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Yang Y, Cai Q, Zhu M, Rong J, Feng X, Wang K. Exploring the double-edged role of cellular senescence in chronic liver disease for new treatment approaches. Life Sci 2025; 373:123678. [PMID: 40324645 DOI: 10.1016/j.lfs.2025.123678] [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: 02/06/2025] [Revised: 04/24/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
Cellular senescence is a fundamental yet complex defense mechanism that restricts excessive proliferation, maintains cellular homeostasis under various stress conditions-such as oncogenic activation and inflammation-and serves as a dynamic stress response program involved in development, aging, and immunity. Its reversibility depends on essential maintenance components. Cellular senescence is a "double-edged sword": on one hand, it limits the malignant proliferation of damaged cells, thereby preventing tumor development. However, by retaining secretory functions, senescent cells can also induce persistent changes in the microenvironment and disrupt homeostasis, leading to tissue inflammation, fibrosis, and carcinogenesis. Senescence plays a critical role in the pathogenesis of various chronic liver diseases, including chronic viral hepatitis, liver fibrosis, and hepatocellular carcinoma. It exerts a dual influence by facilitating immune evasion and inflammation in chronic viral hepatitis, modulating hepatic stellate cell activity in fibrosis, and reshaping the tumor microenvironment to accelerate hepatocarcinogenesis. This article reviews the characteristics of cellular senescence and its role in the pathogenesis of these chronic liver diseases while exploring potential treatment and prevention strategies. The aim is to provide a comprehensive reference for future clinical and research investigations into chronic liver disease.
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Affiliation(s)
- Yiwen Yang
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Qun Cai
- Department of Infectious Diseases and Liver Diseases, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Mingyan Zhu
- Department of Emergency, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Jianning Rong
- Department of Emergency, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Xudong Feng
- Department of Clinical Laboratory, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China.
| | - Ke Wang
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China.
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Zhang Y, Cao W, Wang S, Zhang L, Li X, Zhang Z, Xie Y, Li M. Epigenetic modification of hepatitis B virus infection and related hepatocellular carcinoma. Virulence 2024; 15:2421231. [PMID: 39460469 PMCID: PMC11583590 DOI: 10.1080/21505594.2024.2421231] [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: 09/18/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatitis B virus (HBV) infection poses a challenge to global public health. Persistent liver infection with HBV is associated with an increased risk of developing severe liver disease. The complex interaction between the virus and the host is the reason for the persistent presence of HBV and the risk of tumor development. Chronic liver inflammation, integration of viral genome with host genome, expression of HBx protein, and viral genotype are all key participants in the pathogenesis of hepatocellular carcinoma (HCC). Epigenetic regulation in HBV-associated HCC involves complex interactions of molecular mechanisms that control gene expression and function without altering the underlying DNA sequence. These epigenetic modifications can significantly affect the onset and progression of HCC. This review summarizes recent research on the epigenetic regulation of HBV persistent infection and HBV-HCC development, including DNA methylation, histone modification, RNA modification, non-coding RNA, etc. Enhanced knowledge of these mechanisms will offer fresh perspectives and potential targets for intervention tactics in HBV-HCC.
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Affiliation(s)
- Yaqin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Weihua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shiyu Wang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xinxin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ziyu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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Ringelhan M, Schuehle S, van de Klundert M, Kotsiliti E, Plissonnier ML, Faure-Dupuy S, Riedl T, Lange S, Wisskirchen K, Thiele F, Cheng CC, Yuan D, Leone V, Schmidt R, Hünergard J, Geisler F, Unger K, Algül H, Schmid RM, Rad R, Wedemeyer H, Levrero M, Protzer U, Heikenwalder M. HBV-related HCC development in mice is STAT3 dependent and indicates an oncogenic effect of HBx. JHEP Rep 2024; 6:101128. [PMID: 39290403 PMCID: PMC11406364 DOI: 10.1016/j.jhepr.2024.101128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 05/26/2024] [Accepted: 05/29/2024] [Indexed: 09/19/2024] Open
Abstract
Background & Aims Although most hepatocellular carcinoma (HCC) cases are driven by hepatitis and cirrhosis, a subset of patients with chronic hepatitis B develop HCC in the absence of advanced liver disease, indicating the oncogenic potential of hepatitis B virus (HBV). We investigated the role of HBV transcripts and proteins on HCC development in the absence of inflammation in HBV-transgenic mice. Methods HBV-transgenic mice replicating HBV and expressing all HBV proteins from a single integrated 1.3-fold HBV genome in the presence or absence of wild-type HBx (HBV1.3/HBVxfs) were analyzed. Flow cytometry, molecular, histological and in vitro analyses using human cell lines were performed. Hepatocyte-specific Stat3- and Socs3-knockout was analyzed in HBV1.3 mice. Results Approximately 38% of HBV1.3 mice developed liver tumors. Protein expression patterns, histology, and mutational landscape analyses indicated that tumors resembled human HCC. HBV1.3 mice showed no signs of active hepatitis, except STAT3 activation, up to the time point of HCC development. HBV-RNAs covering HBx sequence, 3.5-kb HBV RNA and HBx-protein were detected in HCC tissue. Interestingly, HBVxfs mice expressing all HBV proteins except a C-terminally truncated HBx (without the ability to bind DNA damage binding protein 1) showed reduced signs of DNA damage response and had a significantly reduced HCC incidence. Importantly, intercrossing HBV1.3 mice with a hepatocyte-specific STAT3-knockout abrogated HCC development. Conclusions Expression of HBV-proteins is sufficient to cause HCC in the absence of detectable inflammation. This indicates the oncogenic potential of HBV and in particular HBx. In our model, HBV-driven HCC was STAT3 dependent. Our study highlights the immediate oncogenic potential of HBV, challenging the idea of a benign highly replicative phase of HBV infection and indicating the necessity for an HBV 'cure'. Impact and implications Although most HCC cases in patients with chronic HBV infection occur after a sequence of liver damage and fibrosis, a subset of patients develops HCC without any signs of advanced liver damage. We demonstrate that the expression of all viral transcripts in HBV-transgenic mice suffices to induce HCC development independent of inflammation and fibrosis. These data indicate the direct oncogenic effects of HBV and emphasize the idea of early antiviral treatment in the 'immune-tolerant' phase (HBeAg-positive chronic HBV infection).
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Affiliation(s)
- Marc Ringelhan
- Second Medical Department, University Hospital Rechts der Isar, Technical University of Munich, School of Medicine & Health, Munich, Germany
- German Centre for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Svenja Schuehle
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Maarten van de Klundert
- Institute of Virology, Technical University of Munich, School of Medicine & Health/Helmholtz Munich, Munich, Germany
| | - Elena Kotsiliti
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | | | | | - Tobias Riedl
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sebastian Lange
- Second Medical Department, University Hospital Rechts der Isar, Technical University of Munich, School of Medicine & Health, Munich, Germany
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine & Health, Technical University of Munich, Munich, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Karin Wisskirchen
- Institute of Virology, Technical University of Munich, School of Medicine & Health/Helmholtz Munich, Munich, Germany
| | - Frank Thiele
- Institute of Virology, Technical University of Munich, School of Medicine & Health/Helmholtz Munich, Munich, Germany
| | - Cho-Chin Cheng
- Institute of Virology, Technical University of Munich, School of Medicine & Health/Helmholtz Munich, Munich, Germany
| | - Detian Yuan
- Institute of Virology, Technical University of Munich, School of Medicine & Health/Helmholtz Munich, Munich, Germany
| | - Valentina Leone
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Research Unit for Radiation Cytogenetics, Helmholtz Munich, Neuherberg, Germany
| | - Ronny Schmidt
- Sciomics GmbH, Karl-Landsteiner-Straβe 6, 69151 Neckargemünd, Germany
| | - Juliana Hünergard
- Institute of Virology, Technical University of Munich, School of Medicine & Health/Helmholtz Munich, Munich, Germany
| | - Fabian Geisler
- Second Medical Department, University Hospital Rechts der Isar, Technical University of Munich, School of Medicine & Health, Munich, Germany
| | - Kristian Unger
- Research Unit for Radiation Cytogenetics, Helmholtz Munich, Neuherberg, Germany
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Hana Algül
- Second Medical Department, University Hospital Rechts der Isar, Technical University of Munich, School of Medicine & Health, Munich, Germany
- Comprehensive Cancer Center TUM (CCCMTUM), University Hospital rechts der Isar, Technical University of Munich, School of Medicine & Health, Munich, Germany
| | - Roland M Schmid
- Second Medical Department, University Hospital Rechts der Isar, Technical University of Munich, School of Medicine & Health, Munich, Germany
| | - Roland Rad
- Second Medical Department, University Hospital Rechts der Isar, Technical University of Munich, School of Medicine & Health, Munich, Germany
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine & Health, Technical University of Munich, Munich, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany
| | - Massimo Levrero
- INSERM Unit 1052, Cancer Research Center of Lyon, Lyon, France
- Hepatology Department, Hospices Civils de Lyon, Lyon, France
- Department of Internal Medicine - DMISM, Sapienza University, Rome, Italy
- Istituto Italiano di Tecnologia (IIT), Rome, Italy
| | - Ulrike Protzer
- German Centre for Infection Research (DZIF), Munich Partner Site, Munich, Germany
- Institute of Virology, Technical University of Munich, School of Medicine & Health/Helmholtz Munich, Munich, Germany
| | - Mathias Heikenwalder
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Virology, Technical University of Munich, School of Medicine & Health/Helmholtz Munich, Munich, Germany
- The M3 Research Center, Medical Faculty, University Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
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Herbein G. Cellular Transformation by Human Cytomegalovirus. Cancers (Basel) 2024; 16:1970. [PMID: 38893091 PMCID: PMC11171319 DOI: 10.3390/cancers16111970] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 05/13/2024] [Accepted: 05/17/2024] [Indexed: 06/21/2024] Open
Abstract
Epstein-Barr virus (EBV), Kaposi sarcoma human virus (KSHV), human papillomavirus (HPV), hepatitis B and C viruses (HBV, HCV), human T-lymphotropic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV) are the seven human oncoviruses reported so far. While traditionally viewed as a benign virus causing mild symptoms in healthy individuals, human cytomegalovirus (HCMV) has been recently implicated in the pathogenesis of various cancers, spanning a wide range of tissue types and malignancies. This perspective article defines the biological criteria that characterize the oncogenic role of HCMV and based on new findings underlines a critical role for HCMV in cellular transformation and modeling the tumor microenvironment as already reported for the other human oncoviruses.
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Affiliation(s)
- Georges Herbein
- Department Pathogens & Inflammation-EPILAB EA4266, University of Franche-Comté (UFC), 25000 Besançon, France;
- Department of Virology, CHU Besançon, 25000 Besançon, France
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Schollmeier A, Basic M, Glitscher M, Hildt E. The impact of HBx protein on mitochondrial dynamics and associated signaling pathways strongly depends on the hepatitis B virus genotype. J Virol 2024; 98:e0042424. [PMID: 38629837 PMCID: PMC11092329 DOI: 10.1128/jvi.00424-24] [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: 03/05/2024] [Accepted: 03/25/2024] [Indexed: 05/15/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infections are strongly associated with liver cirrhosis, inflammation, and hepatocellular carcinoma. In this context, the viral HBx protein is considered as a major factor influencing HBV-associated pathogenesis through deregulation of multiple cellular signaling pathways and is therefore a potential target for prognostic and therapeutic applications. However, HBV-associated pathogenesis differs significantly between genotypes, with the relevant factors and in particular the contribution of the genetic diversity of HBx being largely unknown. To address this question, we studied the specific genotype-dependent impact of HBx on cellular signaling pathways, focusing in particular on morphological and functional parameters of mitochondria. To exclusively investigate the impact of HBx of different genotypes on integrity and function of mitochondria in the absence of additional viral factors, we overexpressed HBx in Huh7 or HepG2 cells. Key signaling pathways were profiled by kinome analysis and correlated with expression levels of mitochondrial and pathogenic markers. Conclusively, HBx of genotypes A and G caused strong disruption of mitochondrial morphology alongside an induction of PTEN-induced putative kinase 1/Parkin-mediated mitophagy. These effects were only moderately dysregulated by genotypes B and E, whereas genotypes C and D exhibit an intermediate effect in this regard. Accordingly, changes in mitochondrial membrane potential and elevated reactive oxygen species production were associated with the HBx-mediated dysfunction among different genotypes. Also, genotype-related differences in mitophagy induction were identified and indicated that HBx-mediated changes in the mitochondria morphology and function strongly depend on the genotype. This indicates a relevant role of HBx in the process of genotype-dependent liver pathogenesis of HBV infections and reveals underlying mechanisms.IMPORTANCEThe hepatitis B virus is the main cause of chronic liver disease worldwide and differs in terms of pathogenesis and clinical outcome among the different genotypes. Furthermore, the viral HBx protein is a known factor in the progression of liver injury by inducing aberrant mitochondrial structures and functions. Consequently, the selective removal of dysfunctional mitochondria is essential to maintain overall cellular homeostasis and cell survival. Consistent with the intergenotypic difference of HBV, our data reveal significant differences regarding the impact of HBx of different genotypes on mitochondrial dynamic and function and thereby on radical oxygen stress levels within the cell. We subsequently observed that the induction of mitophagy differs significantly across the heterogenetic HBx proteins. Therefore, this study provides evidence that HBx-mediated changes in the mitochondria dynamics and functionality strongly depend on the genotype of HBx. This highlights an important contribution of HBx in the process of genotype-dependent liver pathogenesis.
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Affiliation(s)
| | - Michael Basic
- Division of Virology, Paul Ehrlich Institute, Langen, Germany
| | - Mirco Glitscher
- Division of Virology, Paul Ehrlich Institute, Langen, Germany
| | - Eberhard Hildt
- Division of Virology, Paul Ehrlich Institute, Langen, Germany
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6
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Kazzaz SA, Tawil J, Harhaj EW. The aryl hydrocarbon receptor-interacting protein in cancer and immunity: Beyond a chaperone protein for the dioxin receptor. J Biol Chem 2024; 300:107157. [PMID: 38479600 PMCID: PMC11002312 DOI: 10.1016/j.jbc.2024.107157] [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: 01/09/2024] [Revised: 03/04/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
The aryl hydrocarbon receptor (AhR)-interacting protein (AIP) is a ubiquitously expressed, immunophilin-like protein best known for its role as a co-chaperone in the AhR-AIP-Hsp90 cytoplasmic complex. In addition to regulating AhR and the xenobiotic response, AIP has been linked to various aspects of cancer and immunity that will be the focus of this review article. Loss-of-function AIP mutations are associated with pituitary adenomas, suggesting that AIP acts as a tumor suppressor in the pituitary gland. However, the tumor suppressor mechanisms of AIP remain unclear, and AIP can exert oncogenic functions in other tissues. While global deletion of AIP in mice yields embryonically lethal cardiac malformations, heterozygote, and tissue-specific conditional AIP knockout mice have revealed various physiological roles of AIP. Emerging studies have established the regulatory roles of AIP in both innate and adaptive immunity. AIP interacts with and inhibits the nuclear translocation of the transcription factor IRF7 to inhibit type I interferon production. AIP also interacts with the CARMA1-BCL10-MALT1 complex in T cells to enhance IKK/NF-κB signaling and T cell activation. Taken together, AIP has diverse functions that vary considerably depending on the client protein, the tissue, and the species.
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Affiliation(s)
- Sarah A Kazzaz
- Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, Pennsylvania, USA; Medical Scientist Training Program, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - John Tawil
- Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Edward W Harhaj
- Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, Pennsylvania, USA.
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Simon F, Thoma-Kress AK. Intercellular Transport of Viral Proteins. Results Probl Cell Differ 2024; 73:435-474. [PMID: 39242389 DOI: 10.1007/978-3-031-62036-2_18] [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] [Indexed: 09/09/2024]
Abstract
Viruses are vehicles to exchange genetic information and proteins between cells and organisms by infecting their target cells either cell-free, or depending on cell-cell contacts. Several viruses like certain retroviruses or herpesviruses transmit by both mechanisms. However, viruses have also evolved the properties to exchange proteins between cells independent of viral particle formation. This exchange of viral proteins can be directed to target cells prior to infection to interfere with restriction factors and intrinsic immunity, thus, making the target cell prone to infection. However, also bystander cells, e.g. immune cell populations, can be targeted by viral proteins to dampen antiviral responses. Mechanistically, viruses exploit several routes of cell-cell communication to exchange viral proteins like the formation of extracellular vesicles or the formation of long-distance connections like tunneling nanotubes. Although it is known that viral nucleic acids can be transferred between cells as well, this chapter concentrates on viral proteins of human pathogenic viruses covering all Baltimore classes and summarizes our current knowledge on intercellular transport of viral proteins between cells.
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Affiliation(s)
- Florian Simon
- Institute of Clinical and Molecular Virology, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Andrea K Thoma-Kress
- Institute of Clinical and Molecular Virology, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
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Ramakrishnan K, Babu S, Shaji V, Soman S, Leelamma A, Rehman N, Raju R. Hepatitis B Virus Modulated Transcriptional Regulatory Map of Hepatic Cellular MicroRNAs. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:581-597. [PMID: 38064540 DOI: 10.1089/omi.2023.0171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Hepatitis B virus (HBV) is an enveloped, hepatotropic, noncytopathic virus with a partially double-stranded DNA genome. It infects hepatocytes and is associated with progression to liver fibrosis and cirrhosis, culminating in hepatocellular carcinoma (HCC), accounting for 55% of total HCC cases. MicroRNAs (miRNAs) regulated by HBV play an important role in these pathologies. Mapping the miRNAs responsive to HBV and HBV-specific proteins, including HBV X protein (HBx) that harbor the majority of HBV-human protein interactions, could aid accelerate the diagnostics and therapeutics innovation against the infection and associated diseases. With this in mind, we used a unique annotation strategy whereby we first amassed 362 mature HBV responsive-human Differentially Expressed miRNAs (HBV-hDEmiRs). The core experimentally-validated messenger RNA targets of the HBV-hDEmiRs were mostly associated with viral infections and hepatic inflammation processes. Moreover, our annotation strategy enabled the characterization of HBx-dependent/independent HBV-hDEmiRs as a tool for evaluation of the impact of HBx as a therapeutic target. Bioinformatics analysis of the HBV-human protein-protein interactome revealed new insights into the transcriptional regulatory network of the HBV-hDEmiRs. We performed a comparative analysis of data on miRNAs gathered from HBV infected cell line studies and from tissue studies of fibrosis, cirrhosis, and HCC. Accordingly, we propose hsa-miR-15a-5p that is downregulated by multiple HBV proteins, including HBx, as a potential biomarker of HBV infection, and its progression to HCC. In all, this study underscores (1) the complexity of miRNA regulation in response to HBV infection and its progression into other liver pathologies and (2) provides a regulatory map of HBV-hDEmiRs and the underlying mechanisms modulating their expression through a cross talk between HBV viral proteins and human transcription factors.
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Affiliation(s)
| | - Sreeranjini Babu
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
| | - Vineetha Shaji
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
| | - Sowmya Soman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
| | - Anila Leelamma
- Department of Biochemistry, NSS College, Nilamel, Kollam, Kerala, India
| | - Niyas Rehman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
| | - Rajesh Raju
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
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9
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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Huang H, Mehta A, Kalmanovich J, Anand A, Bejarano MC, Garg T, Khan N, Tonpouwo GK, Shkodina AD, Bardhan M. Immunological and inflammatory effects of infectious diseases in circadian rhythm disruption and future therapeutic directions. Mol Biol Rep 2023; 50:3739-3753. [PMID: 36656437 PMCID: PMC9851103 DOI: 10.1007/s11033-023-08276-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 01/11/2023] [Indexed: 01/20/2023]
Abstract
BACKGROUND Circadian rhythm is characterised by daily variations in biological activity to align with the light and dark cycle. These diurnal variations, in turn, influence physiological functions such as blood pressure, temperature, and sleep-wake cycle. Though it is well established that the circadian pathway is linked to pro-inflammatory responses and circulating immune cells, its association with infectious diseases is widely unknown. OBJECTIVE This comprehensive review aims to describe the association between circadian rhythm and host immune response to various kinds of infection. METHODS We conducted a literature search in databases Pubmed/Medline and Science direct. Our paper includes a comprehensive analysis of findings from articles in English which was related to our hypothesis. FINDINGS Molecular clocks determine circadian rhythm disruption in response to infection, influencing the host's response toward infection. Moreover, there is a complex interplay with intrinsic oscillators of pathogens and the influence of specific infectious processes on the CLOCK: BMAL1 pathway. Such mechanisms vary for bacterial and viral infections, both well studied in the literature. However, less is known about the association of parasitic infections and fungal pathogens with circadian rhythm modulation. CONCLUSION It is shown that bidirectional relationships exist between circadian rhythm disruption and infectious process, which contains interplay between the host's and pathogens' circadian oscillator, immune response, and the influence of specific infectious. Further studies exploring the modulations of circadian rhythm and immunity can offer novel explanations of different susceptibilities to infection and can lead to therapeutic avenues in circadian immune modulation of infectious diseases.
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Affiliation(s)
- Helen Huang
- Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Aashna Mehta
- Faculty of Medicine, University of Debrecen, Debrecen, 4032 Hungary
| | | | - Ayush Anand
- B. P. Koirala Institute of Health Sciences, Dharan, Nepal
| | - Maria Chilo Bejarano
- Facultad de Ciencias de la Salud Humana, Universidad Autónoma Gabriel René Moreno, Santa Cruz de la Sierra, Bolivia
| | - Tulika Garg
- Government Medical College and Hospital, Chandigarh, India
| | - Nida Khan
- Jinnah Sindh Medical University, Karachi, Pakistan
| | - Gauvain Kankeu Tonpouwo
- Faculté de Médecine, Université de Lubumbashi, Plaine Tshombé, Lubumbashi, Democratic Republic of the Congo
| | | | - Mainak Bardhan
- ICMR-National Institute of Cholera and Enteric Diseases (NICED), Kolkata, India
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11
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Abstract
In recent years, it has become clear that gut microbiota plays a major role in the human body, both in health and disease. Because of that, the gut microbiome and its impact on human well-being are getting wider and wider attention. Studies focused on the liver are not an exception. However, the majority of the analyses are concentrated on the bacterial part of the gut microbiota, while the fungi living in the human intestines are often omitted or underappreciated. This review is focused on the gut mycobiome as an important factor that should be taken into consideration regarding liver homeostasis and its perturbations. We have collected the findings in this field and we discuss their importance. We aim to emphasize the fungal compositional changes related to liver diseases and, by that, provide novel insights into the directions of liver research and gut microbiota as a therapeutic target for liver diseases.
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Affiliation(s)
- Natalia Szóstak
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Marek Figlerowicz
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Anna Philips
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
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12
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Tourkochristou E, Assimakopoulos SF, Thomopoulos K, Marangos M, Triantos C. NAFLD and HBV interplay - related mechanisms underlying liver disease progression. Front Immunol 2022; 13:965548. [PMID: 36544761 PMCID: PMC9760931 DOI: 10.3389/fimmu.2022.965548] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 11/15/2022] [Indexed: 12/08/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and Hepatitis B virus infection (HBV) constitute common chronic liver diseases with worldwide distribution. NAFLD burden is expected to grow in the coming decade, especially in western countries, considering the increased incidence of diabetes and obesity. Despite the organized HBV vaccinations and use of anti-viral therapies globally, HBV infection remains endemic and challenging public health issue. As both NAFLD and HBV have been associated with the development of progressive fibrosis, cirrhosis and hepatocellular carcinoma (HCC), the co-occurrence of both diseases has gained great research and clinical interest. The causative relationship between NAFLD and HBV infection has not been elucidated so far. Dysregulated fatty acid metabolism and lipotoxicity in NAFLD disease seems to initiate activation of signaling pathways that enhance pro-inflammatory responses and disrupt hepatocyte cell homeostasis, promoting progression of NAFLD disease to NASH, fibrosis and HCC and can affect HBV replication and immune encountering of HBV virus, which may further have impact on liver disease progression. Chronic HBV infection is suggested to have an influence on metabolic changes, which could lead to NAFLD development and the HBV-induced inflammatory responses and molecular pathways may constitute an aggravating factor in hepatic steatosis development. The observed altered immune homeostasis in both HBV infection and NAFLD could be associated with progression to HCC development. Elucidation of the possible mechanisms beyond HBV chronic infection and NAFLD diseases, which could lead to advanced liver disease or increase the risk for severe complications, in the case of HBV-NAFLD co-existence is of high clinical significance in the context of designing effective therapeutic targets.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Stelios F. Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
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13
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Kori M, Arga KY. Human oncogenic viruses: an overview of protein biomarkers in viral cancers and their potential use in clinics. Expert Rev Anticancer Ther 2022; 22:1211-1224. [PMID: 36270027 DOI: 10.1080/14737140.2022.2139681] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
INTRODUCTION Although the idea that carcinogenesis might be caused by viruses was first voiced about 100 years ago, today's data disappointingly show that we have not made much progress in preventing and/or treating viral cancers in a century. According to recent studies, infections are responsible for approximately 13% of cancer development in the world. Today, it is accepted and proven by many authorities that Epstein-Barr virus (EBV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human Herpesvirus 8 (HHV8), Human T-cell Lymphotropic virus 1 (HTLV1) and highly oncogenic Human Papillomaviruses (HPVs) cause or/and contribute to cancer development in humans. AREAS COVERED Considering the insufficient prevention and/or treatment strategies for viral cancers, in this review we present the current knowledge on protein biomarkers of oncogenic viruses. In addition, we aimed to decipher their potential for clinical use by evaluating whether the proposed biomarkers are expressed in body fluids, are druggable, and act as tumor suppressors or oncoproteins. EXPERT OPINION Consequently, we believe that this review will shed light on researchers and provide a guide to find remarkable solutions for the prevention and/or treatment of viral cancers.
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Affiliation(s)
- Medi Kori
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey
| | - Kazim Yalcin Arga
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey.,Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
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14
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Batskikh S, Morozov S, Dorofeev A, Borunova Z, Kostyushev D, Brezgin S, Kostyusheva A, Chulanov V. Previous hepatitis B viral infection-an underestimated cause of pancreatic cancer. World J Gastroenterol 2022; 28:4812-4822. [PMID: 36156926 PMCID: PMC9476854 DOI: 10.3748/wjg.v28.i33.4812] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/15/2022] [Accepted: 08/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The etiology of pancreatic cancer remains unclear. This limits the possibility of prevention and effective treatment. Hepatitis B virus (HBV) is responsible for the development of different types of cancer, but its role in pancreatic cancer is still being discussed. AIM To assess the prevalence of previous HBV infection and to identify viral biomarkers in patients with pancreatic ductal adenocarcinoma (PDAC) to support the role of the virus in etiology of this cancer. METHODS The data of 130 hepatitis B surface antigen-negative subjects were available for the final analysis, including 60 patients with PDAC confirmed by cytology or histology and 70 sex- and age-matched controls. All the participants were tested for HBV biomarkers in blood [antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs) and HBV DNA], and for those with PDAC, biomarkers in resected pancreatic tissues were tested (HBV DNA, HBV pregenomic RNA and covalently closed circular DNA). We performed immunohistochemistry staining of pancreatic tissues for hepatitis B virus X antigen and Ki-67 protein. Non-parametric statistics were used for the analysis. RESULTS Anti-HBc was detected in 18/60 (30%) patients with PDAC and in 9/70 (13%) participants in the control group (P = 0.029). Accordingly, the odds of PDAC in anti-HBc-positive subjects were higher compared to those with no previous HBV infection (odds ratio: 2.905, 95% confidence interval: 1.191-7.084, standard error 0.455). HBV DNA was detected in 8 cases of PDAC and in 6 of them in the pancreatic tumor tissue samples only (all patients were anti-HBc positive). Blood HBV DNA was negative in all subjects of the control group with positive results of the serum anti-HBc test. Among 9 patients with PDAC, 5 revealed signs of replicative competence of the virus (covalently closed circular DNA with or without pregenomic RNA) in the pancreatic tumor tissue samples. Hepatitis B virus X antigen expression and active cell proliferation was revealed by immunohistochemistry in 4 patients with PDAC in the pancreatic tumor tissue samples. CONCLUSION We found significantly higher risks of PDAC in anti-HBc-positive patients. Detection of viral replication and hepatitis B virus X protein expression in the tumor tissue prove involvement of HBV infection in pancreatic cancer development.
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Affiliation(s)
- Sergey Batskikh
- Department of Hepatology, Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia
| | - Sergey Morozov
- Department of Gastroenterology, Hepatology and Nutrition, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow 115446, Russia
| | - Alexey Dorofeev
- Department of Scientific and Clinical Laboratory Research, Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia
| | - Zanna Borunova
- Department of Scientific and Clinical Laboratory Research, Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia
| | - Dmitry Kostyushev
- Laboratory of Genetic Technologies, Sechenov University, Moscow 119435, Russia
- Division of Biotechnology, Scientific Center for Genetics and Life Sciences, Sirius University of Science and Technology, Sochi 354340, Russia
| | - Sergey Brezgin
- Laboratory of Genetic Technologies, Sechenov University, Moscow 119435, Russia
- Division of Biotechnology, Scientific Center for Genetics and Life Sciences, Sirius University of Science and Technology, Sochi 354340, Russia
| | | | - Vladimir Chulanov
- Laboratory of Genetic Technologies, Sechenov University, Moscow 119435, Russia
- Division of Biotechnology, Scientific Center for Genetics and Life Sciences, Sirius University of Science and Technology, Sochi 354340, Russia
- Laboratory of Genetic Technologies and Translational Research, National Medical Research Center for Tuberculosis and Infectious Diseases of Ministry of Health of Russia, Moscow 127994, Russia
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15
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Batskikh S, Morozov S, Kostyushev D. Hepatitis B virus markers in hepatitis B surface antigen negative patients with pancreatic cancer: Two case reports. World J Hepatol 2022; 14:1512-1519. [PMID: 36158906 PMCID: PMC9376784 DOI: 10.4254/wjh.v14.i7.1512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/25/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is a known carcinogen that may be involved in pancreatic cancer development. Detection of HBV biomarkers [especially expression of HBV regulatory X protein (HBx)] within the tumor tissue may provide direct support for this. However, there is still a lack of such reports, particularly in non-endemic regions for HBV infection. Here we present two cases of patients with pancreatic ductal adenocarcinoma, without a history of viral hepatitis, in whom the markers of HBV infection were detected in blood and in the resected pancreatic tissue. CASE SUMMARY The results of examination of two patients with pancreatic cancer, who gave informed consent for participation and publication, were the source for this study. Besides standards of care, special examination to reveal occult HBV infection was performed. This included blood tests for HBsAg, anti-HBc, anti-HBs, HBV DNA, and pancreatic tissue examinations with polymerase chain reaction for HBV DNA, pregenomic HBV RNA (pgRNA HBV), and covalently closed circular DNA HBV (cccDNA) and immunohistochemistry staining for HBxAg and Ki-67. Both subjects were operated on due to pancreatic ductal adenocarcinoma and serum HBsAg was not detected. However, in both of them anti-HBc antibodies were detected in blood, although HBV DNA was not found. Examination of the resected pancreatic tissue gave positive results for HBV DNA, expression of HBx, and active cellular proliferation by Ki-67 index in both cases. However, HBV pgRNA and cccDNA were detected only in case 1. CONCLUSION These cases may reflect potential involvement of HBV infection in the development of pancreatic cancer.
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Affiliation(s)
- Sergey Batskikh
- Department of Hepatology, Moscow Clinical Research Center named after A.S. Loginov, Moscow 111123, Russia
| | - Sergey Morozov
- Department of Gastroenterology, Hepatology and Nutrition, Federal Research Center of Nutrition and Biotechnology, Moscow 115446, Russia.
| | - Dmitry Kostyushev
- Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
- Division of Biotechnology, Sirius University of Science and Technology, Sochi 354340, Russia
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16
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Kim JY, Choi H, Kim HJ, Jee Y, Noh M, Lee MO. Polyploidization of Hepatocytes: Insights into the Pathogenesis of Liver Diseases. Biomol Ther (Seoul) 2022; 30:391-398. [PMID: 35790893 PMCID: PMC9424332 DOI: 10.4062/biomolther.2022.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 05/27/2022] [Accepted: 05/28/2022] [Indexed: 11/26/2022] Open
Abstract
Polyploidization is a process by which cells are induced to possess more than two sets of chromosomes. Although polyploidization is not frequent in mammals, it is closely associated with development and differentiation of specific tissues and organs. The liver is one of the mammalian organs that displays ploidy dynamics in physiological homeostasis during its development. The ratio of polyploid hepatocytes increases significantly in response to hepatic injury from aging, viral infection, iron overload, surgical resection, or metabolic overload, such as that from non-alcoholic fatty liver diseases (NAFLDs). One of the unique features of NAFLD is the marked heterogeneity of hepatocyte nuclear size, which is strongly associated with an adverse liver-related outcome, such as hepatocellular carcinoma, liver transplantation, and liver-related death. Thus, hepatic polyploidization has been suggested as a potential driver in the progression of NAFLDs that are involved in the control of the multiple pathogenicity of the diseases. However, the importance of polyploidy in diverse pathophysiological contexts remains elusive. Recently, several studies reported successful improvement of symptoms of NAFLDs by reducing pathological polyploidy or by controlling cell cycle progression in animal models, suggesting that better understanding the mechanisms of pathological hepatic polyploidy may provide insights into the treatment of hepatic disorders.
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Affiliation(s)
- Ju-Yeon Kim
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
| | - Haena Choi
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
| | - Hyeon-Ji Kim
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 00826, Republic of Korea
| | - Yelin Jee
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
| | - Minsoo Noh
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 00826, Republic of Korea
| | - Mi-Ock Lee
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 00826, Republic of Korea
- Bio-MAX institute, Seoul National University, Seoul 08826, Republic of Korea
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17
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Javadzadeh S, Rajkumar U, Nguyen N, Sarmashghi S, Luebeck J, Shang J, Bafna V. FastViFi: Fast and accurate detection of (Hybrid) Viral DNA and RNA. NAR Genom Bioinform 2022; 4:lqac032. [PMID: 35493723 PMCID: PMC9041341 DOI: 10.1093/nargab/lqac032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 03/04/2022] [Accepted: 03/06/2022] [Indexed: 11/13/2022] Open
Abstract
DNA viruses are important infectious agents known to mediate a large number of human diseases, including cancer. Viral integration into the host genome and the formation of hybrid transcripts are also associated with increased pathogenicity. The high variability of viral genomes, however requires the use of sensitive ensemble hidden Markov models that add to the computational complexity, often requiring > 40 CPU-hours per sample. Here, we describe FastViFi, a fast 2-stage filtering method that reduces the computational burden. On simulated and cancer genomic data, FastViFi improved the running time by 2 orders of magnitude with comparable accuracy on challenging data sets. Recently published methods have focused on identification of location of viral integration into the human host genome using local assembly, but do not extend to RNA. To identify human viral hybrid transcripts, we additionally developed ensemble Hidden Markov Models for the Epstein Barr virus (EBV) to add to the models for Hepatitis B (HBV), Hepatitis C (HCV) viruses and the Human Papillomavirus (HPV), and used FastViFi to query RNA-seq data from Gastric cancer (EBV) and liver cancer (HBV/HCV). FastViFi ran in <10 minutes per sample and identified multiple hybrids that fuse viral and human genes suggesting new mechanisms for oncoviral pathogenicity. FastViFi is available at https://github.com/sara-javadzadeh/FastViFi.
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Affiliation(s)
- Sara Javadzadeh
- Department of Computer Science & Engineering, UC San Diego, La Jolla, California, USA
| | - Utkrisht Rajkumar
- Department of Computer Science & Engineering, UC San Diego, La Jolla, California, USA
| | - Nam Nguyen
- Boundless Bio, Inc. 11099 N Torrey Pines Rd, La Jolla, CA, USA
| | - Shahab Sarmashghi
- Department of Electrical and Computer Engineering, UC San Diego, La Jolla, California, USA
| | - Jens Luebeck
- Bioinformatics & Systems Biology Graduate Program, UC San Diego, La Jolla, California, USA
| | - Jingbo Shang
- Department of Computer Science & Engineering, UC San Diego, La Jolla, California, USA
| | - Vineet Bafna
- Department of Computer Science & Engineering, UC San Diego, La Jolla, California, USA
- Boundless Bio, Inc. 11099 N Torrey Pines Rd, La Jolla, CA, USA
- Moores Cancer Center, UC San Diego, La Jolla, California, USA
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18
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Huang ZH, Lu GY, Qiu LX, Zhong GH, Huang Y, Yao XM, Liu XH, Huang SJ, Wu T, Yuan Q, Wang YB, Su YY, Zhang J, Xia NS. Risk of hepatocellular carcinoma in antiviral treatment-naïve chronic hepatitis B patients treated with entecavir or tenofovir disoproxil fumarate: a network meta-analysis. BMC Cancer 2022; 22:287. [PMID: 35300634 PMCID: PMC8930063 DOI: 10.1186/s12885-022-09413-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Long-term antiviral treatments are associated with a significantly lower hepatocellular carcinoma (HCC) incidence in chronic hepatitis B (CHB) patients by reducing HBV DNA concentrations. However, it is still controversial whether antiviral strategies affect HCC development in antiviral treatment-naïve CHB patients. This study aimed to estimate the incidence of HCC in antiviral treatment-naïve CHB patients who were treated with Entecavir (ETV) and Tenofovir Disoproxil Fumarate (TDF) and compare the efficacy of two treatment regimens in HCC reduction. METHODS The PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases were systematically searched until June 24, 2021. The pooled incidence and 95% confidence interval of HCC were calculated by the Freeman-Tukey double arcsine transformation method. The efficacies of ETV and TDF treatments in HCC reduction were compared through a network meta-analysis. RESULTS A total of 27 studies were identified as eligible for this systematic review. The incidence densities in the ETV and TDF treatment groups were 2.78 (95% CI: 2.21-3.40) and 2.59 (95% CI: 1.51-3.96) per 100 persons-year among patients with preexisting cirrhosis and 0.49 (95% CI: 0.32-0.68) and 0.30 (95% CI: 0.06-0.70) per 100 persons-year among patients without preexisting cirrhosis. As the proportion of CHB patients with preexisting cirrhosis increased, the incidence density of HCC also increased gradually. Compared with other Nucleos(t)ide analogs (NAs) treatments, ETV and TDF treatments significantly lowered the risk of HCC, with hazard ratios (HRs) of 0.60 (95% CI: 0.40-0.90) and 0.56 (95% CI: 0.35-0.89), respectively. However, there was no difference in the incidence density of HCC between ETV and TDF treatments (HR = 0.92, 95% CI: 0.71-1.20) regardless of preexisting cirrhosis. CONCLUSION ETV and TDF treatments were associated with significantly lower risks of HCC than other NAs treatments. However, no difference was observed between ETV and TDF treatments in the risk of HCC development regardless of preexisting cirrhosis among treatment-naïve CHB patients.
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Affiliation(s)
- Ze-Hong Huang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
| | - Gui-Yang Lu
- The First Affiliated Hospital of Xiamen University, Xiamen, 361003, Fujian, China
| | - Ling-Xian Qiu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
| | - Guo-Hua Zhong
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
| | - Yue Huang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
| | - Xing-Mei Yao
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
| | - Xiao-Hui Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
| | - Shou-Jie Huang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
| | - Ting Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
| | - Quan Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
| | - Ying-Bin Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China.
| | - Ying-Ying Su
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China.
| | - Jun Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
| | - Ning-Shao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Strait Collaborative Innovation Center of Biomedicine and Pharmaceutics, School of Public Health, Xiamen University, Fujian, 361102, Xiamen, China
- The Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen, 361102, Fujian, China
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19
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Grohmann C, Marapana DS, Ebert G. Targeted protein degradation at the host-pathogen interface. Mol Microbiol 2021; 117:670-681. [PMID: 34816514 DOI: 10.1111/mmi.14849] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 12/24/2022]
Abstract
Infectious diseases remain a major burden to global health. Despite the implementation of successful vaccination campaigns and efficient drugs, the increasing emergence of pathogenic vaccine or treatment resistance demands novel therapeutic strategies. The development of traditional therapies using small-molecule drugs is based on modulating protein function and activity through the occupation of active sites such as enzyme inhibition or ligand-receptor binding. These prerequisites result in the majority of host and pathogenic disease-relevant, nonenzymatic and structural proteins being labeled "undruggable." Targeted protein degradation (TPD) emerged as a powerful strategy to eliminate proteins of interest including those of the undruggable variety. Proteolysis-targeting chimeras (PROTACs) are rationally designed heterobifunctional small molecules that exploit the cellular ubiquitin-proteasome system to specifically mediate the highly selective and effective degradation of target proteins. PROTACs have shown remarkable results in the degradation of various cancer-associated proteins, and several candidates are already in clinical development. Significantly, PROTAC-mediated TPD holds great potential for targeting and modulating pathogenic proteins, especially in the face of increasing drug resistance to the best-in-class treatments. In this review, we discuss advances in the development of TPD in the context of targeting the host-pathogen interface and speculate on their potential use to combat viral, bacterial, and parasitic infection.
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Affiliation(s)
- Christoph Grohmann
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Danushka S Marapana
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Gregor Ebert
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
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20
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Medhat A, Arzumanyan A, Feitelson MA. Hepatitis B x antigen (HBx) is an important therapeutic target in the pathogenesis of hepatocellular carcinoma. Oncotarget 2021; 12:2421-2433. [PMID: 34853663 PMCID: PMC8629409 DOI: 10.18632/oncotarget.28077] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/04/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is a human pathogen that has infected an estimated two billion people worldwide. Despite the availability of highly efficacious vaccines, universal screening of the blood supply for virus, and potent direct acting anti-viral drugs, there are more than 250 million carriers of HBV who are at risk for the sequential development of hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). More than 800,000 deaths per year are attributed to chronic hepatitis B. Many different therapeutic approaches have been developed to block virus replication, and although effective, none are curative. These treatments have little or no impact upon the portions of integrated HBV DNA, which often encode the virus regulatory protein, HBx. Although given little attention, HBx is an important therapeutic target because it contributes importantly to (a) HBV replication, (b) in protecting infected cells from immune mediated destruction during chronic infection, and (c) in the development of HCC. Thus, the development of therapies targeting HBx, combined with other established therapies, will provide a functional cure that will target virus replication and further reduce or eliminate both the morbidity and mortality associated with chronic liver disease and HCC. Simultaneous targeting of all these characteristics underscores the importance of developing therapies against HBx.
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Affiliation(s)
- Arvin Medhat
- Department of Molecular Cell Biology, Azad University, North Unit, Tehran, Iran
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Mark A Feitelson
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
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21
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Son J, Kim MJ, Lee JS, Kim JY, Chun E, Lee KY. Hepatitis B virus X Protein Promotes Liver Cancer Progression through Autophagy Induction in Response to TLR4 Stimulation. Immune Netw 2021; 21:e37. [PMID: 34796041 PMCID: PMC8568915 DOI: 10.4110/in.2021.21.e37] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/28/2021] [Accepted: 10/20/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus X (HBx) protein has been reported as a key protein regulating the pathogenesis of HBV-induced hepatocellular carcinoma (HCC). Recent evidence has shown that HBx is implicated in the activation of autophagy in hepatic cells. Nevertheless, the precise molecular and cellular mechanism by which HBx induces autophagy is still controversial. Herein, we investigated the molecular and cellular mechanism by which HBx is involved in the TRAF6-BECN1-Bcl-2 signaling for the regulation of autophagy in response to TLR4 stimulation, therefore influencing the HCC progression. HBx interacts with BECN1 (Beclin 1) and inhibits the association of the BECN1-Bcl-2 complex, which is known to prevent the assembly of the pre-autophagosomal structure. Furthermore, HBx enhances the interaction between VPS34 and TRAF6-BECN1 complex, increases the ubiquitination of BECN1, and subsequently enhances autophagy induction in response to LPS stimulation. To verify the functional role of HBx in liver cancer progression, we utilized different HCC cell lines, HepG2, SK-Hep-1, and SNU-761. HBx-expressing HepG2 cells exhibited enhanced cell migration, invasion, and cell mobility in response to LPS stimulation compared to those of control HepG2 cells. These results were consistently observed in HBx-expressed SK-Hep-1 and HBx-expressed SNU-761 cells. Taken together, our findings suggest that HBx positively regulates the induction of autophagy through the inhibition of the BECN1-Bcl-2 complex and enhancement of the TRAF6-BECN1-VPS34 complex, leading to enhance liver cancer migration and invasion.
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Affiliation(s)
- Juhee Son
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Mi-Jeong Kim
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Ji Su Lee
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Ji Young Kim
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | | | - Ki-Young Lee
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Korea
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22
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Yuan Y, Yang F, Wang Y, Guo Y. Factors associated with liver cancer prognosis after hepatectomy: A retrospective cohort study. Medicine (Baltimore) 2021; 100:e27378. [PMID: 34678864 PMCID: PMC8542119 DOI: 10.1097/md.0000000000027378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 06/15/2021] [Accepted: 09/13/2021] [Indexed: 01/05/2023] Open
Abstract
This article was to investigate risk factors influencing liver cancer prognosis after hepatectomy.Patients undergoing hepatectomy after being diagnosed with liver cancer in Zhongshan Hospital Affiliated to Xiamen University were collected in the retrospective cohort study between January 2012 and December 2017, and divided into disease progression and non-progression groups based on their prognostic status. Univariate analysis was performed on the patients' baseline and laboratory test data, with multivariate logistic regression further conducted to investigate the independent risk factors for liver cancer progression after hepatectomy.Among the 288 subjects, 159 had adverse outcomes (death or cancer recurrence). Hepatitis B and high levels of aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase (ALP), direct bilirubin, and total bilirubin as well as low level of lymphocyte (LYM) were found to be associated with disease progression in the univariate analysis, and were introduced into the multivariate logistic regression. The results indicated that patients with high ALP level (odds ratio [OR] = 1.004, 95%CI: 1.002-1.007, P = .003) and with a history of hepatitis B (OR = 2.182, 95%CI: 1.165-4.086, P = .015) had a higher risk of liver cancer progression compared with those of lower ALP level and those without hepatitis B respectively, whereas the elevated level of LYM (OR = 0.710, 95%CI: 0.516-0.978, P = .034) had favorable progression.The elevated ALP level and a history of hepatitis B may increase the risk of death or cancer recurrence, whereas high LYM level may decrease poor progression among liver cancer patients after hepatectomy. More importance should be attached to the improvement of the liver function and treatment of hepatitis B to enable a better outcome for the patients.
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Affiliation(s)
- Yutao Yuan
- Department of Clinical Laboratory, Xiamen Haicang Hospital, Xiamen, P.R. China
| | - Fangnian Yang
- Department of Blood Transfusion, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, P.R. China
| | - Yuanyuan Wang
- Department of Blood Transfusion, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, P.R. China
| | - Yusong Guo
- Department of Blood Transfusion, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, P.R. China
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23
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Liu X, Yin L, Shen S, Hou Y. Inflammation and cancer: paradoxical roles in tumorigenesis and implications in immunotherapies. Genes Dis 2021; 10:151-164. [PMID: 37013041 PMCID: PMC10066281 DOI: 10.1016/j.gendis.2021.09.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/29/2021] [Accepted: 09/23/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammation caused by persistent infections and metabolic disorders is thought to contribute to the increased cancer risk and the accelerated cancer progression. Oppositely, acute inflammation induced by bacteria-based vaccines or that is occurring after cancer selectively inhibits cancer progression and metastasis. However, the interaction between inflammation and cancer may be more complex than the current explanations for the relationship between chronic and acute inflammation and cancer. In this review, we described the impact of inflammation on cancer on the basis of three perspectives, including inflammation with different durations (chronic and acute inflammation), different scopes (systemic and local inflammation) and different occurrence sequences (inflammation occurring after and before cancer). In addition, we also introduced bacteria/virus-based cancer immunotherapies. We perceive that inflammation may be a double-edged sword with cancer-promoting and cancer-suppressing functions in certain cases. We expect to further improve the understanding of the relationship between inflammation and cancer and provide a theoretical basis for further research on their complex interaction.
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Affiliation(s)
- Xinghan Liu
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Lijie Yin
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Sunan Shen
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China
- Corresponding author. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China. Fax: +86 25 8968 8441.
| | - Yayi Hou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China
- Corresponding author. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China. Fax: +86 25 8968 8441.
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24
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Kato Y, Tabata H, Sato K, Nakamura M, Saito I, Nakanishi T. Adenovirus Vectors Expressing Eight Multiplex Guide RNAs of CRISPR/Cas9 Efficiently Disrupted Diverse Hepatitis B Virus Gene Derived from Heterogeneous Patient. Int J Mol Sci 2021; 22:10570. [PMID: 34638909 PMCID: PMC8508944 DOI: 10.3390/ijms221910570] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/22/2021] [Accepted: 09/24/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatitis B virus (HBV) chronically infects more than 240 million people worldwide, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Genome editing using CRISPR/Cas9 could provide new therapies because it can directly disrupt HBV genomes. However, because HBV genome sequences are highly diverse, the identical target sequence of guide RNA (gRNA), 20 nucleotides in length, is not necessarily present intact in the target HBV DNA in heterogeneous patients. Consequently, possible genome-editing drugs would be effective only for limited numbers of patients. Here, we show that an adenovirus vector (AdV) bearing eight multiplex gRNA expression units could be constructed in one step and amplified to a level sufficient for in vivo study with lack of deletion. Using this AdV, HBV X gene integrated in HepG2 cell chromosome derived from a heterogeneous patient was cleaved at multiple sites and disrupted. Indeed, four targets out of eight could not be cleaved due to sequence mismatches, but the remaining four targets were cleaved, producing irreversible deletions. Accordingly, the diverse X gene was disrupted at more than 90% efficiency. AdV containing eight multiplex gRNA units not only offers multiple knockouts of genes, but could also solve the problems of heterogeneous targets and escape mutants in genome-editing therapy.
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MESH Headings
- Adenoviridae/genetics
- Adenoviridae/physiology
- CRISPR-Cas Systems
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/therapy
- Carcinoma, Hepatocellular/virology
- Cell Line, Tumor
- Gene Editing/methods
- Genetic Vectors/genetics
- HEK293 Cells
- Hep G2 Cells
- Hepatitis B virus/genetics
- Hepatitis B virus/metabolism
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/therapy
- Hepatitis B, Chronic/virology
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/therapy
- Liver Neoplasms/virology
- RNA, Guide, CRISPR-Cas Systems/genetics
- RNA, Guide, CRISPR-Cas Systems/metabolism
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Viral Regulatory and Accessory Proteins/genetics
- Viral Regulatory and Accessory Proteins/metabolism
- Virus Replication/genetics
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Affiliation(s)
- Yuya Kato
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Foundation, Shinagawa-ku, Tokyo 141-0021, Japan; (Y.K.); (H.T.); (M.N.); (T.N.)
| | - Hirotaka Tabata
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Foundation, Shinagawa-ku, Tokyo 141-0021, Japan; (Y.K.); (H.T.); (M.N.); (T.N.)
- Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
| | - Kumiko Sato
- Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
| | - Mariko Nakamura
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Foundation, Shinagawa-ku, Tokyo 141-0021, Japan; (Y.K.); (H.T.); (M.N.); (T.N.)
- Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
- Center for Biomedical Research Resources, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Izumu Saito
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Foundation, Shinagawa-ku, Tokyo 141-0021, Japan; (Y.K.); (H.T.); (M.N.); (T.N.)
- Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
- Department of Physiology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Tomoko Nakanishi
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Foundation, Shinagawa-ku, Tokyo 141-0021, Japan; (Y.K.); (H.T.); (M.N.); (T.N.)
- Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
- Center for Biomedical Research Resources, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
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25
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Khoo T, Lam D, Olynyk JK. Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease. World J Gastroenterol 2021; 27:4831-4845. [PMID: 34447229 PMCID: PMC8371504 DOI: 10.3748/wjg.v27.i29.4831] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/14/2021] [Accepted: 07/21/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections with the hepatitis B and C viruses have significant worldwide health and economic impacts. Previous treatments for hepatitis C such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients. The introduction of directly acting curative antiviral therapy for hepatitis C and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments. Decreasing the prevalence of hepatitis B and C have concurrently reduced transmission rates and hence, the number of new infections. Antiviral treatments have decreased the rates of liver decompensation and as a result, lowered hospitalisation and mortality rates for both chronic hepatitis B and C infection. The quality of life of chronically infected patients has also been improved significantly by modern treatment. Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis. Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation. This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes from liver disease.
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Affiliation(s)
- Tiffany Khoo
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - Danielle Lam
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - John K Olynyk
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
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26
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Fragkou N, Sideras L, Panas P, Emmanouilides C, Sinakos E. Update on the association of hepatitis B with intrahepatic cholangiocarcinoma: Is there new evidence? World J Gastroenterol 2021; 27:4252-4275. [PMID: 34366604 PMCID: PMC8316913 DOI: 10.3748/wjg.v27.i27.4252] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/12/2021] [Accepted: 06/18/2021] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a subgroup of cholangiocarcinoma that accounts for about 10%-20% of the total cases. Infection with hepatitis B virus (HBV) is one of the most important predisposing factors leading to the formation of iCCA. It has been recently estimated based on abundant epidemiological data that the association between HBV infection and iCCA is strong with an odds ratio of about 4.5. The HBV-associated mechanisms that lead to iCCA are under intense investigation. The diagnosis of iCCA in the context of chronic liver disease is challenging and often requires histological confirmation to distinguish from hepatocellular carcinoma. It is currently unclear whether antiviral treatment for HBV can decrease the incidence of iCCA. In terms of management, surgical resection remains the mainstay of treatment. There is a need for effective treatment modalities beyond resection in both first- and second-line treatment. In this review, we summarize the epidemiological evidence that links the two entities, discuss the pathogenesis of HBV-associated iCCA, and present the available data on the diagnosis and management of this cancer.
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Affiliation(s)
- Nikolaos Fragkou
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Lazaros Sideras
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Panteleimon Panas
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | | | - Emmanouil Sinakos
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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27
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Dzobo K. The Role of Viruses in Carcinogenesis and Molecular Targeting: From Infection to Being a Component of the Tumor Microenvironment. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 25:358-371. [PMID: 34037476 DOI: 10.1089/omi.2021.0052] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
About a tenth of all cancers are caused by viruses or associated with viral infection. Recent global events including the coronavirus disease-2019 (COVID-19) pandemic means that human encounter with viruses is increased. Cancer development in individuals with viral infection can take many years after infection, demonstrating that the involvement of viruses in cancer development is a long and complex process. This complexity emanates from individual genetic heterogeneity and the many steps involved in cancer development owing to viruses. The process of tumorigenesis is driven by the complex interaction between several viral factors and host factors leading to the creation of a tumor microenvironment (TME) that is ideal and promotes tumor formation. Viruses associated with human cancers ensure their survival and proliferation through activation of several cellular processes including inflammation, migration, and invasion, resistance to apoptosis and growth suppressors. In addition, most human oncoviruses evade immune detection and can activate signaling cascades including the PI3K-Akt-mTOR, Notch and Wnt pathways associated with enhanced proliferation and angiogenesis. This expert review examines and synthesizes the multiple biological factors related to oncoviruses, and the signaling cascades activated by these viruses contributing to viral oncogenesis. In particular, I examine and review the Epstein-Barr virus, human papillomaviruses, and Kaposi's sarcoma herpes virus in a context of cancer pathogenesis. I conclude with a future outlook on therapeutic targeting of the viruses and their associated oncogenic pathways within the TME. These anticancer strategies can be in the form of, but not limited to, antibodies and inhibitors.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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28
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Guo J, Gao XS. Prediction models for development of hepatocellular carcinoma in chronic hepatitis B patients. World J Clin Cases 2021; 9:3238-3251. [PMID: 34002133 PMCID: PMC8107908 DOI: 10.12998/wjcc.v9.i14.3238] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/11/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is a major health problem in Asian-Pacific regions. Antiviral therapy reduces, but does not completely prevent, HCC development. Thus, there is a need for accurate risk prediction to assist prognostication and decisions on the need for antiviral therapy and HCC surveillance. A few risk scores have been developed to predict the occurrence of HCC in CHB patients. Initially, the scores were derived from untreated CHB patients. With the development and extensive clinical application of nucleos(t)ide analog(s) (NA), the number of risk scores based on treated CHB patients has increased gradually. The components included in risk scores may be categorized into host factors and hepatitis B virus factors. Hepatitis activities, hepatitis B virus factors, and even liver fibrosis or cirrhosis are relatively controlled by antiviral therapy. Therefore, variables that are more dynamic during antiviral therapy have since been included in risk scores. However, host factors are more difficult to modify. Most existing scores derived from Asian populations have been confirmed to be accurate in predicting HCC development in CHB patients from Asia, while these scores have not offered excellent predictability in Caucasian patients. These findings support that more relevant variables should be considered to provide individualized predictions that are easily applied to CHB patients of different ethnicities. CHB patients should receive different intensities of HCC surveillance according to their risk category.
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Affiliation(s)
- Jiang Guo
- Department of Interventional Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xue-Song Gao
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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29
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Huang FY, Wong DKH, Seto WK, Mak LY, Cheung TT, Yuen MF. Tumor suppressive role of mitochondrial sirtuin 4 in induction of G2/M cell cycle arrest and apoptosis in hepatitis B virus-related hepatocellular carcinoma. Cell Death Discov 2021; 7:88. [PMID: 33931611 PMCID: PMC8087836 DOI: 10.1038/s41420-021-00470-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 03/06/2021] [Accepted: 04/03/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is developed from uncontrolled cell growth after the malignant transformation of hepatocytes. The hepatitis B virus (HBV) X protein (HBx) has shown to induce cell cycle progression and hepatocarcinogenesis. A sub-fraction of HBx is localized in the mitochondria. Sirtuin 4 (SIRT4), a mitochondrial protein, has been demonstrated to play a tumor-suppressive role in many cancers, including HCC. However, little is known about the association between mitochondrial HBx and SIRT4 during hepatocarcinogenesis. We aimed to investigate the clinical significance and functional role of SIRT4 in HBV-related HCC. SIRT4 expression was significantly lower in the HCC tissues collected from 30 patients with HBV-related HCC than in normal liver tissues from control patients (p < 0.0001). TCGA data analysis indicated that SIRT4 expression was also lower in patients with HBV infection than in those without, and SIRT4 levels were positively associated with better patient survival. Similarly, HCC cell lines had lower SIRT4 expression than normal liver cell lines (all p < 0.01). Among the HCC cell lines, those harbored HBV had a lower SIRT4 expression than those without HBV (p < 0.0001). In vitro experiments revealed that stable HBx transfection suppressed SIRT4 expression in both HepG2 and Huh7 cells (both p < 0.001). Ectopic SIRT4 overexpression alone could induce cellular senescence through arresting cell-cycle progression at G2/M, and inducing cell apoptosis in HCC cells. Mechanistically, SIRT4 upregulated cell-cycle governing genes p16 and p21 protein expression, suppressed CyclinB1/Cdc2 and Cdc25c which normally induce cell-cycle progression, and suppressed survivin to induce apoptosis. Our findings demonstrate the interaction between HBV and SIRT4 in the context of HCC. SIRT4 involves in G2/M DNA damage checkpoint control and genomic stability in hepatocarcinogenesis, which could be targeted for future anticancer strategies.
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Affiliation(s)
- Fung-Yu Huang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Tan-To Cheung
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China.,Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China. .,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China.
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30
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Péneau C, Zucman-Rossi J, Nault JC. Genomics of Viral Hepatitis-Associated Liver Tumors. J Clin Med 2021; 10:1827. [PMID: 33922394 PMCID: PMC8122827 DOI: 10.3390/jcm10091827] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/15/2021] [Accepted: 04/18/2021] [Indexed: 12/25/2022] Open
Abstract
Virus-related liver carcinogenesis is one of the main contributors of cancer-related death worldwide mainly due to the impact of chronic hepatitis B and C infections. Three mechanisms have been proposed to explain the oncogenic properties of hepatitis B virus (HBV) infection: induction of chronic inflammation and cirrhosis, expression of HBV oncogenic proteins, and insertional mutagenesis into the genome of infected hepatocytes. Hepatitis B insertional mutagenesis modifies the function of cancer driver genes and could promote chromosomal instability. In contrast, hepatitis C virus promotes hepatocellular carcinoma (HCC) occurrence mainly through cirrhosis development whereas the direct oncogenic role of the virus in human remains debated. Finally, adeno associated virus type 2 (AAV2), a defective DNA virus, has been associated with occurrence of HCC harboring insertional mutagenesis of the virus. Since these tumors developed in a non-cirrhotic context and in the absence of a known etiological factor, AAV2 appears to be the direct cause of tumor development in these patients via a mechanism of insertional mutagenesis altering similar oncogenes and tumor suppressor genes targeted by HBV. A better understanding of virus-related oncogenesis will be helpful to develop new preventive strategies and therapies directed against specific alterations observed in virus-related HCC.
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Affiliation(s)
- Camille Péneau
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
- Hôpital Européen Georges Pompidou, APHP, F-75015 Paris, France
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
- Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, F-93000 Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, F-93000 Bobigny, France
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31
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Otoguro T, Tanaka T, Kasai H, Kobayashi N, Yamashita A, Fukuhara T, Ryo A, Fukai M, Taketomi A, Matsuura Y, Moriishi K. Establishment of a Cell Culture Model Permissive for Infection by Hepatitis B and C Viruses. Hepatol Commun 2021; 5:634-649. [PMID: 33860122 PMCID: PMC8034569 DOI: 10.1002/hep4.1653] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 11/19/2020] [Accepted: 11/22/2020] [Indexed: 12/18/2022] Open
Abstract
Compared with each monoinfection, coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) is well known to increase the risks of developing liver cirrhosis and hepatocellular carcinoma. However, the mechanism by which HBV/HCV coinfection is established in hepatocytes is not well understood. Common cell culture models for coinfection are required to examine viral propagation. In this study, we aimed to establish a cell line permissive for both HBV and HCV infection. We first prepared a HepG2 cell line expressing sodium taurocholate cotransporting polypeptide, an HBV receptor, and then selected a cell line highly permissive for HBV infection, G2/NT18-B. After transduction with a lentivirus-encoding microRNA-122, the cell line harboring the highest level of replicon RNA was selected and then treated with anti-HCV compounds to eliminate the replicon RNA. The resulting cured cell line was transduced with a plasmid-encoding CD81. The cell line permissive for HCV infection was cloned and then designated the G2BC-C2 cell line, which exhibited permissiveness for HBV and HCV propagation. JAK inhibitor I potentiated the HCV superinfection of HBV-infected cells, and fluorescence-activated cell-sorting analysis indicated that HBV/HCV double-positive cells accounted for approximately 30% of the coinfected cells. Among several host genes tested, cyclooxygenase-2 showed synergistic induction by coinfection compared with each monoinfection. Conclusion: These data indicate that our in vitro HBV/HCV coinfection system provides an easy-to-use platform for the study of host and viral responses against coinfection and the development of antiviral agents targeting HBV and HCV.
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Affiliation(s)
- Teruhime Otoguro
- Department of MicrobiologyGraduate School of Medical ScienceUniversity of YamanashiYamanashiJapan
| | - Tomohisa Tanaka
- Department of MicrobiologyGraduate School of Medical ScienceUniversity of YamanashiYamanashiJapan
| | - Hirotake Kasai
- Department of MicrobiologyGraduate School of Medical ScienceUniversity of YamanashiYamanashiJapan
| | - Nobuhiro Kobayashi
- Department of Gastroenterological Surgery IGraduate School of MedicineHokkaido UniversityHokkaidoJapan
| | - Atsuya Yamashita
- Department of MicrobiologyGraduate School of Medical ScienceUniversity of YamanashiYamanashiJapan
| | - Takasuke Fukuhara
- Department of Molecular VirologyResearch Institute for Microbial DiseasesOsaka UniversityOsakaJapan.,Department of Microbiology and ImmunologyGraduate School of MedicineHokkaido UniversityHokkaidoJapan
| | - Akihide Ryo
- Department of MicrobiologyYokohama City University Graduate School of MedicineKanagawaJapan
| | - Moto Fukai
- Department of Gastroenterological Surgery IGraduate School of MedicineHokkaido UniversityHokkaidoJapan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery IGraduate School of MedicineHokkaido UniversityHokkaidoJapan
| | - Yoshiharu Matsuura
- Department of Molecular VirologyResearch Institute for Microbial DiseasesOsaka UniversityOsakaJapan
| | - Kohji Moriishi
- Department of MicrobiologyGraduate School of Medical ScienceUniversity of YamanashiYamanashiJapan
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Siddiqui ZI, Azam SA, Khan WH, Afroz M, Farooqui SR, Amir F, Azmi MI, Anwer A, Khan S, Mehmankhah M, Parveen S, Kazim SN. An in vitro Study on the Role of Hepatitis B Virus X Protein C-Terminal Truncation in Liver Disease Development. Front Genet 2021; 12:633341. [PMID: 33777103 PMCID: PMC7994528 DOI: 10.3389/fgene.2021.633341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 02/02/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatitis B virus X protein C-terminal 127 amino acid truncation is often found expressed in hepatocellular carcinoma (HCC) tissue samples. The present in vitro study tried to determine the role of this truncation mutant in the hepatitis B-related liver diseases such as fibrosis, cirrhosis, HCC, and metastasis. HBx gene and its 127 amino acid truncation mutant were cloned in mammalian expression vectors and transfected in human hepatoma cell line. Changes in cell growth/proliferation, cell cycle phase distribution, expression of cell cycle regulatory genes, mitochondrial depolarization, and intracellular reactive oxygen species (ROS) level were analyzed. Green fluorescent protein (GFP)-tagged version of HBx and the truncation mutant were also created and the effects of truncation on HBx intracellular expression pattern and localization were studied. Effect of time lapse on protein expression pattern was also analyzed. The truncation mutant of HBx is more efficient in inducing cell proliferation, and causes more ROS production and less mitochondrial depolarization as compared with wild type (wt) HBx. In addition, gene expression is altered in favor of carcinogenesis in the presence of the truncation mutant. Furthermore, mitochondrial perinuclear aggregation is achieved earlier in the presence of the truncation mutant. Therefore, HBx C-terminal 127 amino acid truncation might be playing important roles in the development of hepatitis B-related liver diseases by inducing cell proliferation, altering gene expression, altering mitochondrial potential, inducing mitochondrial clustering and oxidative stress, and changing HBx expression pattern.
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Affiliation(s)
- Zaheenul Islam Siddiqui
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.,Department of Microbiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Syed Ali Azam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Wajihul Hasan Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Masarrat Afroz
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Sabihur Rahman Farooqui
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Fatima Amir
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Md Iqbal Azmi
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Ayesha Anwer
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Saniya Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Mahboubeh Mehmankhah
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Shama Parveen
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Syed Naqui Kazim
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
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HBV-Integration Studies in the Clinic: Role in the Natural History of Infection. Viruses 2021; 13:v13030368. [PMID: 33652619 PMCID: PMC7996909 DOI: 10.3390/v13030368] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/21/2021] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major global health problem causing acute and chronic liver disease that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) is essential for viral replication and the establishment of a persistent infection. Integrated HBV DNA represents another stable form of viral DNA regularly observed in the livers of infected patients. HBV DNA integration into the host genome occurs early after HBV infection. It is a common occurrence during the HBV life cycle, and it has been detected in all the phases of chronic infection. HBV DNA integration has long been considered to be the main contributor to liver tumorigenesis. The recent development of highly sensitive detection methods and research models has led to the clarification of some molecular and pathogenic aspects of HBV integration. Though HBV integration does not lead to replication-competent transcripts, it can act as a stable source of viral RNA and proteins, which may contribute in determining HBV-specific T-cell exhaustion and favoring virus persistence. The relationship between HBV DNA integration and the immune response in the liver microenvironment might be closely related to the development and progression of HBV-related diseases. While many new antiviral agents aimed at cccDNA elimination or silencing have been developed, integrated HBV DNA remains a difficult therapeutic challenge.
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Abstract
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in nearly 1 million deaths every year. Many of these patients die from severe liver diseases, including HCC. HBV may induce HCC through the induction of chronic liver inflammation, which can cause oxidative stress and DNA damage. However, many studies also indicated that HBV could induce HCC via the alteration of hepatocellular physiology that may involve genetic and epigenetic changes of the host DNA, the alteration of cellular signaling pathways, and the inhibition of DNA repair mechanisms. This alteration of cellular physiology can lead to the accumulation of DNA damages and the promotion of cell cycles and predispose hepatocytes to oncogenic transformation.
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Affiliation(s)
- Jiyoung Lee
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA.
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35
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Han C, Yu T, Qin W, Liao X, Huang J, Liu Z, Yu L, Liu X, Chen Z, Yang C, Wang X, Mo S, Zhu G, Su H, Li J, Qin X, Gui Y, Mo Z, Li L, Peng T. Genome-wide association study of the TP53 R249S mutation in hepatocellular carcinoma with aflatoxin B1 exposure and infection with hepatitis B virus. J Gastrointest Oncol 2020; 11:1333-1349. [PMID: 33457005 PMCID: PMC7807280 DOI: 10.21037/jgo-20-510] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 12/16/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Exposure to dietary aflatoxin B1 (AFB1) induces DNA damage and mutation in the TP53 gene at codon 249, known as the TP53 R249S mutation, and is a major risk factor for hepatocellular carcinoma (HCC). AFB1 and the hepatitis B virus (HBV) together exert synergistic effects that promote carcinogenesis and TP53 R249S mutation in HCC. METHODS A genome-wide association study (GWAS) of whole genome exons was conducted using 485 HCC patients with chronic HBV infection. This was followed by an independent replication study conducted using 270 patients with chronic HBV infection. Immunohistochemistry was used to evaluate TP53 expression in all samples. This showed a correlation between codon 249 mutations and TP53 expression. Susceptibility variants for the TP53 R249S mutation in HCC were identified based on both the GWAS and replication study. The associations between identified variants and the expression levels of their located genes were analyzed in 20 paired independent samples. RESULTS The likelihood of positive TP53 expression was found to be higher in HCC patients with the R249S mutation both in the GWAS (P<0.001) and the replication study (P=0.006). The combined analyses showed that the TP53 R249S mutation was significantly associated with three single nucleotide polymorphisms (SNPs): ADAMTS18 rs9930984 (adjusted P=4.84×10-6), WDR49 rs75218075 (adjusted P=7.36×10-5), and SLC8A3 rs8022091 (adjusted P=0.042). The TP53 R249S mutation was found to be highly associated with the TT genotypes of rs9930984 (additive model, P=0.01; dominant model, P=6.43×10-5) and rs75218075 (additive model, P=0.002; dominant model, P=2.16×10-4). Additionally, ADAMTS18 mRNA expression was significantly higher in HCC tissue compared with its expression in paired non-tumor tissue (P=0.041), and patients carrying the TT genotype at rs9930984 showed lower ADAMTS18 expression in non-tumor tissue compared with patients carrying the GT genotype (P=0.0028). WDR49 expression was markedly lower in HCC tissue compared with paired non-tumor tissue (P=0.0011). CONCLUSIONS TP53 expression is significantly associated with the R249S mutation in HCC. Our collective results suggest that rs9930984, rs75218075, and rs8022091 are associated with R249S mutation susceptibility in HCC patients exposed to AFB1 and HBV infection.
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Affiliation(s)
- Chuangye Han
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
- School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Wei Qin
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jianlu Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Long Yu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoguang Liu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhiwei Chen
- Department of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou, China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shutian Mo
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hao Su
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jiaquan Li
- Medical Scientific Research Center, Guangxi Medical University, Nanning, China
| | - Xue Qin
- Department of Clinical Laboratory, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ying Gui
- Department of Clinical Laboratory, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zengnan Mo
- Center for Genomics and Personalized Medicine, Guangxi Medical University, Nanning, China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Kayesh MEH, Amako Y, Hashem MA, Murakami S, Ogawa S, Yamamoto N, Hifumi T, Miyoshi N, Sugiyama M, Tanaka Y, Mizokami M, Kohara M, Tsukiyama-Kohara K. Development of an in vivo delivery system for CRISPR/Cas9-mediated targeting of hepatitis B virus cccDNA. Virus Res 2020; 290:198191. [PMID: 33049308 DOI: 10.1016/j.virusres.2020.198191] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/03/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B virus (HBV) infection constitutes a global health issue with limited current therapeutic efficacy owing to the persistence of viral episomal DNA (cccDNA). The CRISPR/Cas9 system, a newly developed, powerful tool for genome editing and potential gene therapy, requires efficient delivery of CRISPR components for successful therapeutic application. Here, we investigated the effects of lentiviral- or adeno-associated virus 2 (AAV2) vector-mediated delivery of 3 guide (g)RNAs/Cas9 selected from 16 gRNAs. These significantly suppressed HBV replication in cells, with WJ11/Cas9 exhibiting highest efficacy and chosen for in vivo study. AAV2/WJ11-Cas9 also significantly inhibited HBV replication and significantly reduced cccDNA in the tested cells. Moreover, AAV2/WJ11-Cas9 enhanced entecavir effects when used in combination, indicative of different modes of action. Notably, in humanized chimeric mice, AAV2/WJ11-Cas9 significantly suppressed HBcAg, HBsAg, and HBV DNA along with cccDNA in the liver tissues without significant cytotoxicity; accordingly, next generation sequencing data showed no significant genomic mutations. To our knowledge, this represents the first evaluation of the CRISPR/Cas9 system using an HBV natural infection mode. Therefore, WJ11/Cas9 delivered by comparatively safer AAV2 vectors may provide a new therapeutic strategy for eliminating HBV infection and serve as an effective platform for curing chronic HBV infection.
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Affiliation(s)
- Mohammad Enamul Hoque Kayesh
- Laboratory of Animal Hygiene, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan; Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan; Department of Microbiology and Public Health, Patuakhali Science and Technology University, Bangladesh
| | - Yutaka Amako
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Md Abul Hashem
- Laboratory of Animal Hygiene, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan; Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan
| | - Shuko Murakami
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shintaro Ogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Naoki Yamamoto
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Tatsuro Hifumi
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan; Department of Veterinary Histopathology, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan
| | - Noriaki Miyoshi
- Department of Veterinary Histopathology, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan
| | - Masaya Sugiyama
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Chiba, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Chiba, Japan
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Kyoko Tsukiyama-Kohara
- Laboratory of Animal Hygiene, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan; Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan.
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37
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Lu MP, Weng YY, Yang YS. Single-Molecule Ex Situ Atomic Force Microscopy Allows Detection of Individual Antibody-Antigen Interactions on a Semiconductor Chip Surface. ADVANCED NANOBIOMED RESEARCH 2020; 1:2000035. [PMID: 33349816 PMCID: PMC7744838 DOI: 10.1002/anbr.202000035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/22/2020] [Indexed: 11/16/2022] Open
Abstract
Although in situ atomic force microscopy (AFM) allows single‐molecule detection of antibody–antigen binding, the practical applications of in situ AFM for disease diagnosis are greatly limited, due to its operational complexity and long operational times, including the execution time for the surface chemical/biological treatments in the equipped glass liquid cell. Herein, a method of graphically superimposed alignment that enables ex situ AFM analysis of an immobilized antibody at the same location on a semiconductor chip surface before and after incubation with its antigen is presented. All of the required chemical/biological treatments are executed feasibly using standard laboratory containers, allowing single‐molecule ex situ AFM detection to be conducted with great practicality, flexibility, and versatility. As an example, the analysis of hepatitis B virus X protein (HBx) and its IgG antibody is described. Using ex situ AFM, individual information on the topographical characteristics of the immobilized single and aggregated IgG antibodies on the chip surface is extracted and the data are analyzed statistically. Furthermore, in a statistical manner, the changes in AFM‐measured heights of the individual and aggregated IgG antibodies that occur as a result of changes in conformation upon formation of IgG–HBx complexes are investigated.
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Affiliation(s)
- Ming-Pei Lu
- Taiwan Semiconductor Research Institute National Applied Research Laboratories Hsinchu 30078 Taiwan
| | - Ying-Ya Weng
- Department of Electrical and Computer Engineering Biomedical Engineering National Chiao Tung University Hsinchu Taiwan
| | - Yuh-Shyong Yang
- Department of Biological Science and Technology National Chiao Tung University Hsinchu Taiwan
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38
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Affiliation(s)
- Jie Li
- School of Medicine Huaqiao University Quanzhou 362021 P. R. China
| | - Jieqing Liu
- School of Medicine Huaqiao University Quanzhou 362021 P. R. China
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Li SK, Tang HC, Leung MMH, Zou W, Chan WL, Zhou Y, Ng IOL, Ching YP. Centrosomal protein TAX1BP2 inhibits centrosome-microtubules aberrations induced by hepatitis B virus X oncoprotein. Cancer Lett 2020; 492:147-161. [PMID: 32827601 DOI: 10.1016/j.canlet.2020.08.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/10/2020] [Accepted: 08/06/2020] [Indexed: 11/21/2022]
Abstract
Liver cancer (hepatocellular carcinoma, HCC) is one of the most prevalent cancers worldwide. Several etiological factors of HCC, including hepatitis B or hepatitis C virus infection, liver cirrhosis and aflatoxin B1 intake has been identified. HBx, which is an oncogenic protein encoded by the hepatitis B virus, is strongly associated with hepatocarcinogenesis. Using stable HBx-expressing cell, we showed that HBx induced chromosome gain, with amplification of centrosomes numbers and deregulation of centrosome ultrastructure. To dissect the mechanism for chromosome instability, our result revealed that HBx contributed to a hyperactive centrosome-microtubule dynamics by accelerating microtubule nucleation and polymerization. Further investigations suggested that HBx interacted with a centrosome linker protein TAX1BP2, which has previously been shown to function as an intrinsic block of centrosome amplification and a tumour suppressor in HCC. Restoring TAX1BP2 was able to block HBx-mediated centrosome amplification and abolish the HBx-mediated centrosome aberration, thereby suppressing chromosome instability. Thus, we demonstrate here a mechanism by which HBx deregulates centrosome-microtubule dynamics through interacting with TAX1BP2, which underlines the possibility of restoration of TAX1BP2 to rescue cells from chromosome instability.
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Affiliation(s)
- Sai-Kam Li
- School of Biomedical Sciences, Hong Kong
| | | | | | - Wenjun Zou
- School of Biomedical Sciences, Hong Kong
| | | | - Yuan Zhou
- School of Biomedical Sciences, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research (The University of Hong Kong), The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong
| | - Yick Pang Ching
- School of Biomedical Sciences, Hong Kong; State Key Laboratory of Liver Research (The University of Hong Kong), The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong.
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40
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Chen X, Xu J, Wang P, Shang L, Guo J, Huang L, Jiang YA, Chen J, Chen H, Shang Y, Zhang Q. Metallophosphoesterase 1, a novel candidate gene in hepatocellular carcinoma malignancy and recurrence. Cancer Biol Ther 2020; 21:1005-1013. [PMID: 33054568 DOI: 10.1080/15384047.2020.1824480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND There is an unmet need to identify novel mechanism-based prognostic genes associated with hepatocellular carcinoma (HCC) recurrence that can predict patient outcomes and provide therapeutic targets. This study aims to identify potential novel driver genes and mutations in HCC. METHODS Single nucleotide variations (SNVs) contributing to HCC recurrence were identified using whole-exome sequencing of 5 DNA samples extracted from a single HCC patient with HBV-induced cirrhosis. SNVs were verified in primary HCC (n = 87), recurrent HCC (n = 34), and benign liver disease with cirrhosis tissues (n = 43). A candidate gene was identified, and its association and function in HCC development and recurrence were examined. RESULTS 177 SNVs were identified and 70 SNVs were verified. A MPPE1 missense mutation on chr18_11897016 was the most frequent mutation (16.5%) in primary and recurrent HCC tissues, occurring with a higher frequency in recurrent HCC than primary HCC or benign liver tumor tissues. The MPPE1 mutation was significantly associated with HCC recurrence (P = .003), TNM stage (P = .002), and Child-Pugh classification (P = .039), and was an independent risk factor for HCC recurrence (HR = 1.969; 95%CI = 1.043-3.714, P = .037). Analysis of publically available data deposited in the GEO and TCGA showed MPPE1 expression levels were significantly increased in HCC tumor samples compared to adjacent nontumor tissues. The knockdown of MPPE1 in HCC cell lines significantly inhibited cell proliferation, migration and invasion, induced cell cycle arrest and apoptosis in vitro, and inhibited xenograft tumor growth in nude mice in vivo (P < .05). CONCLUSIONS MPPE1 is a novel gene associated with HCC malignancy and recurrence.
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Affiliation(s)
- Xinguo Chen
- Institute of Liver Surgery, Third Medical Centre of Chinese PLA General Hospital , Beijing, China
| | - Jing Xu
- Medical Research Center, Southern University of Science and Technology Hospital , Shenzhen, China.,National Translational Science Center for Molecular Medicine & Department of Cell Biology, The Fourth Military Medical University , Xi'an, China
| | - Peixiao Wang
- Institute of Liver Surgery, Third Medical Centre of Chinese PLA General Hospital , Beijing, China.,Department of Gastroenterology, Henan Children's Hospital , Zhengzhou, China
| | - Lei Shang
- Department of Health Statistics, Faculty of Preventive Medicine, Fourth Military Medical University , Xi'an, China
| | - Jing Guo
- Medical Department, Third Medical Centre of Chinese PLA General Hospital , Beijing, China
| | - Lihong Huang
- Medical Department, Third Medical Centre of Chinese PLA General Hospital , Beijing, China
| | - Yide A Jiang
- Institute of Sanofi Genzyme R&D Center, Genzyme - a Sanofi Company , Framingham, MA, USA
| | - Jinhong Chen
- Medical Department, Third Medical Centre of Chinese PLA General Hospital , Beijing, China
| | - Huijuan Chen
- Institute of Liver Surgery, Third Medical Centre of Chinese PLA General Hospital , Beijing, China
| | - Yukui Shang
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, The Fourth Military Medical University , Xi'an, China
| | - Qing Zhang
- Institute of Liver Surgery, Third Medical Centre of Chinese PLA General Hospital , Beijing, China
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Zeng G, Gill US, Kennedy PTF. Prioritisation and the initiation of HCC surveillance in CHB patients: lessons to learn from the COVID-19 crisis. Gut 2020; 69:1907-1912. [PMID: 32451325 PMCID: PMC7295856 DOI: 10.1136/gutjnl-2020-321627] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Georgia Zeng
- Faculty of Medicine, UNSW, Sydney, New South Wales, Australia
| | - Upkar S Gill
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Patrick T F Kennedy
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
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42
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Herbein G, Nehme Z. Polyploid Giant Cancer Cells, a Hallmark of Oncoviruses and a New Therapeutic Challenge. Front Oncol 2020; 10:567116. [PMID: 33154944 PMCID: PMC7591763 DOI: 10.3389/fonc.2020.567116] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 09/11/2020] [Indexed: 12/19/2022] Open
Abstract
Tumors are renowned as intricate systems that harbor heterogeneous cancer cells with distinctly diverse molecular signatures, sizes and genomic contents. Among those various genomic clonal populations within the complex tumoral architecture are the polyploid giant cancer cells (PGCC). Although described for over a century, PGCC are increasingly being recognized for their prominent role in tumorigenesis, metastasis, therapy resistance and tumor repopulation after therapy. A shared characteristic among all tumors triggered by oncoviruses is the presence of polyploidy. Those include Human Papillomaviruses (HPV), Epstein Barr Virus (EBV), Hepatitis B and C viruses (HBV and HCV, respectively), Human T-cell lymphotropic virus-1 (HTLV-1), Kaposi's sarcoma herpesvirus (KSHV) and Merkel polyomavirus (MCPyV). Distinct viral proteins, for instance Tax for HTLV-1 or HBx for HBV have demonstrated their etiologic role in favoring the appearance of PGCC. Different intriguing biological mechanisms employed by oncogenic viruses, in addition to viruses with high oncogenic potential such as human cytomegalovirus, could support the generation of PGCC, including induction of endoreplication, inactivation of tumor suppressors, development of hypoxia, activation of cellular senescence and others. Interestingly, chemoresistance and radioresistance have been reported in the context of oncovirus-induced cancers, for example KSHV and EBV-associated lymphomas and high-risk HPV-related cervical cancer. This points toward a potential linkage between the previously mentioned players and highlights PGCC as keystone cancer cells in virally-induced tumors. Subsequently, although new therapeutic approaches are actively needed to fight PGCC, attention should also be drawn to reveal the relationship between PGCC and oncoviruses, with the ultimate goal of establishing effective therapeutic platforms for treatment of virus-associated cancers. This review discusses the presence of PGCCs in tumors induced by oncoviruses, biological mechanisms potentially favoring their appearance, as well as their consequent implication at the clinical and therapeutic level.
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Affiliation(s)
- Georges Herbein
- Pathogens & Inflammation/EPILAB Laboratory, EA 4266, University of Franche-Comté, Université Bourgogne Franche-Comté (UBFC), Besançon, France.,Department of Virology, CHRU Besancon, Besançon, France
| | - Zeina Nehme
- Pathogens & Inflammation/EPILAB Laboratory, EA 4266, University of Franche-Comté, Université Bourgogne Franche-Comté (UBFC), Besançon, France.,Faculty of Sciences, Lebanese University, Beirut, Lebanon
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43
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Chang S, Wang LHC, Chen BS. Investigating Core Signaling Pathways of Hepatitis B Virus Pathogenesis for Biomarkers Identification and Drug Discovery via Systems Biology and Deep Learning Method. Biomedicines 2020; 8:biomedicines8090320. [PMID: 32878239 PMCID: PMC7555687 DOI: 10.3390/biomedicines8090320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/19/2020] [Accepted: 08/21/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B Virus (HBV) infection is a major cause of morbidity and mortality worldwide. However, poor understanding of its pathogenesis often gives rise to intractable immune escape and prognosis recurrence. Thus, a valid systematic approach based on big data mining and genome-wide RNA-seq data is imperative to further investigate the pathogenetic mechanism and identify biomarkers for drug design. In this study, systems biology method was applied to trim false positives from the host/pathogen genetic and epigenetic interaction network (HPI-GEN) under HBV infection by two-side RNA-seq data. Then, via the principal network projection (PNP) approach and the annotation of KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, significant biomarkers related to cellular dysfunctions were identified from the core cross-talk signaling pathways as drug targets. Further, based on the pre-trained deep learning-based drug-target interaction (DTI) model and the validated pharmacological properties from databases, i.e., drug regulation ability, toxicity, and sensitivity, a combination of promising multi-target drugs was designed as a multiple-molecule drug to create more possibility for the treatment of HBV infection. Therefore, with the proposed systems medicine discovery and repositioning procedure, we not only shed light on the etiologic mechanism during HBV infection but also efficiently provided a potential drug combination for therapeutic treatment of Hepatitis B.
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Affiliation(s)
- Shen Chang
- Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan;
| | - Lily Hui-Ching Wang
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan;
| | - Bor-Sen Chen
- Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan;
- Correspondence:
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Ahodantin J, Lekbaby B, Bou Nader M, Soussan P, Kremsdorf D. Hepatitis B virus X protein enhances the development of liver fibrosis and the expression of genes associated with epithelial-mesenchymal transitions and tumor progenitor cells. Carcinogenesis 2020; 41:358-367. [PMID: 31175830 DOI: 10.1093/carcin/bgz109] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 05/03/2019] [Accepted: 06/06/2019] [Indexed: 12/24/2022] Open
Abstract
The hepatitis B virus X protein (HBx) has pleiotropic biological effects, which underlies its potential role in cell transformation. However, its involvement in hepatic fibrosis remains unclear. In this study, we wanted to clarify, in vivo, the role of HBx protein in the development of liver fibrosis. Mice transgenic for the full-length HBx (FL-HBx) were used. To create liver fibrosis, FL-HBx transgenic and control mice were chronically exposed to carbon tetrachloride (CCl4). Modulation of the expression of proteins involved in matrix remodeling, hepatic metabolism and epithelial-mesenchymal transition (EMT) were investigated. In transgenic mice, FL-HBx expression potentiates CCl4-induced liver fibrosis with increased expression of proteins involved in matrix remodeling (Collagen1a, α-Sma, PdgfR-β, MMP-13). In FL-HBx transgenic mice, an increase in EMT was observed with a higher transcription of two inflammatory cytokines (TNF-α and TGF-β) and a decrease of glutamine synthetase expression level. This was associated with a sustained cell cycle and hepatocyte polyploidy alteration consistent with p38 and ERK1/2 overactivation, increase of PLK1 transcription, accumulation of SQSTM1/p62 protein and increase expression of Beclin-1. This correlates with a higher expression of tumor progenitor cell markers (AFP, Ly6D and EpCam), indicating a higher risk of progression from fibrosis to hepatocellular carcinoma (HCC) in the presence of FL-HBx protein. In conclusion, our results show that FL-HBx protein enhances the development of liver fibrosis and contributes to the progression of liver disease from chronic hepatitis to HCC.
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Affiliation(s)
- James Ahodantin
- Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France.,Centre National de la Recherche Scientifique (CNRS, ERL8255), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France
| | - Bouchra Lekbaby
- Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France.,Centre National de la Recherche Scientifique (CNRS, ERL8255), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France
| | - Myriam Bou Nader
- Team Proliferation Stress and Liver Physiopathology, Genome and Cancer, Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France.,Sorbonne Unversité, USPC, Paris, France.,Université Paris Descartes, Paris, France.,Université Paris Diderot, Paris, France
| | - Patrick Soussan
- Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France.,Centre National de la Recherche Scientifique (CNRS, ERL8255), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France
| | - Dina Kremsdorf
- Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France.,Centre National de la Recherche Scientifique (CNRS, ERL8255), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France
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Association of RASSF1A hypermethylation with risk of HBV/HCV-induced hepatocellular carcinoma: A meta-analysis. Pathol Res Pract 2020; 216:153099. [PMID: 32853942 DOI: 10.1016/j.prp.2020.153099] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/19/2020] [Accepted: 03/07/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Researchers have discovered a large number of DNA methylation patterns in human cancer. These cancer-specific methylation patterns can provide information for the diagnosis, treatment, and prognosis of cancer. Methylation studies can find new biomarkers based on epigenetic analysis and apply these biomarkers to clinical oncology. Many studies on the association between RAASF1A methylation status and susceptibility to hepatitis B virus (HBV)/hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) have reached controversial conclusions. Hence, the current review comprehensively assessed the correlation between Ras association domain family 1A (RASSF1A) methylation and the risk of the HCV/HBV-induced HCC. METHODS The appropriated publications were extracted in EMBASE, PubMed, Web of Science, Cochrane Library, and China National Knowledge Infrastructure databases using STATA 5.0 software. The odds ratios (ORs) with 95 % confidence interval (95 % CI) of RASSF1A methylation were computed. RESULTS A total of 1015 HBV/HCV-related HCC samples, 124 non-HBV/HCV-related HCC (NBNC-HCC) samples, and 1225 nontumorous controls were extracted and examined in this research. The frequency of the methylated RASSF1A in the HBV/HCV-related tumor cases displayed a significantly increased OR compared with the overall nontumor samples (OR = 19.372, 95 % CI = 11.060-33.931, P = 0.000). The frequency of the methylated RASSF1A in HBV/HCV-related neoplasm cases displayed a significantly increased OR compared with the non-HBV/HCV-related neoplasm (NBNC-neoplasm) samples (OR = 2.150, 95 % CI = 1.398-3.308, P = 0.000). Compared with normal, chronic hepatitis B or C, cirrhosis, and paracancerous samples, the pooled OR of the RASSF1A promoter methylation in the HBV/HCV-induced HCC samples was 62.785(95 % CI = 35.224-111.909), 25.07 (95 % CI = 13.85-45.36), 6.89 (95 % CI = 3.33-14.264) and 9.02 (95 % CI = 0.91-89.80), respectively. The rate of RASSF1A hypermethylation was robustly correlated with tumor size and vascular invasion, and the pooled OR was 0.346 (95 % CI = 0.210 - 0.569) and 0.081 (95 % CI = 0.022 - 0.303), respectively. CONCLUSION Results showed robust associations between RASSF1A gene methylation in promoter region and enhanced HBV/HCV-related HCC susceptibility, thereby revealing that RASSF1A methylation status may serve as an important indicator for HCC oncogenesis.
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Hodge K, Makjaroen J, Robinson J, Khoomrung S, Pisitkun T. Deep Proteomic Deconvolution of Interferons and HBV Transfection Effects on a Hepatoblastoma Cell Line. ACS OMEGA 2020; 5:16796-16810. [PMID: 32685848 PMCID: PMC7364717 DOI: 10.1021/acsomega.0c01865] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/15/2020] [Indexed: 05/13/2023]
Abstract
Interferons are commonly utilized in the treatment of chronic hepatitis B virus (HBV) infection but are not effective for all patients. A deep understanding of the limitations of interferon treatment requires delineation of its activity at multiple "omic" levels. While myriad studies have characterized the transcriptomic effects of interferon treatment, surprisingly, few have examined interferon-induced effects at the proteomic level. To remedy this paucity, we stimulated HepG2 cells with both IFN-α and IFN-λ and performed proteomic analysis versus unstimulated cells. Alongside, we examined the effects of HBV transfection in the same cell line, reasoning that parallel IFN and HBV analysis might allow determination of cases where HBV transfection counters the effects of interferons. More than 6000 proteins were identified, with multiple replicates allowing for differential expression analysis at high confidence. Drawing on a compendium of transcriptomic data, as well as proteomic half-life data, we suggest means by which transcriptomic results diverge from our proteomic results. We also invoke a recent multiomic study of HBV-related hepatocarcinoma (HCC), showing that despite HBV's role in initiating HCC, the regulated proteomic landscapes of HBV transfection and HCC do not strongly align. Special focus is applied to the proteasome, with numerous components divergently altered under IFN and HBV-transfection conditions. We also examine alterations of other protein groups relevant to HLA complex peptide display, unveiling intriguing alterations in a number of ubiquitin ligases. Finally, we invoke genome-scale metabolic modeling to predict relevant alterations to the metabolic landscape under experimental conditions. Our data should be useful as a resource for interferon and HBV researchers.
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Affiliation(s)
- Kenneth Hodge
- The
Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
| | - Jiradej Makjaroen
- The
Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
| | - Jonathan Robinson
- Department
of Biology and Biological Engineering, National Bioinformatics Infrastructure
Sweden, Science for Life Laboratory, Chalmers
University of Technology, Kemivägen 10, Gothenburg 412 96, Sweden
- Wallenberg
Center for Protein Research, Chalmers University
of Technology, Kemivägen
10, Gothenburg 412 96, Sweden
| | - Sakda Khoomrung
- Metabolomics
and Systems Biology, Department of Biochemistry, and Siriraj Metabolomics
and Phenomics Center Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Center
for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
| | - Trairak Pisitkun
- The
Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
- . Phone: +6692-537-0549
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47
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Wan Q, Song D, Li H, He ML. Stress proteins: the biological functions in virus infection, present and challenges for target-based antiviral drug development. Signal Transduct Target Ther 2020; 5:125. [PMID: 32661235 PMCID: PMC7356129 DOI: 10.1038/s41392-020-00233-4] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/26/2020] [Accepted: 06/13/2020] [Indexed: 02/06/2023] Open
Abstract
Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson’s diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.
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Affiliation(s)
- Qianya Wan
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Dan Song
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Huangcan Li
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Ming-Liang He
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China. .,CityU Shenzhen Research Institute, Shenzhen, China.
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48
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Lee HW. [Long Term Efficacy of Antiviral Therapy: Mortality and Incidence of Hepatocellular Carcinoma]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2020; 74:251-257. [PMID: 31765553 DOI: 10.4166/kjg.2019.74.5.251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/14/2019] [Accepted: 11/15/2019] [Indexed: 01/27/2023]
Abstract
Multiple studies have shown that oral antiviral therapies reduced the incidence of hepatocellular carcinoma (HCC) and improved the survival of patients with chronic hepatitis B when compared with that of untreated patients. In particular, entecavir and tenofovir share the qualities of high efficacy in reducing the HBV DNA levels, and they have excellent tolerability and safety. These drugs modified the natural history of liver fibrosis, improve liver function, decrease the incidence of HCC, decrease the need for liver transplantation, and improve survival. Many studies have suggested that long-term antiviral therapy reduces the risk of HCC and liver cirrhosis in patients with chronic hepatitis. The mechanism of these drugs in reducing the risk of HCC is not clear. This article reviews the mechanisms of carcinogenic HBV by conducting a review of the literature on the efficacy of therapy for reducing the risk of HCC. A few recent articles have suggested that tenofovir offers advantages over entecavir in terms of HCC prevention, but these articles have the inherent limitations of observational data. No other head-to-head randomized trials exist. Further randomized studies would help provide stronger evidence of the association between the type of antiviral agent and the HCC outcomes. Only achieving complete viral eradication from the liver will truly decrease the mortality and incidence of HCC.
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Affiliation(s)
- Hyun Woong Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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49
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Zhu K, Huang W, Wang W, Liao L, Li S, Yang S, Xu J, Li L, Meng M, Xie Y, He S, Tang W, Zhou H, Liang L, Gao H, Zhao Y, Hou Z, Tan J, Li R. Up-regulation of S100A4 expression by HBx protein promotes proliferation of hepatocellular carcinoma cells and its correlation with clinical survival. Gene 2020; 749:144679. [PMID: 32330536 DOI: 10.1016/j.gene.2020.144679] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/02/2020] [Accepted: 04/14/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Hepatocellular carcinoma is one of the most common cancers worldwide. HBV-related HCC has characteristics of faster progression and worse prognosis. Previous studies have confirmed that HBx protein plays numbers of important roles in development of HBV-HCC. However, the molecular mechanism of carcinogenicity of HBx is still not well documented. METHODS Firstly, a HCC cell line over-expressing HBx was established and its function was verified. Subsequently, the differentially expressed genes were detected by transcriptome sequencing technology and use the Western Blot technology to detect the up-regulated genes in HBx overexpressed cells, and the functional correlation of the genes was analyzed. Finally, tissue microarray was used to correlate up-regulated gene with clinical follow-up data to verify correlation with clinical prognosis. RESULTS Over-expression of HBx could promote cell proliferation, and over-expression of HBx could up-regulate the expression of S100A4 protein. ShRNA experiments showed that HBx promoted cell proliferation by upregulating the expression of S100A4. IFN-α2b can down-regulate the expression of S100A4 and inhibit the proliferation of HCC cells. The expression of S100A4 in cancer was significantly up-regulated compared with adjacent tissues, and was also significantly associated with tumors volume, the expression of PD-L1 and the survival time of patients with HCC. CONCLUSION In general, S100A4 may be an effective therapeutic target for HBV-HCC. And the connection between S100A4 and HBV are not clear yet. This study may play a guiding role in the future clinical treatment of HCC.
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Affiliation(s)
- Kai Zhu
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Wenwen Huang
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Wenju Wang
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Liwei Liao
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Shuo Li
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Songlin Yang
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Jingyi Xu
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Lin Li
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Mingyao Meng
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Yanhua Xie
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Shan He
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Weiwei Tang
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Haodong Zhou
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Luxin Liang
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Hui Gao
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Yiyi Zhao
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Zongliu Hou
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Jing Tan
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China.
| | - Ruhong Li
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China.
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Sagnelli E, Macera M, Russo A, Coppola N, Sagnelli C. Epidemiological and etiological variations in hepatocellular carcinoma. Infection 2020; 48:7-17. [PMID: 31347138 DOI: 10.1007/s15010-019-01345-y] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer and a leading cause of cancer-related deaths worldwide. The major risk factors for HCC development are chronic liver disease and cirrhosis due to hepatitis B virus (HBV) and/or hepatitis C virus (HCV), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, intake of aflatoxin-contaminated food, diabetes, and obesity. RESULTS In Western countries, the number of NASH-related HCC cases is increasing, that of HBV- or HCV-related cases is declining due to the wide application of HBV universal vaccination and the introduction of effective therapies against HBV and HCV infections, and that of alcohol-related cases remaining substantially unchanged. Nevertheless, the burden of HCC is expected to increase worldwide in the next few decades, due to the population growth and aging expected in coming years. Overall, the abovementioned changes and future variations in lifestyle and in the impact of environmental factors in Western countries and a decreasing exposure to dietary aflatoxins and improved socio-economic conditions in developing countries will create new HCC epidemiology in the next few decades. CONCLUSION A substantial further reduction in cases of HCC requires a wider application of universal HBV vaccination and effective treatment of HBV- and HCV-related chronic hepatitis and cirrhosis, more effective campaigns to favor correct dietary habits and reduce alcohol consumption and the intensification of studies on HCC pathogenesis for future optimized prevention strategies.
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Affiliation(s)
- Evangelista Sagnelli
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80131, Naples, Italy.
| | - Margherita Macera
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80131, Naples, Italy
| | - Antonio Russo
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80131, Naples, Italy
| | - Nicola Coppola
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80131, Naples, Italy
| | - Caterina Sagnelli
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80131, Naples, Italy
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