 (HMGB1) to promote invasion and metastasis of HCC in an autocrine/paracrine manner. HBx triggered an increase of cytoplasmic calcium and activated CAMKK/CAMKIV pathway, leading to subsequent translocation and release of HMGB1. HMGB1 neutralizing antibody, as well as calcium chelator or inhibitors of CAMKK/CAMKIV, could remarkably reduce invasion and metastasis of HCC cells in vitro and in a murine HCC metastasis model in vivo. Furthermore, the level of HMGB1 in patient serum and tumor tissues was positively correlated with HBV DNA load. We demonstrate an inverse relationship between HMGB1 in tumor cytoplasm and overall prognosis of HCC patients. CONCLUSION HBx promotes the progression of HCC through translocation and secretion of HMGB1 from tumor cells via calcium dependent cascades. These data indicates that HMGB1 could serve as a novel prognostic biomarker and potential therapeutic target for HBV-related HCC.
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Affiliation(s)
- Shuzhen Chen
- National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Zihui Dong
- National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Pinghua Yang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xianming Wang
- National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Guangzhi Jin
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Han Yu
- National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Lei Chen
- National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Liang Li
- National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Liang Tang
- National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Shilei Bai
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hexin Yan
- National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Feng Shen
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wenming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wen Wen
- National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
| | - Hongyang Wang
- National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China; Ministry of Education (MOE) Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Second Military Medical University, Shanghai, China.
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Zhang X, Lv L, Ouyang X, Zhang S, Fang J, Cai L, Li D. Association of TIP30 expression and prognosis of hepatocellular carcinoma in patients with HBV infection. Cancer Med 2016; 5:2180-9. [PMID: 27418384 PMCID: PMC5055146 DOI: 10.1002/cam4.728] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 03/09/2016] [Accepted: 03/12/2016] [Indexed: 12/30/2022] Open
Abstract
Altered expression of TIP30, a tumor suppressor, has been observed in many cancers. In this study, we have evaluated the expression of TIP30 in the tissues of 209 hepatocellular carcinomas (HCC) and their adjacent tissues by using a high‐density tissue microarray, and analyzed its correlation with the clinical pathological parameters of the patients. The results revealed negative or weak expression of TIP30 in 43.5% (91/209) of the HCC tissues, and in only 27% (56/209) of the adjacent tissues. The expression level of TIP30 in HCC was inversely correlated with serum alpha‐fetoprotein (AFP) levels, HBV infection, and tumor differentiation. Multivariate analysis for survival indicated that serum HBV infection was the most significant predictor of poor prognosis in HCC (P = 0.0023), and TIP30 expression and tumor differentiation were also independent indicators in this respect (P = 0.0364 and P = 0.0397, respectively). Patients with medium or high expression levels of TIP30 (TIP30++/+++) had a better 5‐year overall survival rate than those with low/negative (TIP30+/−) expression (P < 0.001). TIP30+/−/HBV+ patients had the worst 5‐year overall survival rate, whereas TIP30++/+++/HBV− patients had the best. To further explore the correlation between TIP30 and HBV infection in HCC, HBV+ hepatoblastoma cell‐line HepG2 2.2.15 and HCC cell‐line Hep3B were used. Upon silencing of HBV, we observed an upregulation of TIP30 and decreased cell proliferation. In the in vivo studies, we found that the mice inoculated with HepG2 2.2.15 cells with HBV silencing had a prolonged tumor latency and a longer life span, as compared to the control mice inoculated with untreated control cells. In conclusion, the results suggest that downregulation of TIP30 may result from HBV infection, and subsequently promotes the progression of HCC.
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Affiliation(s)
- Xia Zhang
- Department of Hepatology, Fuzhou General Hospital, Nanjing Command, Fuzhou 350025, China
| | - Lizhi Lv
- Department of Hepatobiliary Surgery, Fuzhou General Hospital, Nanjing Command, Fuzhou 350025, China
| | - Xuenong Ouyang
- Department of Oncology, Fuzhou General Hospital, Nanjing Command, Fuzhou 350025, China
| | - Shi'an Zhang
- Department of Hepatology, Fuzhou General Hospital, Nanjing Command, Fuzhou 350025, China
| | - Jian Fang
- Department of Hepatology, Fuzhou General Hospital, Nanjing Command, Fuzhou 350025, China
| | - Lirong Cai
- Department of Hepatology, Fuzhou General Hospital, Nanjing Command, Fuzhou 350025, China
| | - Dongliang Li
- Department of Hepatology, Fuzhou General Hospital, Nanjing Command, Fuzhou 350025, China.
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22
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Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol 2016; 64:S84-S101. [PMID: 27084040 DOI: 10.1016/j.jhep.2016.02.021] [Citation(s) in RCA: 676] [Impact Index Per Article: 75.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 02/17/2016] [Accepted: 02/17/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) development through direct and indirect mechanisms. HBV DNA integration into the host genome occurs at early steps of clonal tumor expansion and induces both genomic instability and direct insertional mutagenesis of diverse cancer-related genes. Prolonged expression of the viral regulatory protein HBx and/or altered versions of the preS/S envelope proteins dysregulates cell transcription and proliferation control and sensitizes liver cells to carcinogenic factors. Accumulation of preS1 large envelope proteins and/or preS2/S mutant proteins activates the unfold proteins response, that can contribute to hepatocyte transformation. Epigenetic changes targeting the expression of tumor suppressor genes occur early in the development of HCC. A major role is played by the HBV protein, HBx, which is recruited on cellular chromatin and modulates chromatin dynamics at specific gene loci. Compared with tumors associated with other risk factors, HBV-related tumors have a higher rate of chromosomal alterations, p53 inactivation by mutations and overexpression of fetal liver/hepatic progenitor cells genes. The WNT/β-catenin pathway is also often activated but HBV-related tumors display a low rate of activating β-catenin mutations. HBV-related HCCs may arise on non-cirrhotic livers, further supporting the notion that HBV plays a direct role in liver transformation by triggering both common and etiology specific oncogenic pathways in addition to stimulating the host immune response and driving liver chronic necro-inflammation.
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Affiliation(s)
- Massimo Levrero
- Cancer Research Center of Lyon (CRCL) - INSERM U1052, Lyon, France; IIT Centre for Life Nanoscience (CLNS), Rome, Italy; Dept of Internal Medicine (DMISM), Sapienza University, Rome, Italy.
| | - Jessica Zucman-Rossi
- Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France; Université Paris Diderot, Paris, France.
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23
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Maina EK, Abana CZ, Bukusi EA, Sedegah M, Lartey M, Ampofo WK. Plasma concentrations of transforming growth factor beta 1 in non-progressive HIV-1 infection correlates with markers of disease progression. Cytokine 2016; 81:109-16. [PMID: 26986868 DOI: 10.1016/j.cyto.2016.02.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 02/17/2016] [Accepted: 02/18/2016] [Indexed: 12/15/2022]
Abstract
The human immunodeficiency virus (HIV) infection shows variable rate of disease progression. The underlying biological and molecular mechanisms involved in determining progression of HIV infection are not fully understood. The aims of this study were to determine plasma concentrations of active TGF β 1, Th1 and Th2 cytokines in patients with non-progressive and those with progressive HIV-1 infection, as well as to determine if there is an association of these cytokines to disease progression. In a cross-sectional study of 61 HIV-1 infected individuals categorized according to disease progression as having non-progressive HIV-1 infection (n=14) and progressive infection (n=47), plasma levels of active TGF β 1, INF-γ, TNF-α, IL-10, IL-1β, IL-12p70 and IL-13 were compared with HIV uninfected healthy controls (n=12). Plasma concentration of these cytokines was measured using a highly sensitive luminex200 XMAP assay. Pearson correlation test was used to assess the correlation of cytokines with CD4+ and CD8+ T cells, CD4:CD8 ratio and plasma HIV-1 RNA in the different study groups. Plasma concentrations of TGF β 1 and IL-10 were significantly decreased while IL-1β, IL-12p70 and TNF-α were increased in patients with non-progressive HIV-1 infection compared to patients with progressive infection. Plasma levels of TGF β 1 and IL-10 showed an inverse correlation with CD8+ T cell counts and CD4:CD8 ratios in patients with non-progressive HIV-1 infection, while plasma HIV-1 RNA positively correlated with CD4+ T cell counts. Plasma levels of TNF-α, IL-1β, IL-12p70 and IL-13 positively correlated with CD4+ T cell counts and inversely correlated with plasma HIV-1 RNA, CD8+ T cell count and CD4:CD8 ratio in patients with non-progressive infection. The correlation of cytokines to the state of T-lymphocyte and plasma HIV-1 RNA found in this study may provide insight into the role of cytokines in both progressive and non-progressive HIV-1 infection. Additionally, these findings may have implications for systemic cytokine-based therapies in HIV-1 infection.
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Affiliation(s)
- Edward K Maina
- Department of Virology, Noguchi Memorial Institute for Medical Research, College of Health Sciences (CHS), University of Ghana, Ghana; Centre for Microbiology Research, Kenya Medical Research Institute, Kenya.
| | - C Z Abana
- Department of Virology, Noguchi Memorial Institute for Medical Research, College of Health Sciences (CHS), University of Ghana, Ghana
| | - E A Bukusi
- Centre for Microbiology Research, Kenya Medical Research Institute, Kenya
| | - M Sedegah
- Malaria Program, Naval Medical Research Centre, USA
| | - M Lartey
- Department of Medicine, School of Medicine & Dentistry, CHS, University of Ghana, Ghana
| | - W K Ampofo
- Department of Virology, Noguchi Memorial Institute for Medical Research, College of Health Sciences (CHS), University of Ghana, Ghana
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24
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Guerrieri F, Belloni L, Pediconi N, Levrero M. Pathobiology of Hepatitis B Virus-Induced Carcinogenesis. ACTA ACUST UNITED AC 2016. [DOI: 10.1007/978-3-319-22330-8_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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25
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Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis. Sci Rep 2015; 5:16552. [PMID: 26559755 PMCID: PMC4642271 DOI: 10.1038/srep16552] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 10/15/2015] [Indexed: 02/07/2023] Open
Abstract
Activation of hepatic stellate cells (HSCs) by transforming growth factor-β1 (TGF-β1) initiates HBV-associated fibrogenesis. The mechanism of TGF-β1 modulating HSC activation is not fully uncovered. We hypothesized a positive feedback signaling loop of TGF-β1-CD147 promoting liver fibrogenesis by activation of HSCs. Human HSC cell line LX-2 and spontaneous liver fibrosis model derived from HBV transgenic mice were used to evaluate the activation of molecules in the signaling loop. Wound healing and cell contraction assay were performed to detect the CD147-overexpressed HSC migration and contraction. The transcriptional regulation of CD147 by TGF-β1/Smad4 was determined using dual-luciferase reporter assay and chromatin immunoprecipitation. We found that a positive reciprocal regulation between TGF-β1 and CD147 mediated HSC activation. CD147 over-expression promoted HSC migration and accelerated TGF-β1-induced cell contraction. Phosphorylation of Smad2 and Smad3 in cooperation with Smad4 mediated the TGF-β1-regulated CD147 expression. Smad4 activated the transcription by direct interaction with CD147 promoter. Meanwhile, CD147 modulated the activated phenotype of HSCs through the ERK1/2 and Sp1 which up-regulated α-SMA, collagen I, and TGF-β1 synthesis. These findings indicate that TGF-β1-CD147 loop plays a key role in regulating the HSC activation and combination of TGF-β receptor inhibitor and anti-CD147 antibody might be promised to reverse fibrogenesis.
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26
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Luo MXM, Wong SH, Chan MTV, Yu L, Yu SSB, Wu F, Xiao Z, Wang X, Zhang L, Cheng ASL, Ng SSM, Chan FKL, Cho CH, Yu J, Sung JJY, Wu WKK. Autophagy Mediates HBx-Induced Nuclear Factor-κB Activation and Release of IL-6, IL-8, and CXCL2 in Hepatocytes. J Cell Physiol 2015; 230:2382-9. [PMID: 25708728 DOI: 10.1002/jcp.24967] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 02/18/2015] [Indexed: 12/30/2022]
Abstract
Hepatitis B virus (HBV) and one of its encoded proteins, HBV X protein (HBx), have been shown to induce autophagy in hepatoma cells. Substantial evidence indicates that autophagy is a potent suppressor of inflammation. However, sporadic reports suggest that autophagy could promote pro-inflammatory cytokine expression and inflammation in some biological contexts. Here, we show that overexpression of HBx induces LC3B-positive autophagosome formation, increases autophagic flux and enhances the expression of ATG5, ATG7, and LC3B-II in normal hepatocytes. Abrogation of autophagy by small interfering RNA against ATG5 and ATG7 prevents HBx-induced formation of autophagosomes. Autophagy inhibition also abrogates HBx-induced activation of nuclear factor-κB (NF-κB) and production of interleukin-6 (IL-6), IL-8, and CXCL2. These findings suggest that autophagy is required for HBx-induced NF-κB activation and pro-inflammatory cytokine production and could shed new light on the complex role of autophagy in the modulation of inflammation.
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Affiliation(s)
- Millore X M Luo
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Sunny H Wong
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Matthew T V Chan
- Department of Anaesthesia & Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
| | - Le Yu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Sidney S B Yu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Feng Wu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhangang Xiao
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiaojuan Wang
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Lin Zhang
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Alfred S L Cheng
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Simon S M Ng
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Francis K L Chan
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Chi H Cho
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Joseph J Y Sung
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - William K K Wu
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Department of Anaesthesia & Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
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27
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Feng H, Fan J, Qiu H, Wang Z, Yan Z, Yuan L, Guan L, Du X, Song Z, Han X, Liu J. Chuanminshen violaceum polysaccharides improve the immune responses of foot-and-mouth disease vaccine in mice. Int J Biol Macromol 2015; 78:405-16. [PMID: 25934108 DOI: 10.1016/j.ijbiomac.2015.04.044] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2015] [Revised: 03/27/2015] [Accepted: 04/08/2015] [Indexed: 10/23/2022]
Abstract
Water-soluble polysaccharides from Chuanminshen violaceum (CVPS) were evaluated for their physicochemical properties, monosaccharide composition, and adjuvant potential to specific cellular and humoral immune responses in a mouse model of foot-and-mouth disease virus (FMDV) vaccination. The average molecular weight (Mw) of the CVPS was 968.31 kDa. The monosaccharide components of the CVPS was rhamnose, arabinose, fucose, mannose, glucose, and galactose with a relative mass of 6.29%, 21.87%, 16.59%, 12.54%, 13.07%, and 28.05%, respectively. Administering CVPS as an adjuvant significantly enhanced the phagocytic capacity of peritoneal macrophages, splenocyte proliferation, and the activity of NK cells and CTL as well as increased FMDV-specific IgG and IgG subclass antibody titers. Moreover, CVPS increased the expression of IL-2, IFN-γ, and IL-4 in CD4(+) T cells and IFN-γ expression in CD8(+) T cells. Additionally, CVPS enhanced CD40(+), CD80(+), and CD86(+) expression on DCs. Moreover, CVPS upregulated MHC-I/II, TLR-2/4 mRNA levels. In contrast, CVPS downregulated TGF-β mRNA expression and the frequency of CD4(+)CD25(+)Foxp3(+) Treg cells. Taken together, these results indicate that administering CVPS as an adjuvant enhances both cellular and humoral immune responses via the TLR-2 and TLR-4 signalling pathways, thereby promoting DC maturation and suppressing TGF-β expression and Treg frequency.
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Affiliation(s)
- Haibo Feng
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing 402460, PR China.
| | - Jing Fan
- Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, Sichuan 610051, PR China
| | - Hong Qiu
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing 402460, PR China
| | - Zhenhua Wang
- Department of Animal and Veterinary Science, Chengdu Vocational College of Agricultural Science and Technology, WenJiang, Sichuan 611130, PR China
| | - Zhiqiang Yan
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing 402460, PR China
| | - Lihua Yuan
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing 402460, PR China
| | - Lu Guan
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing 402460, PR China
| | - Xiaogang Du
- Applied Biophysics and Immune Engineering Laboratory, College of Life and Science, Sichuan Agricultural University, Ya'an, Sichuan 625014, PR China
| | - Zhenhui Song
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing 402460, PR China
| | - Xingfa Han
- Department of Animal and Veterinary Science, Chengdu Vocational College of Agricultural Science and Technology, WenJiang, Sichuan 611130, PR China
| | - Juan Liu
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing 402460, PR China.
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28
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Chen Y, Williams V, Filippova M, Filippov V, Duerksen-Hughes P. Viral carcinogenesis: factors inducing DNA damage and virus integration. Cancers (Basel) 2014; 6:2155-86. [PMID: 25340830 PMCID: PMC4276961 DOI: 10.3390/cancers6042155] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 10/03/2014] [Accepted: 10/09/2014] [Indexed: 12/13/2022] Open
Abstract
Viruses are the causative agents of 10%-15% of human cancers worldwide. The most common outcome for virus-induced reprogramming is genomic instability, including accumulation of mutations, aberrations and DNA damage. Although each virus has its own specific mechanism for promoting carcinogenesis, the majority of DNA oncogenic viruses encode oncogenes that transform infected cells, frequently by targeting p53 and pRB. In addition, integration of viral DNA into the human genome can also play an important role in promoting tumor development for several viruses, including HBV and HPV. Because viral integration requires the breakage of both the viral and the host DNA, the integration rate is believed to be linked to the levels of DNA damage. DNA damage can be caused by both endogenous and exogenous factors, including inflammation induced by either the virus itself or by co-infections with other agents, environmental agents and other factors. Typically, cancer develops years to decades following the initial infection. A better understanding of virus-mediated carcinogenesis, the networking of pathways involved in transformation and the relevant risk factors, particularly in those cases where tumorigenesis proceeds by way of virus integration, will help to suggest prophylactic and therapeutic strategies to reduce the risk of virus-mediated cancer.
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Affiliation(s)
- Yan Chen
- Department of Basic Science, Loma Linda University, Loma Linda, CA 92354, USA.
| | - Vonetta Williams
- Department of Basic Science, Loma Linda University, Loma Linda, CA 92354, USA.
| | - Maria Filippova
- Department of Basic Science, Loma Linda University, Loma Linda, CA 92354, USA.
| | - Valery Filippov
- Department of Basic Science, Loma Linda University, Loma Linda, CA 92354, USA.
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29
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Suhail M, Abdel-Hafiz H, Ali A, Fatima K, Damanhouri GA, Azhar E, Chaudhary AGA, Qadri I. Potential mechanisms of hepatitis B virus induced liver injury. World J Gastroenterol 2014; 20:12462-12472. [PMID: 25253946 PMCID: PMC4168079 DOI: 10.3748/wjg.v20.i35.12462] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic active hepatitis (CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma. The histological end points of CAH are chronic inflammation, fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers. The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis, inflammation and cytokine production and liver scaring (fibrosis). The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components. The viral and cellular factors that contribute to liver injury are discussed in this article. Liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients. The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury.
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30
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Yang P, Markowitz GJ, Wang XF. The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma. Natl Sci Rev 2014; 1:396-412. [PMID: 25741453 DOI: 10.1093/nsr/nwu038] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In contrast to a majority of cancer types, the initiation of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue, with one of the most prevalent etiological factors being hepatitis B virus (HBV). Transformation of the liver in HBV-associated HCC often follows from or accompanies long-term symptoms of chronic hepatitis, inflammation and cirrhosis, and viral load is a strong predictor for both incidence and progression of HCC. Besides aiding in transformation, HBV plays a crucial role in modulating the accumulation and activation of both cellular components of the microenvironment, such as immune cells and fibroblasts, and non-cellular components of the microenvironment, such as cytokines and growth factors, markedly influencing disease progression and prognosis. This review will explore some of these components and mechanisms to demonstrate both underlying themes and the inherent complexity of these interacting systems in the initiation, progression, and metastasis of HBV-positive HCC.
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Affiliation(s)
- Pengyuan Yang
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA ; CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Geoffrey J Markowitz
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Xiao-Fan Wang
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
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31
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Xu HZ, Liu YP, Guleng B, Ren JL. Hepatitis B Virus-Related Hepatocellular Carcinoma: Pathogenic Mechanisms and Novel Therapeutic Interventions. Gastrointest Tumors 2014; 1:135-45. [PMID: 26676160 DOI: 10.1159/000365307] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Infection with the hepatitis B virus (HBV) is one of most important risk factors for hepatocellular carcinoma (HCC). Indeed, HBV is considered a group 1 human carcinogen and is a highly oncogenic agent. HBV cannot be effectively controlled or completely eliminated, so chronic HBV infection is a public health challenge worldwide. SUMMARY It is now believed that HBV-induced HCC involves a complex interaction between multiple viral and host factors. Many factors contribute to HBV-associated HCC, including products of HBV, viral integration and mutation, and host susceptibility. This review outlines the main pathogenic mechanisms with a focus on those that suggest novel targets for the prevention and treatment of HCC. KEY MESSAGE HBV infection is an important risk factor for HCC. Understanding the interaction between viral and host factors in HBV-induced HCC will reveal potential targets for future therapies. PRACTICAL IMPLICATIONS The two main therapeutic strategies consist of antiviral agents and immunotherapy-based approaches. Dendritic cell-based immunotherapy is promising for restoring the T cell-mediated antiviral immune response. Another approach is the specific expansion of the host's pool of HBV-specific T cells. Stimulation of the Toll-like receptors (TLRs), particularly TLR9, provides another means of boosting the antiviral response. Combination therapy with cytokines (interferon gamma and tumor necrosis factor alpha) plus lamivudine is more effective than these agents used alone. Therapeutic vaccines are being developed as an alternative to long-term antiviral treatment or as an adjunct.
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Affiliation(s)
- Hong-Zhi Xu
- Department of Gastroenterology, Zhongshan Hospital affiliated with Xiamen University, Xiamen, China
| | - Yun-Peng Liu
- Department of Gastroenterology, Zhongshan Hospital affiliated with Xiamen University, Xiamen, China
| | - Bayasi Guleng
- Department of Gastroenterology, Zhongshan Hospital affiliated with Xiamen University, Xiamen, China ; Medical College of Xiamen University, Xiamen, China
| | - Jian-Lin Ren
- Department of Gastroenterology, Zhongshan Hospital affiliated with Xiamen University, Xiamen, China
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32
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Dhaouadi N, Li JY, Feugier P, Gustin MP, Dab H, Kacem K, Bricca G, Cerutti C. Computational identification of potential transcriptional regulators of TGF-ß1 in human atherosclerotic arteries. Genomics 2014; 103:357-70. [PMID: 24819318 DOI: 10.1016/j.ygeno.2014.05.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 03/17/2014] [Accepted: 05/03/2014] [Indexed: 11/17/2022]
Abstract
TGF-ß is protective in atherosclerosis but deleterious in metastatic cancers. Our aim was to determine whether TGF-ß transcriptional regulation is tissue-specific in early atherosclerosis. The computational methods included 5 steps: (i) from microarray data of human atherosclerotic carotid tissue, to identify the 10 best co-expressed genes with TGFB1 (TGFB1 gene cluster), (ii) to choose the 11 proximal promoters, (iii) to predict the TFBS shared by the promoters, (iv) to identify the common TFs co-expressed with the TGFB1 gene cluster, and (v) to compare the common TFs in the early lesions to those identified in advanced atherosclerotic lesions and in various cancers. Our results show that EGR1, SP1 and KLF6 could be responsible for TGFB1 basal expression, KLF6 appearing specific to atherosclerotic lesions. Among the TFs co-expressed with the gene cluster, transcriptional activators (SLC2A4RG, MAZ) and repressors (ZBTB7A, PATZ1, ZNF263) could be involved in the fine-tuning of TGFB1 expression in atherosclerosis.
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Affiliation(s)
- Nedra Dhaouadi
- EA 4173 Génomique Fonctionnelle de l'Hypertension Artérielle, Université de Lyon, Université Lyon 1, Hôpital Nord-Ouest Villefranche-sur-Saône, 8 avenue Rockefeller, F-69373 Lyon, France; Unité de Physiologie Intégrée, Laboratoire de Pathologies Vasculaires, Université de Carthage, Faculté des Sciences de Bizerte, Bizerte, Tunisia
| | - Jacques-Yuan Li
- EA 4173 Génomique Fonctionnelle de l'Hypertension Artérielle, Université de Lyon, Université Lyon 1, Hôpital Nord-Ouest Villefranche-sur-Saône, 8 avenue Rockefeller, F-69373 Lyon, France
| | - Patrick Feugier
- EA 4173 Génomique Fonctionnelle de l'Hypertension Artérielle, Université de Lyon, Université Lyon 1, Hôpital Nord-Ouest Villefranche-sur-Saône, 8 avenue Rockefeller, F-69373 Lyon, France
| | - Marie-Paule Gustin
- EA 4173 Génomique Fonctionnelle de l'Hypertension Artérielle, Université de Lyon, Université Lyon 1, Hôpital Nord-Ouest Villefranche-sur-Saône, 8 avenue Rockefeller, F-69373 Lyon, France
| | - Houcine Dab
- Unité de Physiologie Intégrée, Laboratoire de Pathologies Vasculaires, Université de Carthage, Faculté des Sciences de Bizerte, Bizerte, Tunisia
| | - Kamel Kacem
- Unité de Physiologie Intégrée, Laboratoire de Pathologies Vasculaires, Université de Carthage, Faculté des Sciences de Bizerte, Bizerte, Tunisia
| | - Giampiero Bricca
- EA 4173 Génomique Fonctionnelle de l'Hypertension Artérielle, Université de Lyon, Université Lyon 1, Hôpital Nord-Ouest Villefranche-sur-Saône, 8 avenue Rockefeller, F-69373 Lyon, France
| | - Catherine Cerutti
- EA 4173 Génomique Fonctionnelle de l'Hypertension Artérielle, Université de Lyon, Université Lyon 1, Hôpital Nord-Ouest Villefranche-sur-Saône, 8 avenue Rockefeller, F-69373 Lyon, France.
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Cool CD, Voelkel NF, Bull T. Viral infection and pulmonary hypertension: is there an association? Expert Rev Respir Med 2014; 5:207-16. [DOI: 10.1586/ers.11.17] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Feitelson MA, Bonamassa B, Arzumanyan A. The roles of hepatitis B virus-encoded X protein in virus replication and the pathogenesis of chronic liver disease. Expert Opin Ther Targets 2014; 18:293-306. [PMID: 24387282 DOI: 10.1517/14728222.2014.867947] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Hepatitis B virus (HBV) is a major cause of chronic liver disease (CLD) and hepatocellular carcinoma (HCC) worldwide. More than 350 million people are at risk for HCC, and with few treatment options available, therapeutic approaches to targets other than the virus polymerase will be needed. This review suggests that the HBV-encoded X protein, HBx, would be an outstanding target because it contributes to the biology and pathogenesis of HBV in three fundamental ways. AREAS COVERED First, HBx is a trans-activating protein that stimulates virus gene expression and replication, thereby promoting the development and persistence of the carrier state. Second, HBx partially blocks the development of immune responses that would otherwise clear the virus, and protects infected hepatocytes from immune-mediated destruction. Thus, HBx contributes to the development of CLD without virus clearance. Third, HBx alters patterns of host gene expression that make possible the emergence of HCC. The selected literature cited is from the National Library of Medicine (Pubmed and Medline). EXPERT OPINION Understanding the mechanisms, whereby HBx supports virus replication and promotes pathogenesis, suggests that HBx will be an important therapeutic target against both virus replication and CLD aimed at the chemoprevention of HCC.
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Affiliation(s)
- Mark A Feitelson
- Temple University, College of Science and Technology, Department of Biology , Room 409 BioLife Science Building, 1900 N. 12th Street, Philadelphia, PA 19122 , USA +1 215 204 8434 ; +1 215 204 8359 ;
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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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Xie N, Chen X, Zhang T, Liu B, Huang C. Using proteomics to identify the HBx interactome in hepatitis B virus: how can this inform the clinic? Expert Rev Proteomics 2013; 11:59-74. [PMID: 24308553 DOI: 10.1586/14789450.2014.861745] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatitis B virus (HBV) is a small and enveloped DNA virus, of which chronic infection is the main risk factor of liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus X protein (HBx) is a multifunctional protein encoded by HBV genome, which have significant effects on HBV replication and pathogenesis. Through directly interacting with cellular proteins, HBx is capable to promote HBV replication, regulate transcription of host genes, disrupt protein degradation, modulate signaling pathway, manipulate cell death and deregulate cell cycle. In this review, we briefly discuss the diversified effects of HBx-interactome and their potential clinical significances.
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Affiliation(s)
- Na Xie
- The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, P.R. China
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LV WEI, DUAN QIANGLIN, WANG LEMIN, GONG ZHU, YANG FAN, SONG YANLI. Gene expression levels of cytokines in peripheral blood mononuclear cells from patients with pulmonary embolism. Mol Med Rep 2013; 7:1245-50. [DOI: 10.3892/mmr.2013.1344] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Accepted: 02/18/2013] [Indexed: 11/06/2022] Open
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Arzumanyan A, Reis HMGPV, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 2013; 13:123-35. [PMID: 23344543 DOI: 10.1038/nrc3449] [Citation(s) in RCA: 611] [Impact Index Per Article: 50.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal cancer, with increasing worldwide incidence, that is mainly associated with chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections. There are few effective treatments partly because the cell- and molecular-based mechanisms that contribute to the pathogenesis of this tumour type are poorly understood. This Review outlines pathogenic mechanisms that seem to be common to both viruses and which suggest innovative approaches to the prevention and treatment of HCC.
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Affiliation(s)
- Alla Arzumanyan
- Department of Biology and Sbarro Health Research Organization, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, Pennsylvania 19122, USA
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Du X, Zhao B, Li J, Cao X, Diao M, Feng H, Chen X, Chen Z, Zeng X. Astragalus polysaccharides enhance immune responses of HBV DNA vaccination via promoting the dendritic cell maturation and suppressing Treg frequency in mice. Int Immunopharmacol 2012; 14:463-70. [PMID: 23006659 DOI: 10.1016/j.intimp.2012.09.006] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Revised: 08/29/2012] [Accepted: 09/10/2012] [Indexed: 12/18/2022]
Abstract
Astragalus polysaccharides (APS), an extract from a kind of Chinese traditional herb Astragalus membranaceus, was proved to have strong immunoregulatory properties. In this study, APS was employed as an adjuvant of Hepatitis B virus (HBV) DNA vaccine (pcDS2) and its' effects on immune system of mice were investigated. Our data demonstrated that APS as an adjuvant could increase the HBsAg-specific antibody level as well as the proliferating activity of T cells. APS also could induce CD4(+) T cells to produce IL-4, IL-2 and IFN-γ and enhance IFN-γ expression of CD8(+) T cells. Moreover, APS could induce the robust activity of the cytotoxic lymphocytes (CTL). Additionally, APS could stimulate the dendritic cells (DC) maturation which is characterized by up-regulation of MHC I/II, CD40, CD80 and CD86, and decreased the frequency of the regulatory T cells (nTreg). Collectively, these findings suggest that APS is a potent adjuvant for the hepatitis B DNA vaccine and can enhance the immune responses of HBV DNA vaccine via promoting DC maturation and inhibit the Treg frequency.
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Affiliation(s)
- Xiaogang Du
- Applied Biophysics and Immune Engineering Laboratory, College of Life Science, Sichuan Agriculture University, Ya'an, Sichuan 625014, China
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Arzumanyan A, Sambandam V, Clayton MM, Choi SS, Xie G, Diehl AM, Yu DY, Feitelson MA. Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Res 2012; 72:5912-20. [PMID: 22986746 DOI: 10.1158/0008-5472.can-12-2329] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The hepatitis B virus (HBV) encoded X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). Aberrant activation of the Hedgehog (Hh) pathway has been linked to many tumor types including HCC. Thus, experiments were designed to test the hypothesis that HBx promotes HCC via activation of Hh signaling. HBx expression correlated with an upregulation of Hh markers in human liver cancer cell lines, in liver samples from HBV infected patients with HCC, and in the livers of HBx transgenic mice (HBxTg) that develop hepatitis, steatosis, and dysplasia, culminating in the appearance of HCC. The findings in human samples provide clinical validation for the in vitro results and those in the HBxTg. Blockade of Hh signaling inhibited HBx stimulation of cell migration, anchorage-independent growth, tumor development in HBxTg, and xenograft growth in nude mice. Results suggest that the ability of HBx to promote cancer is at least partially dependent upon the activation of the Hh pathway. This study provides biologic evidence for the role of Hh signaling in the pathogenesis of HBV-mediated HCC and suggests cause and effect for the first time. The observation that inhibition of Hh signaling partially blocked the ability of HBx to promote growth and migration in vitro and tumorigenesis in two animal models implies that Hh signaling may represent an "oncogene addiction" pathway for HBV-associated HCC. This work could be central to designing specific treatments that target early development and progression of HBx-mediated HCC.
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Affiliation(s)
- Alla Arzumanyan
- Department of Biology, Temple University, Philadelphia, Pennsylvania 19122, USA.
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42
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Du X, Chen X, Zhao B, Lv Y, Zhang H, Liu H, Chen Z, Chen Y, Zeng X. Astragalus polysaccharides enhance the humoral and cellular immune responses of hepatitis B surface antigen vaccination through inhibiting the expression of transforming growth factor β and the frequency of regulatory T cells. ACTA ACUST UNITED AC 2012; 63:228-35. [PMID: 22077226 DOI: 10.1111/j.1574-695x.2011.00845.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Astragalus polysaccharides (APS), extracted from the root of Astragalus membranaceus, a traditional Chinese medicinal herb, have extensive pharmacological and strong immunomodulatory effects. In this study, the potential adjuvant effect of APS on humoral and cellular immune responses to hepatitis B subunit vaccine was investigated. Coadministration of APS with recombinant hepatitis B surface antigen significantly increased antigen-specific antibody production, T-cell proliferation and CTL (cytotoxic T lymphocyte) activity. Production of interferon-γ (IFN-γ), interleukin-2 (IL-2) and IL-4 in CD4(+) T cells and of IFN-γ in CD8(+) T cells were dramatically increased. Furthermore, expression of the genes PFP, GraB, Fas L and Fas were up-regulated; interestingly, expression of transforming growth factor β (TGF-β) and the frequency of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) were down-regulated. Expression of Toll-like receptor 4 (TLR4) was significantly increased by administration of APS. Together, these results suggest that APS is a potent adjuvant for the hepatitis B subunit vaccine and can enhance both humoral and cellular immune responses via activating the TLR4 signaling pathway and inhibit the expression of TGF-β and frequency of Treg cells.
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Affiliation(s)
- Xiaogang Du
- Applied Biophysics and Immune Engineering Laboratory, College of Life Science, Sichuan Agriculture University, Ya'an, Sichuan, China
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Mason WS. Hepadnaviruses and Hepatocellular Carcinoma. CANCER ASSOCIATED VIRUSES 2012:531-569. [DOI: 10.1007/978-1-4614-0016-5_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Loss of E-cadherin is associated with acquisition of metastatic capacity. Numerous studies suggest histone deacetylation and/or hypermethylation of CpG islands in E-cadherin gene (CDH1) are major mechanisms responsible for E-cadherin silencing in different tumors and cancer cell lines. The Hepatitis B virus (HBV) encoded X antigen, HBx, contributes importantly to the development of hepatocellular carcinoma (HCC) using multiple mechanisms. Experiments were designed to test if in addition to CDH1 hypermethylation HBx promotes epigenetic modulation of E-cadherin transcriptional activity through histone deacetylation and miR-373. The relationships between HBx, E-cadherin, mSin3A, Snail-1 and miR-373 were evaluated in HBx expressing (HepG2X) and control (HepG2CAT) cells by western blotting, immunoprecipitation, chromatin immunoprecipitation as well as by immunohistochemical staining of liver and tumor tissue sections from HBV infected patients. In HepG2X cells, decreased levels of E-cadherin and elevated levels of mSin3A and Snail-1 were detected. Reciprocal immunoprecipitation with anti-HBx and anti-mSin3A demonstrated mutual binding. Further, HBx-mSin3A co-localization was detected by immunofluorescent staining. HBx down-regulated E-cadherin expression by the recruitment of the mSin3A/HDAC complex to the Snail-binding sites in human CDH1. Histone deacetylation inhibition by Trichostatin A treatment restored E-cadherin expression. Mir-373, a positive regulator of E-cadherin expression, was down-regulated by HBx in HepG2X cells and tissue sections from HBV infected patients. Thus, histone deacetylation of CDH1 and down-regulation of miR-373, together with the previously demonstrated hyper-methylation of CDH1 by HBx, may be important for the understanding of HBV-related carcinogenesis.
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Pollicino T, Saitta C, Raimondo G. Hepatocellular carcinoma: the point of view of the hepatitis B virus. Carcinogenesis 2011; 32:1122-32. [PMID: 21665892 DOI: 10.1093/carcin/bgr108] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- Teresa Pollicino
- Department of Internal Medicine, Unit of Clinical and Molecular Hepatology, University Hospital of Messina, Via Consolare Valeria, Messina, Italy.
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Xie HY, Cheng J, Xing CY, Wang JJ, Su R, Wei XY, Zhou L, Zheng SS. Evaluation of hepatitis B viral replication and proteomic analysis of HepG2.2.15 cell line after knockdown of HBx. Hepatobiliary Pancreat Dis Int 2011; 10:295-302. [PMID: 21669574 DOI: 10.1016/s1499-3872(11)60049-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) is one of the major pathogens of human liver disease. Studies have shown that HBV X protein (HBx) plays an important role in promoting viral gene expression and replication. In this study we performed a global proteomic profiling to identify the downstream functional proteins of HBx, thereby detecting the mechanisms of action of HBx on virion replication. METHODS HBx in the HepG2.2.15 cell line was knocked down by the transfection of small interfering RNA (siRNA). The replication level of HBV was evaluated by microparticle enzyme immunoassay analysis of HBsAg and HBeAg in the culture supernatant, and real-time quantitative PCR analysis of HBV DNA. Two-dimensional electrophoresis combined with MALDI-TOF/TOF was performed to analyze the changes in protein expression profile after treatment with HBx siRNA. RESULTS Knockdown of HBx disturbed HBV replication in vitro. HBx target siRNA significantly inhibited the expression of HBsAg, HBeAg and the replication of HBV DNA. Twelve significantly changed proteins (7 upregulated and 5 downregulated) were successfully identified by MALDI-TOF/TOF using proteomics differential expression analysis after the knockdown of HBx. Among these identified proteins, HSP70 was validated by Western blotting. CONCLUSION The results of the study indicated the positive effect of HBx on HBV replication, and a group of downstream target proteins of HBx may be responsible for this effect.
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Affiliation(s)
- Hai-Yang Xie
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, and Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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Wu S, Yang C, Guo S, Fei L, Luo N, Fu X, Chen Y, Wu Y. Stimulation of B7-H1 in hepatocarcinoma cells by hepatitis B virus X antigen. Immunol Invest 2011; 39:754-69. [PMID: 20840059 DOI: 10.3109/08820139.2010.494193] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The cross-talk between the hepatitis B virus X protein (HBx) and B7-H1 in hepatocarcinoma (HCC) is unclear. This study analyzed the potential relationships between HBx and B7-H1 in hepatocarcinogenesis. One of human HCC cell lines, HepG2 cells, was transfected to stably express HBx protein (HBx(+)-HepG2). The transcription of B7-H1 mRNA was increased significantly in these cells compared to cells transfected with control vector (HBx(-)-HepG2), as confirmed by a comparative genome-wide microarray analysis (Capitalbio) and real time quantitative PCR (qPCR). Flow cytometry and western-blot further demonstrated that B7-H1 protein synthesis was enhanced in HBx(+)-HepG2 cells. Site-directed mutagenesis of promoter constructs revealed that the transcription factor (NF)-κB binding site between 128 and 137 bp upstream of B7-H1 gene transcriptional start site is primarily responsible for HBx-mediated B7-H1 expression. Co-culture experiments with HBx(+)-HepG2/T cells showed that the number of apoptotic T cells increased profoundly, and this effect could be partially prevented when a neutralizing mAb against B7-H1 was added to the culture, demonstrating that B7-H1 signaling can promote T cell apoptosis. Our results suggest that the expression of B7-H1 in hepatocarcimona cells can be initiated by HBx antigen, thus inducing T cell apoptosis and finally potentially facilitates the genesis of HCC.
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Affiliation(s)
- Shengxi Wu
- Institute of Immunology, PLA, The Third Military Medical University, Chongqing 400038, PR China
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Singh AK, Swarnalatha M, Kumar V. c-ETS1 facilitates G1/S-phase transition by up-regulating cyclin E and CDK2 genes and cooperates with hepatitis B virus X protein for their deregulation. J Biol Chem 2011; 286:21961-70. [PMID: 21515670 DOI: 10.1074/jbc.m111.238238] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Recent studies on the molecular mechanisms responsible for cell cycle deregulation in cancer have puzzled out the role of oncogenes in mediating unscheduled cellular proliferation. This is reminiscence of their activity as proto-oncogenes that drives scheduled cell cycle progression under physiological conditions. Working on the cell cycle regulatory activity of proto-oncogene, we observed that c-ETS1 transcriptionally up-regulated both cyclin E and CDK2 genes, the master regulators of G(1)/S-phase transition. The process was mediated by kinetic coherence of c-ETS1 expression and its recruitment to both promoters during G(1)/S-phase transition. Furthermore, enforced expression of c-ETS1 helped G(0)-arrested cells to progress into G(1)/S-phases apparently due to the activation of cyclin E/CDK2 genes. Physiological induction of c-ETS1 by EGF showed the remodeling of mononucleosomes bound to the c-ETS1 binding site on both promoters during their activation. The exchange of HDAC1 with histone acetyltransferase-p300 was contemporaneous to the chromatin remodeling with consequent increase in histone H3K9 acetylation. Furthermore, the ATP-dependent chromatin remodeler hBRM1 recruitment was also associated with nucleosome remodeling and promoter occupancy of phospho-Ser5 RNA polymerase II. Intriguingly, the activity of the HBx viral oncoprotein was dependent on c-ETS1 in a hepatotropic manner, which led to the activation of cyclin E/CDK2 genes. Thus, cyclin E and CDK2 genes are key physiological effectors of the c-ETS1 proto-oncogene. Furthermore, c-ETS1 is indispensable for the hepatotropic action of HBx in cell cycle deregulation.
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Affiliation(s)
- Anup Kumar Singh
- Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
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Bedossa P. La fibrose au cours de l’hépatite B : un processus dynamique. ACTA ACUST UNITED AC 2010; 34 Suppl 2:S103-8. [DOI: 10.1016/s0399-8320(10)70028-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Zou Q, Zhong Y, Su H, Kang Y, Jin J, Liu Q, Geng S, Zhao G, Wang B. Enhancement of humoral and cellular responses to HBsAg DNA vaccination by immunization with praziquantel through inhibition TGF-beta/Smad2,3 signaling. Vaccine 2010; 28:2032-8. [PMID: 20188260 DOI: 10.1016/j.vaccine.2009.10.101] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Praziquantel (PZQ), which is used to treat all forms of schistosomiasis, has been shown to induce strong T cell activities and decrease T regulatory cell levels. In our study, we investigated whether PZQ may be used as an adjuvant for a hepatitis B surface antigen (HBsAg) DNA vaccine (pcD-S2) in eliciting strong humoral and cellular responses. Our data demonstrate that PZQ as an adjuvant increased T cell proliferation and an HBsAg-specific antibody response that was characterized by a higher ratio of IgG2a/IgG1. Moreover, a higher level of IFN-gamma in CD4(+) and CD8(+) T cells were elicited. In addition, a significantly antigen-specific cytotoxic T lymphocyte response was also observed. The expression of TGF-beta can be induced by HBsAg, while PZQ as an adjuvant can inhibit the expression of TGF-beta and TGF-beta/Smad2,3 signaling. The frequency of CD4(+)CD25(+)Foxp3(+) Treg cells was reduced. Importantly, the regulatory function of CD4(+)CD25(+) Treg cells was correspondingly impaired. Together, these results suggest that PZQ can enhance humoral and cellular responses to HBsAg DNA vaccination through inhibition TGF-beta/Smad2,3 signaling.
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Affiliation(s)
- Qiang Zou
- State Key Laboratory for Agro-Biotechnology, Department of Microbiology and Immunology, College of Biological Science, China Agricultural University, Beijing 100193, China
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