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1
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Wu D, Sun X, Li X, Zuo Z, Yan D, Yin W. RRM2 Regulates Hepatocellular Carcinoma Progression Through Activation of TGF-β/Smad Signaling and Hepatitis B Virus Transcription. Genes (Basel) 2024; 15:1575. [PMID: 39766842 PMCID: PMC11675542 DOI: 10.3390/genes15121575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a type of malignant tumor with high morbidity and mortality. Untimely treatment and high recurrence are currently the major challenges for HCC. The identification of potential targets of HCC progression is crucial for the development of new therapeutic strategies. METHODS Bioinformatics analyses have been employed to discover genes that are differentially expressed in clinical cases of HCC. A variety of pharmacological methods, such as MTT, colony formation, EdU, Western blotting, Q-PCR, wound healing, Transwell, cytoskeleton F-actin filaments, immunohistochemistry (IHC), hematoxylin-eosin (HE) staining, and dual-luciferase reporter assay analyses, were utilized to study the pharmacological effects and potential mechanisms of ribonucleotide reductase regulatory subunit M2 (RRM2) in HCC. RESULTS RRM2 expression is significantly elevated in HCC, which is well correlated with poor clinical outcomes. Both in vitro and in vivo experiments demonstrated that RRM2 promoted HCC cell growth and metastasis. Mechanistically, RRM2 modulates the EMT phenotype of HCC, and further studies have shown that RRM2 facilitates the activation of the TGF-β/Smad signaling pathway. SB431542, an inhibitor of TGF-β signaling, significantly inhibited RRM2-induced cell migration. Furthermore, RRM2 expression was correlated with diminished survival in HBV-associated HCC patients. RRM2 knockdown decreased the levels of HBV RNA, pgRNA, cccDNA, and HBV DNA in HepG2.2.15 cells exhibiting sustained HBV infection, while RRM2 knockdown inhibited the activity of the HBV Cp, Xp, and SpI promoters. CONCLUSION RRM2 is involved in the progression of HCC by activating the TGF-β/Smad signaling pathway. RRM2 increases HBV transcription in HBV-expressing HCC cells. Targeting RRM2 may be of potential value in the treatment of HCC.
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Affiliation(s)
- Dandan Wu
- State Key Lab of Pharmaceutical Biotechnology (SKLPB), College of Life Sciences in Nanjing University (Xianlin Campus), Nanjing University, Nanjing 210046, China; (D.W.); (X.S.); (X.L.)
| | - Xinning Sun
- State Key Lab of Pharmaceutical Biotechnology (SKLPB), College of Life Sciences in Nanjing University (Xianlin Campus), Nanjing University, Nanjing 210046, China; (D.W.); (X.S.); (X.L.)
| | - Xin Li
- State Key Lab of Pharmaceutical Biotechnology (SKLPB), College of Life Sciences in Nanjing University (Xianlin Campus), Nanjing University, Nanjing 210046, China; (D.W.); (X.S.); (X.L.)
| | - Zongchao Zuo
- The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China;
| | - Dong Yan
- Department of Cardiology, Affiliated Hospital of Nanjing University of TCM, Nanjing 210023, China;
| | - Wu Yin
- State Key Lab of Pharmaceutical Biotechnology (SKLPB), College of Life Sciences in Nanjing University (Xianlin Campus), Nanjing University, Nanjing 210046, China; (D.W.); (X.S.); (X.L.)
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2
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Li D, Hamadalnil Y, Tu T. Hepatitis B Viral Protein HBx: Roles in Viral Replication and Hepatocarcinogenesis. Viruses 2024; 16:1361. [PMID: 39339838 PMCID: PMC11437454 DOI: 10.3390/v16091361] [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: 07/30/2024] [Revised: 08/20/2024] [Accepted: 08/21/2024] [Indexed: 09/30/2024] Open
Abstract
Hepatitis B virus (HBV) infection remains a major public health concern worldwide, with approximately 296 million individuals chronically infected. The HBV-encoded X protein (HBx) is a regulatory protein of 17 kDa, reportedly responsible for a broad range of functions, including viral replication and oncogenic processes. In this review, we summarize the state of knowledge on the mechanisms underlying HBx functions in viral replication, the antiviral effect of therapeutics directed against HBx, and the role of HBx in liver cancer development (including a hypothetical model of hepatocarcinogenesis). We conclude by highlighting major unanswered questions in the field and the implications of their answers.
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Affiliation(s)
- Dong Li
- The Westmead Institute for Medical Research, Faculty of Medicine, The University of Sydney, Westmead, NSW 2145, Australia;
| | | | - Thomas Tu
- The Westmead Institute for Medical Research, Faculty of Medicine, The University of Sydney, Westmead, NSW 2145, Australia;
- Centre for Infectious Diseases and Microbiology, Sydney Infectious Diseases Institute, The University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia
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3
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Maio N, Heffner AL, Rouault TA. Iron‑sulfur clusters in viral proteins: Exploring their elusive nature, roles and new avenues for targeting infections. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119723. [PMID: 38599324 PMCID: PMC11139609 DOI: 10.1016/j.bbamcr.2024.119723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/13/2024] [Accepted: 04/01/2024] [Indexed: 04/12/2024]
Abstract
Viruses have evolved complex mechanisms to exploit host factors for replication and assembly. In response, host cells have developed strategies to block viruses, engaging in a continuous co-evolutionary battle. This dynamic interaction often revolves around the competition for essential resources necessary for both host cell and virus replication. Notably, iron, required for the biosynthesis of several cofactors, including iron‑sulfur (FeS) clusters, represents a critical element in the ongoing competition for resources between infectious agents and host. Although several recent studies have identified FeS cofactors at the core of virus replication machineries, our understanding of their specific roles and the cellular processes responsible for their incorporation into viral proteins remains limited. This review aims to consolidate our current knowledge of viral components that have been characterized as FeS proteins and elucidate how viruses harness these versatile cofactors to their benefit. Its objective is also to propose that viruses may depend on incorporation of FeS cofactors more extensively than is currently known. This has the potential to revolutionize our understanding of viral replication, thereby carrying significant implications for the development of strategies to target infections.
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Affiliation(s)
- Nunziata Maio
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
| | - Audrey L Heffner
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Tracey A Rouault
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA
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4
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Zhang SZ, Lobo A, Li PF, Zhang YF. Sialylated glycoproteins and sialyltransferases in digestive cancers: Mechanisms, diagnostic biomarkers, and therapeutic targets. Crit Rev Oncol Hematol 2024; 197:104330. [PMID: 38556071 DOI: 10.1016/j.critrevonc.2024.104330] [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: 10/11/2023] [Revised: 03/12/2024] [Accepted: 03/19/2024] [Indexed: 04/02/2024] Open
Abstract
Sialic acid (SA), as the ultimate epitope of polysaccharides, can act as a cap at the end of polysaccharide chains to prevent their overextension. Sialylation is the enzymatic process of transferring SA residues onto polysaccharides and is catalyzed by a group of enzymes known as sialyltransferases (SiaTs). It is noteworthy that the sialylation level of glycoproteins is significantly altered when digestive cancer occurs. And this alteration exhibits a close correlation with the progression of these cancers. In this review, from the perspective of altered SiaTs expression levels and changed glycoprotein sialylation patterns, we summarize the pathogenesis of gastric cancer (GC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC). Furthermore, we propose potential early diagnostic biomarkers and prognostic indicators for different digestive cancers. Finally, we summarize the therapeutic value of sialylation in digestive system cancers.
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Affiliation(s)
- Shao-Ze Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Amara Lobo
- Department of Critical Care Medicine Holy Family Hospital, St Andrew's Road, Bandra (West), Mumbai 400050, India
| | - Pei-Feng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
| | - Yin-Feng Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
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5
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Gómez-Moreno A, Ploss A. Mechanisms of Hepatitis B Virus cccDNA and Minichromosome Formation and HBV Gene Transcription. Viruses 2024; 16:609. [PMID: 38675950 PMCID: PMC11054251 DOI: 10.3390/v16040609] [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: 03/13/2024] [Revised: 04/11/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatitis B virus (HBV) is the etiologic agent of chronic hepatitis B, which puts at least 300 million patients at risk of developing fibrosis, cirrhosis, and hepatocellular carcinoma. HBV is a partially double-stranded DNA virus of the Hepadnaviridae family. While HBV was discovered more than 50 years ago, many aspects of its replicative cycle remain incompletely understood. Central to HBV persistence is the formation of covalently closed circular DNA (cccDNA) from the incoming relaxed circular DNA (rcDNA) genome. cccDNA persists as a chromatinized minichromosome and is the major template for HBV gene transcription. Here, we review how cccDNA and the viral minichromosome are formed and how viral gene transcription is regulated and highlight open questions in this area of research.
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Affiliation(s)
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
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6
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Wang F, Song H, Xu F, Xu J, Wang L, Yang F, Zhu Y, Tan G. Role of hepatitis B virus non-structural protein HBx on HBV replication, interferon signaling, and hepatocarcinogenesis. Front Microbiol 2023; 14:1322892. [PMID: 38188582 PMCID: PMC10767994 DOI: 10.3389/fmicb.2023.1322892] [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: 10/17/2023] [Accepted: 12/07/2023] [Indexed: 01/09/2024] Open
Abstract
Hepatitis B, a global health concern caused by the hepatitis B virus (HBV), infects nearly 2 billion individuals worldwide, as reported by the World Health Organization (WHO). HBV, a hepatotropic DNA virus, predominantly targets and replicates within hepatocytes. Those carrying the virus are at increased risk of liver cirrhosis and hepatocellular carcinoma, resulting in nearly 900,000 fatalities annually. The HBV X protein (HBx), encoded by the virus's open reading frame x, plays a key role in its virulence. This protein is integral to viral replication, immune modulation, and liver cancer progression. Despite its significance, the precise molecular mechanisms underlying HBx remain elusive. This review investigates the HBx protein's roles in HBV replication, interferon signaling regulation, and hepatocellular carcinoma progression. By understanding the complex interactions between the virus and its host mediated by HBx, we aim to establish a solid foundation for future research and the development of HBx-targeted therapeutics.
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Affiliation(s)
- Fei Wang
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Hongxiao Song
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Fengchao Xu
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jing Xu
- Health Examination Center, The First Hospital of Jilin University, Changchun, China
| | - Le Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Fan Yang
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yujia Zhu
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Guangyun Tan
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
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7
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Panneerselvam S, Wilson C, Kumar P, Abirami D, Pamarthi J, Reddy MS, Varghese J. Overview of hepatocellular carcinoma: from molecular aspects to future therapeutic options. Cell Adh Migr 2023; 17:1-21. [PMID: 37726886 PMCID: PMC10512929 DOI: 10.1080/19336918.2023.2258539] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 09/08/2023] [Indexed: 09/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the seventh most highly prevalent malignant tumor globally and the second most common cause of mortality. HCC develops with complex pathways that occur through multistage biological processes. Non-alcoholic fatty liver disease, metabolic-associated fatty liver disease, alcoholic liver disease, autoimmune hepatitis, hepatitis B, and hepatitis C are the causative etiologies of HCC. HCC develops as a result of epigenetic changes, protein-coding gene mutations, and altered signaling pathways. Biomarkers and potential therapeutic targets for HCC open up new possibilities for treating the disease. Immune checkpoint inhibitors are included in the treatment options in combination with molecular targeted therapy.
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Affiliation(s)
- Sugan Panneerselvam
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Cornelia Wilson
- Natural and Applied Sciences, School of Psychology and Life Sciences, Canterbury Christ Church University, Discovery Park, Sandwich, UK
| | - Prem Kumar
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Dinu Abirami
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Jayakrishna Pamarthi
- Multi-Disciplinary Research Unit, Madras Medical College, Chennai, Tamil Nadu, India
| | - Mettu Srinivas Reddy
- The Director and Head, Liver Transplant and HPB surgery, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Joy Varghese
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
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8
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Wang H, Zhang J. The glucose metabolic reprogramming in hepatitis B virus infection and hepatitis B virus associated diseases. J Gastroenterol Hepatol 2023; 38:1886-1891. [PMID: 37654246 DOI: 10.1111/jgh.16340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 08/01/2023] [Accepted: 08/14/2023] [Indexed: 09/02/2023]
Abstract
Hepatitis B virus (HBV) infection is closely related to viral hepatitis, liver cirrhosis, and hepatocellular carcinoma. HBV infection can reprogram metabolism processes of the host cells including glucose metabolism. The aberrant glucose metabolism may aid in viral infection and immune escape and may contribute to liver associated pathology. In this review, we discussed the interplay between HBV infection and glucose metabolism, which may provide new insights into HBV infection and pathology, novel intervention targets for HBV-related diseases.
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Affiliation(s)
- Hangle Wang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Ministry of Health (Peking University), Peking University Health Science Center, Beijing, China
| | - Jun Zhang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Ministry of Health (Peking University), Peking University Health Science Center, Beijing, China
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9
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Feitelson MA, Arzumanyan A, Spector I, Medhat A. Hepatitis B x (HBx) as a Component of a Functional Cure for Chronic Hepatitis B. Biomedicines 2022; 10:biomedicines10092210. [PMID: 36140311 PMCID: PMC9496119 DOI: 10.3390/biomedicines10092210] [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: 07/22/2022] [Revised: 08/22/2022] [Accepted: 09/02/2022] [Indexed: 11/20/2022] Open
Abstract
Patients who are carriers of the hepatitis B virus (HBV) are at high risk of chronic liver disease (CLD) which proceeds from hepatitis, to fibrosis, cirrhosis and to hepatocellular carcinoma (HCC). The hepatitis B-encoded X antigen, HBx, promotes virus gene expression and replication, protects infected hepatocytes from immunological destruction, and promotes the development of CLD and HCC. For virus replication, HBx regulates covalently closed circular (ccc) HBV DNA transcription, while for CLD, HBx triggers cellular oxidative stress, in part, by triggering mitochondrial damage that stimulates innate immunity. Constitutive activation of NF-κB by HBx transcriptionally activates pro-inflammatory genes, resulting in hepatocellular destruction, regeneration, and increased integration of the HBx gene into the host genome. NF-κB is also hepatoprotective, which sustains the survival of infected cells. Multiple therapeutic approaches include direct-acting anti-viral compounds and immune-stimulating drugs, but functional cures were not achieved, in part, because none were yet devised to target HBx. In addition, many patients with cirrhosis or HCC have little or no virus replication, but continue to express HBx from integrated templates, suggesting that HBx contributes to the pathogenesis of CLD. Blocking HBx activity will, therefore, impact multiple aspects of the host–virus relationship that are relevant to achieving a functional cure.
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Affiliation(s)
- Mark A. Feitelson
- Room 409 Biolife Building, Department of Biology, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, PA 19122, USA
- Correspondence: ; Tel.: +1-215-204-8434
| | - Alla Arzumanyan
- Room 409 Biolife Building, Department of Biology, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, PA 19122, USA
| | | | - Arvin Medhat
- Department of Molecular Cell Biology, Islamic Azad University Tehran North Branch, Tehran 1975933411, Iran
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10
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Hepatitis B Virus-Associated Hepatocellular Carcinoma. Viruses 2022; 14:v14050986. [PMID: 35632728 PMCID: PMC9146458 DOI: 10.3390/v14050986] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/02/2022] [Accepted: 05/03/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.
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11
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Firoz A, Ali HM, Rehman S, Rather IA. Gastric Cancer and Viruses: A Fine Line between Friend or Foe. Vaccines (Basel) 2022; 10:vaccines10040600. [PMID: 35455349 PMCID: PMC9025827 DOI: 10.3390/vaccines10040600] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/28/2022] [Accepted: 04/11/2022] [Indexed: 02/01/2023] Open
Abstract
Gastric cancer (GC) is a significant health concern worldwide, with a GLOBOCAN estimate of 1.08 million novel cases in 2020. It is the leading cause of disability-adjusted life years lost to cancer, with the fourth most common cancer in males and the fifth most common cancer in females. Strategies are pursued across the globe to prevent gastric cancer progression as a significant fraction of gastric cancers have been linked to various pathogenic (bacterial and viral) infections. Early diagnosis (in Asian countries), and non-invasive and surgical treatments have helped manage this disease with 5-year survival for stage IA and IB tumors ranging between 60% and 80%. However, the most prevalent aggressive stage III gastric tumors undergoing surgery have a lower 5-year survival rate between 18% and 50%. These figures point to a need for more efficient diagnostic and treatment strategies, for which the oncolytic viruses (OVs) appear to have some promise. OVs form a new therapeutic agent class that induces anti-tumor immune responses by selectively killing tumor cells and inducing systemic anti-tumor immunity. On the contrary, several oncogenic viruses have been shown to play significant roles in malignancy progression in the case of gastric cancer. Therefore, this review evaluates the current state of research and advances in understanding the dual role of viruses in gastric cancer.
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Affiliation(s)
- Ahmad Firoz
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.F.); (H.M.A.)
- Princess Dr Najla Bint Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hani Mohammed Ali
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.F.); (H.M.A.)
- Princess Dr Najla Bint Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Suriya Rehman
- Department of Epidemic Disease Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University (IAU), Dammam 31441, Saudi Arabia
- Correspondence: (S.R.); (I.A.R.)
| | - Irfan A. Rather
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.F.); (H.M.A.)
- Correspondence: (S.R.); (I.A.R.)
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12
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Hepatitis B Viral Protein HBx and the Molecular Mechanisms Modulating the Hallmarks of Hepatocellular Carcinoma: A Comprehensive Review. Cells 2022; 11:cells11040741. [PMID: 35203390 PMCID: PMC8870387 DOI: 10.3390/cells11040741] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
With 296 million cases estimated worldwide, chronic hepatitis B virus (HBV) infection is the most common risk factor for hepatocellular carcinoma (HCC). HBV-encoded oncogene X protein (HBx), a key multifunctional regulatory protein, drives viral replication and interferes with several cellular signalling pathways that drive virus-associated hepatocarcinogenesis. This review article provides a comprehensive overview of the role of HBx in modulating the various hallmarks of HCC by supporting tumour initiation, progression, invasion and metastasis. Understanding HBx-mediated dimensions of complexity in driving liver malignancies could provide the key to unlocking novel and repurposed combinatorial therapies to combat HCC.
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13
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Zheng C, Liu M, Ge Y, Qian Y, Fan H. HBx increases chromatin accessibility and ETV4 expression to regulate dishevelled-2 and promote HCC progression. Cell Death Dis 2022; 13:116. [PMID: 35121725 PMCID: PMC8816937 DOI: 10.1038/s41419-022-04563-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 01/04/2022] [Accepted: 01/20/2022] [Indexed: 12/24/2022]
Abstract
Hepatitis B virus (HBV) infection is the predominant causes of hepatocellular carcinoma (HCC). HBV X protein (HBx), as the most frequently integrated viral gene sequence following HBV infection, plays a critical role in the pathogenesis of HCC. H3K27ac is a characteristic marker for identifying active enhancers and even indicates chromatin accessibility associated with super-enhancers (SEs). In this study, H3K27ac ChIP-seq was applied for high-quality SE annotation of HBx-induced SEs and chromatin accessibility evaluation. The results indicated that HBx preferentially affects enrichment of H3K27ac in transcription factor signaling pathway genes, including ETV4. RNA-seq indicated that ETV4 is upregulated by HBx and that upregulated ETV4 promotes HCC progression. Interestingly, ETV4 was also included in the 568 cancer driver gene pool obtained by the Integrative OncoGenomics pipeline. However, the biological function and mechanism of ETV4 remain incompletely understood. In vivo and in vitro, we found that increased ETV4 expression promotes HCC cell migration and invasion by upregulating DVL2 and activating Wnt/β-catenin. The mRNA and protein levels of ETV4 are higher in tumor tissues compared with adjacent tissues, and high expression of ETV4 is associated with poor prognosis in HCC patients. In summary, we first confirm that ETV4 is significantly upregulated by HBx and involved in SE-associated chromatin accessibility. Increased expression of ETV4 promotes HCC cell invasion and metastasis by upregulating DVL2. The present study provides insight into the ETV4-DVL2-β-catenin axis in HBV-related HCC, which will be helpful for treating patients with aggressive HCC.
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Affiliation(s)
- Chuqian Zheng
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China
| | - Min Liu
- School of Life Science and Technology, Southeast University, Nanjing, China
| | - Yanping Ge
- School of Life Science and Technology, Southeast University, Nanjing, China
| | - Yanyan Qian
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China
| | - Hong Fan
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
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14
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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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15
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Stalla F, Armandi A, Marinoni C, Fagoonee S, Pellicano R, Caviglia GP. Chronic hepatitis B virus infection and fibrosis: novel non-invasive approaches for diagnosis and risk stratification. Minerva Gastroenterol (Torino) 2021; 68:306-318. [PMID: 33871225 DOI: 10.23736/s2724-5985.21.02911-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Despite the availability of an effective vaccination, chronic hepatitis B virus (HBV) infection is still a major health concern worldwide. Chronic HBV infection can lead to fibrosis accumulation and overtime to cirrhosis, the principal risk factor for liver failure and hepatocellular carcinoma development. Liver biopsy is still considered the gold standard for fibrosis assessment, even though it is invasive and not exempt of complications. Overtime, several non-invasive methods for the detection of liver fibrosis have been developed and gradually introduced into clinical practice. However, their main limitation is the poor performance for the detection of intermediate stages of fibrosis. Finally, novel serological biomarkers, polygenic risk scores and imaging methods have been proposed in last years as novel promising tools to correctly identify the degree of liver fibrosis and to monitor liver disease progression. In this narrative review, we provide an overview on the novel non-invasive approaches for the evaluation of liver fibrosis and risk stratification of patients with chronic hepatitis B.
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Affiliation(s)
- Francesco Stalla
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Angelo Armandi
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Marinoni
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Center, Torino, Italy
| | - Rinaldo Pellicano
- Division of Gastroenterology, Molinette Hospital - Città della Salute e della Scienza di Torino, Turin, Italy
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16
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D'souza S, Lau KCK, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020; 26:5759-5783. [PMID: 33132633 PMCID: PMC7579760 DOI: 10.3748/wjg.v26.i38.5759] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/03/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.
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Affiliation(s)
- Simmone D'souza
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Keith CK Lau
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Carla S Coffin
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Trushar R Patel
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge T1K3M4, AB, Canada
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17
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Niedźwiedzka-Rystwej P, Grywalska E, Hrynkiewicz R, Wołącewicz M, Becht R, Roliński J. The Double-Edged Sword Role of Viruses in Gastric Cancer. Cancers (Basel) 2020; 12:cancers12061680. [PMID: 32599870 PMCID: PMC7352989 DOI: 10.3390/cancers12061680] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 06/14/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
Due to its high morbidity and mortality, gastric cancer is a topic of a great concern throughout the world. Major ways of treatment are gastrectomy and chemotherapy, unfortunately they are not always successful. In a search for more efficient therapy strategies, viruses and their potential seem to be an important issue. On one hand, several oncogenic viruses have been noticed in the case of gastric cancer, making the positive treatment even more advantageous, but on the other, viruses exist with a potential therapeutic role in this malignancy.
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Affiliation(s)
- Paulina Niedźwiedzka-Rystwej
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
- Correspondence:
| | - Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (E.G.); (J.R.)
| | - Rafał Hrynkiewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
| | - Mikołaj Wołącewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
| | - Rafał Becht
- Clinical Department of Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University of Szczecin, 70-204 Szczecin, Poland;
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (E.G.); (J.R.)
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18
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Xu T, Li L, Liu YC, Cao W, Chen JS, Hu S, Liu Y, Li LY, Zhou H, Meng XM, Huang C, Zhang L, Li J, Zhou H. CRISPR/Cas9-related technologies in liver diseases: from feasibility to future diversity. Int J Biol Sci 2020; 16:2283-2295. [PMID: 32760197 PMCID: PMC7378651 DOI: 10.7150/ijbs.33481] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 12/17/2019] [Indexed: 12/11/2022] Open
Abstract
Liver diseases are one of the leading causes of mortality in the world, mainly caused by different etiological agents, alcohol consumption, viruses, drug intoxication, and malnutrition. The maturation of gene therapy has heralded new avenues for developing effective interventions for these diseases. Derived from a remarkable microbial defense system, clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins 9 system (CRISPR/Cas9 system) is driving innovative applications from basic biology to biotechnology and medicine. Recently, the mutagenic function of CRISPR/Cas9 system has been widely adopted for genome and disease research. In this review, we describe the development and applications of CRISPR/Cas9 system on liver diseases for research or translational applications, while highlighting challenges as well as future avenues for innovation.
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Affiliation(s)
- Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
- Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China
| | - Li Li
- Department of Pathology and Pathophysiology, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Yu-chen Liu
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518039, China
| | - Wei Cao
- Shenzhen Qianhai Icecold IT Co., Ltd. China
| | - Jia-si Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
- Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China
| | - Shuang Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
- Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China
| | - Ying Liu
- Hefei Institutes of Physical Science, Chinese Academy of Sciences; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei, Anhui, PR China
| | - Liang-yun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
- Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China
| | - Hong Zhou
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
- Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China
- Anhui Provincial Cancer Hospital, West Branch of The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, P.R. China
| | - Xiao-ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
- Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
- Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China
| | - Lei Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
- Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
- Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China
| | - Huan Zhou
- National Drug Clinical Trial Institution, the First Affiliated Hospital of Bengbu Medical College
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19
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Jegal ME, Jung SY, Han YS, Kim YJ. C-terminal truncated HBx reduces doxorubicin cytotoxicity via ABCB1 upregulation in Huh-7 hepatocellular carcinoma cells. BMB Rep 2019. [PMID: 30982500 PMCID: PMC6549916 DOI: 10.5483/bmbrep.2019.52.5.312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV) encoding the HBV x protein (HBx) is a known causative agent of hepatocellular carcinoma (HCC). Its pathogenic activities in HCC include interference with several signaling pathways associated with cell proliferation and apoptosis. Mutant C-terminal-truncated HBx isoforms are frequently found in human HCC and have been shown to enhance proliferation and invasiveness leading to HCC malignancy. We investigated the molecular mechanism of the reduced doxorubicin cytotoxicity by C-terminal truncated HBx. Cells transfected with C-terminal truncated HBx exhibited reduced cytotoxicity to doxorubicin compared to those transfected with full-length HBx. The doxorubicin resistance of cells expressing C-terminal truncated HBx correlated with upregulation of the ATP binding cassette subfamily B member 1(ABCB1) transporter, resulting in the enhanced efflux of doxorubicin. Inhibiting the activity of ABCB1 and silencing ABCB1 expression by small interfering ribonucleic acid (siRNA) increased the cytotoxicity of doxorubicin. These results indicate that elevated ABCB1 expression induced by C-terminal truncation of HBx was responsible for doxorubicin resistance in HCC. Hence, co-treatment with an ABCB1 inhibitor and an anticancer agent may be effective for the treatment of patients with liver cancer containing the C-terminal truncated HBx.
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Affiliation(s)
- Myeong-Eun Jegal
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Korea
| | - Seung-Youn Jung
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Korea
| | - Yu-Seon Han
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Korea
| | - Yung-Jin Kim
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Korea
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20
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Zhang Y, Li J, Wang S, Yang F, Zhou Y, Liu Y, Zhu W, Shi X. HBx‑associated long non‑coding RNA activated by TGF‑β promotes cell invasion and migration by inducing autophagy in primary liver cancer. Int J Oncol 2019; 56:337-347. [PMID: 31746419 DOI: 10.3892/ijo.2019.4908] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 03/07/2019] [Indexed: 12/25/2022] Open
Abstract
Hepatitis B virus (HBV) x protein (HBx) has been reported as the primary pathogenic factor involved in HBV‑related liver cancer; however, the mechanisms underlying how HBx promotes tumor‑associated invasion and metastasis remain unclear. Long noncoding RNA activated by transforming growth factor (TGF)‑β (lncRNA‑ATB) is a novel oncogenic lncRNA stimulated by TGF‑β, which is closely associated with the invasion and metastasis of liver cancer. In the present study, whether lncRNA‑ATB was involved in HBx‑mediated hepatocarcinogenesis was investigated. The expression of lncRNA‑ATB in 26 primary liver cancer tissues and lentivirus transfected HBx‑HepG2 cell lines was detected, and it was revealed that more advanced tumor‑node‑metastasis staging and increased expression of lncRNA‑ATB in liver cancer tissues were significantly associated with HBV infection. It was further demonstrated that the expression levels of lncRNA‑ATB and TGF‑β were elevated in HepG2 cells following HBx‑vector transfection, which was accompanied with increased autophagy. Conversely, knockdown of lncRNA‑ATB or TGF‑β could suppress this effect. Furthermore, such suppression on autophagy in HepG2 cells could be alleviated by the induction of starvation. In addition, the invasive and migration abilities of HBx‑HepG2 cells were increased compared with HepG2 cells, while knockdown of lncRNA‑ATB or TGF‑β could reduce these abilities. In conclusion, the results of the present study revealed that HBx was closely associated with oncogenic lncRNA‑ATB. HBx‑induced autophagy could upregulate the expression of TGF‑β and lncRNA‑ATB. This may be considered to be a potential mechanism underlying HBV‑induced hepatocarcinogenesis.
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Affiliation(s)
- Yuheng Zhang
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Jun Li
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Shuai Wang
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Faji Yang
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Yuan Zhou
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Yang Liu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Wei Zhu
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Xiaolei Shi
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
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21
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Su KJ, Yu YL. Downregulation of SHIP2 by Hepatitis B Virus X Promotes the Metastasis and Chemoresistance of Hepatocellular Carcinoma through SKP2. Cancers (Basel) 2019; 11:cancers11081065. [PMID: 31357665 PMCID: PMC6721294 DOI: 10.3390/cancers11081065] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 07/24/2019] [Accepted: 07/25/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV)-encoded X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). The protein SH2 domain containing inositol 5-phosphatase 2 (SHIP2) belongs to the family of enzymes that dephosphorylate the 5 position of PI(3,4,5)P3 to produce PI(3,4)P2. Expression of SHIP2 has been associated with several cancers including HCC. However, its role in the development of HBV-related HCC remains elusive. In this study, we performed tissue microarray analysis using 49 cases of HCC to explore SHIP2 expression changes and found that SHIP2 was downregulated in HBV-positive HCC. In addition, S-phase kinase-associated protein 2 (SKP2), a component of the E3 ubiquitin–ligase complex, was increased in HCC cell lines that overexpressed HBx, which also showed a notable accumulation of polyubiquitinated SHIP2. Moreover, HCC cells with silenced SHIP2 had increased expression of mesenchymal markers, which promotes cell migration, enhances glucose uptake, and leads to resistance to the chemotherapy drug (5-Fluorouracil, 5-FU). Taken together, our results demonstrate that HBx downregulates SHIP2 through SKP2 and suggest a potential role for SHIP2 in HBx-mediated HCC migration.
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Affiliation(s)
- Kuo-Jung Su
- The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 404, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - Yung-Luen Yu
- The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 404, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan.
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan.
- Drug Development Center, China Medical University, Taichung 404, Taiwan.
- Department of Biotechnology, Asia University, Taichung 413, Taiwan.
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22
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Xu Q, Gu S, Liang J, Lin Z, Zheng S, Yan J. The Biological Function of Hepatitis B Virus X Protein in Hepatocellular Carcinoma. Oncol Res 2019; 27:509-514. [PMID: 29891022 PMCID: PMC7848407 DOI: 10.3727/096504018x15278771272963] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major malignant tumors that lead to death. Chronic hepatitis B virus infection is an important risk factor for HCC initiation. HBx protein, encoded by the HBV X gene, is a significant factor that promotes HBV-related HCC, although the exact molecular mechanism remains unclear. This article summarizes the pathological roles and related mechanisms of HBx in HCC. HBx plays a carcinogenic role by promoting cell proliferation, metastasis, and angiogenesis and inhibiting apoptosis in HCC. A detailed study of the biological functions of HBx will help to elucidate the mechanism of hepatocarcinogenesis and lead to the development of novel therapeutic targets for the treatment of HBV-related HCC.
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Affiliation(s)
- Qiaodong Xu
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Songgang Gu
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Jiahong Liang
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Zhihua Lin
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Shaodong Zheng
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Jiang Yan
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
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23
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Qiu L, Wang T, Xu X, Wu Y, Tang Q, Chen K. Long Non-Coding RNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Regulation, Functions, and Underlying Mechanisms. Int J Mol Sci 2017; 18:ijms18122505. [PMID: 29168767 PMCID: PMC5751108 DOI: 10.3390/ijms18122505] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 11/13/2017] [Accepted: 11/20/2017] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death in the world. Hepatitis B virus (HBV) and its X gene-encoded protein (HBx) play important roles in the progression of HCC. Although long non-coding RNAs (lncRNAs) cannot encode proteins, growing evidence indicates that they play essential roles in HCC progression, and contribute to cell proliferation, invasion and metastasis, autophagy, and apoptosis by targeting a large number of pivotal protein-coding genes, miRNAs, and signaling pathways. In this review, we briefly outline recent findings of differentially expressed lncRNAs in HBV-related HCC, with particular focus on several key lncRNAs, and discuss their regulation by HBV/HBx, their functions, and their underlying molecular mechanisms in the progression of HCC.
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Affiliation(s)
- Lipeng Qiu
- Institute of Life Sciences, Jiangsu University, Zhenjiang 212013, China.
| | - Tao Wang
- Institute of Life Sciences, Jiangsu University, Zhenjiang 212013, China.
| | - Xiuquan Xu
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China.
| | - Yihang Wu
- Department of Pharmacy, College of Life Sciences, China Jiliang University, Hangzhou 310018, China.
| | - Qi Tang
- Institute of Life Sciences, Jiangsu University, Zhenjiang 212013, China.
| | - Keping Chen
- Institute of Life Sciences, Jiangsu University, Zhenjiang 212013, China.
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24
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Gómez-Moreno A, Garaigorta U. Hepatitis B Virus and DNA Damage Response: Interactions and Consequences for the Infection. Viruses 2017; 9:v9100304. [PMID: 29048354 PMCID: PMC5691655 DOI: 10.3390/v9100304] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 10/13/2017] [Accepted: 10/18/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is a major etiologic agent of acute and chronic hepatitis, and end-stage liver disease. Establishment of HBV infection, progression to persistency and pathogenesis are determined by viral and cellular factors, some of which remain still undefined. Key steps of HBV life cycle e.g., transformation of genomic viral DNA into transcriptionally active episomal DNA (cccDNA) or transcription of viral mRNAs from cccDNA, take place in the nucleus of infected cells and strongly depend on enzymatic activities provided by cellular proteins. In this regard, DNA damage response (DDR) pathways and some DDR proteins are being recognized as important factors regulating the infection. On one hand, HBV highjacks specific DDR proteins to successfully complete some of the steps of its life cycle. On the other hand, HBV subverts DDR pathways to presumably create a cellular environment that favours its replication. Direct consequences of these interactions are: HBV DNA integration into host chromosomal DNA, and accumulation of mutations in host chromosomal DNA that could eventually trigger carcinogenic processes, which would explain in part the incidence of hepatocellular carcinoma in chronically infected patients. Unravelling the interactions that HBV establishes with DDR pathways might help identify new molecular targets for therapeutic intervention.
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Affiliation(s)
- Andoni Gómez-Moreno
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
| | - Urtzi Garaigorta
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain.
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25
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Li J, Verhaar AP, Pan Q, de Knegt RJ, Peppelenbosch MP. Serum levels of caspase-cleaved cytokeratin 18 (CK18-Asp396) predict severity of liver disease in chronic hepatitis B. Clin Exp Gastroenterol 2017; 10:203-209. [PMID: 28860836 PMCID: PMC5560566 DOI: 10.2147/ceg.s135526] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background and aim Caspase-cleaved cytokeratin 18 (CK18-Asp396) is a potential clinically useful biomarker in liver disease as it is released from hepatocytes during apoptosis. In this study, we investigated serum CK18-Asp396 levels in chronic hepatitis B (CHB). Patients and methods Overall, 163 patients with CHB were included. Serum CK18-Asp396 levels were determined by enzyme-linked immunosorbent assay (ELISA), and results were related to steatosis grade, histological activity index, inflammation score, and METAVIR fibrosis grade as well as to viral load, serum levels of liver enzymes, and albumin. Receiver operating characteristic analysis was used to evaluate the diagnostic performance of serum CK18-Asp396 levels for assessing disease activity. Results A higher level of serum CK 18 concentrations was found in patients with significant inflammation vs no significant inflammation (378.5 [interquartile range {IQR}: 173.2–629.6] vs 137.3 [87.5–197.7], P < 0.05; approximately threefold increase) and in patients with significant fibrosis vs no significant fibrosis (177.8 [IQR: 120.8–519.1] vs 142.7 [IQR: 88.8–214.4], P < 0.05; 1.25-fold increase). There was no differential CK 18 level by degree of steatosis. CK 18 was an independent predictor of significant inflammation with an 82% specificity and a 94% negative predictive value. We found the strongest correlation of CK 18 with alanine aminotransferase and aspartate aminotransferase (both r = 0.52; P < 0.001), but less with albumin (r = −0.24; P < 0.05) and viral load (log) (r = 0.19; P < 0.05). Conclusion CHB appears to be accompanied by continuous high levels of hepatocyte apoptosis as judged from serum CK 18, suggesting that elimination of the infected compartment constitutes a defensive strategy against disease. Accordingly, CK 18 works as an independent predictor of significant inflammation with a high specificity.
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Affiliation(s)
- Juan Li
- Erasmus MC Cancer Institute, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Auke P Verhaar
- Erasmus MC Cancer Institute, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Qiuwei Pan
- Erasmus MC Cancer Institute, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Robert Jacobus de Knegt
- Erasmus MC Cancer Institute, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Maikel P Peppelenbosch
- Erasmus MC Cancer Institute, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
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Reactive Oxygen Species-Mediated c-Jun NH 2-Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction. J Virol 2017; 91:JVI.00001-17. [PMID: 28515304 DOI: 10.1128/jvi.00001-17] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Accepted: 05/07/2017] [Indexed: 02/08/2023] Open
Abstract
Autophagy is closely associated with the regulation of hepatitis B virus (HBV) replication. HBV X protein (HBx), a multifunctional regulator in HBV-associated biological processes, has been demonstrated to be crucial for autophagy induction by HBV. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we demonstrated that HBx induced autophagosome formation independently of the class I phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway. In contrast, the class III PI3K(VPS34)/beclin-1 pathway was revealed to be critical for HBx-induced autophagosome formation. Further study showed that HBx did not affect the level of VPS34 and beclin-1 expression but inhibited beclin-1/Bcl-2 association, and c-Jun NH2-terminal kinase (JNK) signaling was found to be important for this process. Moreover, it was found that HBx treatment led to the generation of reactive oxygen species (ROS), and inhibition of ROS activity abrogated both JNK activation and autophagosome formation. Of importance, ROS-JNK signaling was also revealed to play an important role in HBV-induced autophagosome formation and subsequent HBV replication. These data may provide deeper insight into the mechanisms of autophagy induction by HBx and help in the design of new therapeutic strategies against HBV infection.IMPORTANCE HBx plays a key role in diverse HBV-associated biological processes, including autophagy induction. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we found that HBx induced autophagy independently of the class I PI3K/AKT/mTOR signaling pathway, while the class III PI3K(VPS34)/beclin-1 pathway was revealed to be crucial for this process. Further data showed that ROS-JNK activation by HBx resulted in the release of beclin-1 from its association with Bcl-2 to form a complex with VPS34, thus enhancing autophagosome formation. Of importance, ROS-JNK signaling was also demonstrated to be critical for HBV replication via regulation of autophagy induction. These data help to elucidate the molecular mechanisms of autophagy induction by HBx/HBV and might be useful for designing novel therapeutic approaches to HBV infection.
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27
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Li X, Zheng Y, Zhu H, Lin X, Zhang Y, Zhao Y, Hu J, Li J. Risk of Onset of Hematological Malignancies in Patients Infected with the Hepatitis B Virus: Results from a Large-Scale Retrospective Cohort Study in China. Acta Haematol 2017; 137:209-213. [PMID: 28514772 DOI: 10.1159/000468973] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/05/2017] [Indexed: 12/13/2022]
Abstract
The hepatitis B virus (HBV) is a major global issue, because an increased risk of hepatocellular carcinoma among patients infected with HBV is well established. Recently, it has been suggested that HBV is associated with other human cancers. However, the association between HBV and the risk of onset of hematological malignancies remains controversial. The aim of this large-scale retrospective cohort study was to evaluate the association between HBV infection and hematological malignancies. A retrospective analysis of 86,115 newly admitted patients at Shanghai Ruijin Hospital was performed. A cohort of patients previously exposed to HBV (n = 1,874) and a cohort of individuals without a positive test for anti-hepatitis B core antigen (anti-HBc; n = 45,118) were compared to assess the risk of hematological malignancies. Anti-HBc was positive in 61.2% cases and 54.3% controls (p = 0.0001). The risk of B cell non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and multiple myeloma was higher in the HBV-infected cohort than in the non-HBV-infected cohort. In conclusion, patients infected with HBV have a substantially increased risk of hematological malignancies.
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Affiliation(s)
- Xiaoyang Li
- Department of Hematology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, PR China
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Xu Y, Qi Y, Luo J, Yang J, Xie Q, Deng C, Su N, Wei W, Shi D, Xu F, Li X, Xu P. Hepatitis B Virus X Protein Stimulates Proliferation, Wound Closure and Inhibits Apoptosis of HuH-7 Cells via CDC42. Int J Mol Sci 2017; 18:ijms18030586. [PMID: 28282856 PMCID: PMC5372602 DOI: 10.3390/ijms18030586] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 02/16/2017] [Accepted: 03/04/2017] [Indexed: 12/26/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection has been considered as the major cause of hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) has been reported to be oncogenic. The underlying mechanisms of HBV-related HCC are not fully understood, and the role played by the HBx protein in HBV induced carcinogenesis remains controversial. CDC42, a member of the Rho GTPase family, has been reported to be overexpressed in several different cancers, including HBV-related HCC. However, the specific role of CDC42 in HCC development remains unclear. Here, we investigated the cellular mechanisms by which CDC42 was responsible for the higher proliferation of HuH-7 cells mediated by HBx. We found that the expression level of CDC42 and its activity were significantly increased in HuH-7-HBx cells. The deficiency of CDC42 using the CRISPR/Cas9 system and inhibition by specific inhibitor CASIN led to the reduction of HBx-mediated proliferation. Furthermore, we observed that IQ Motif Containing GTPase Activating Protein 1 (IQGAP1), the downstream mediator of the CDC42 pathway, might be involved in the carcinogenesis induced by HBx. Therefore, the HBx/CDC42/IQGAP1 signaling pathway may potentially play an important role in HBx-mediated carcinogenesis.
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Affiliation(s)
- Yongru Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning 530005, China.
| | - Yingzi Qi
- State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
| | - Jing Luo
- State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
| | - Jing Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
- Key Laboratory of Combinatorial Biosynthesis and Drug Discoveryof Ministry of Education, School of Pharmaceutical Sciences, School of Basic Medical Science, Wuhan University, Wuhan 430071, China.
| | - Qi Xie
- State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
- Key Laboratory of Combinatorial Biosynthesis and Drug Discoveryof Ministry of Education, School of Pharmaceutical Sciences, School of Basic Medical Science, Wuhan University, Wuhan 430071, China.
| | - Chen Deng
- State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
| | - Na Su
- State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
| | - Wei Wei
- State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
| | - Deshun Shi
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning 530005, China.
| | - Feng Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
| | - Xiangping Li
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning 530005, China.
| | - Ping Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
- Key Laboratory of Combinatorial Biosynthesis and Drug Discoveryof Ministry of Education, School of Pharmaceutical Sciences, School of Basic Medical Science, Wuhan University, Wuhan 430071, China.
- Graduate School, Anhui Medical University, Hefei 230032, China.
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Shin GC, Kang HS, Lee AR, Kim KH. Hepatitis B virus-triggered autophagy targets TNFRSF10B/death receptor 5 for degradation to limit TNFSF10/TRAIL response. Autophagy 2016; 12:2451-2466. [PMID: 27740879 DOI: 10.1080/15548627.2016.1239002] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Death receptors of TNFSF10/TRAIL (tumor necrosis factor superfamily member 10) contribute to immune surveillance against virus-infected or transformed cells by promoting apoptosis. Many viruses evade antiviral immunity by modulating TNFSF10 receptor signaling, leading to persistent infection. Here, we report that hepatitis B virus (HBV) X protein (HBx) restricts TNFSF10 receptor signaling via macroautophagy/autophagy-mediated degradation of TNFRSF10B/DR5, a TNFSF10 death receptor, and thus permits survival of virus-infected cells. We demonstrate that the expression of the TNFRSF10B protein is dramatically reduced both in liver tissues of chronic hepatitis B patients and in cell lines transfected with HBV or HBx. HBx-mediated downregulation of TNFRSF10B is caused by the lysosomal, but not proteasomal, degradation pathway. Immunoblotting analysis of LC3B and SQSTM1, and microscopy analysis of tandem-fluorescence-tagged LC3B revealed that HBx promotes complete autophagy. Inhibition of autophagy with a pharmacological inhibitor and LC3B knockdown revealed that HBx-induced autophagy is crucial for TNFRSF10B degradation. Immunoprecipitation and GST affinity isolation assays showed that HBx directly interacts with TNFRSF10B and recruits it to phagophores, the precursors to autophagosomes. We confirmed that autophagy activation is related to the downregulation of the TNFRSF10B protein in liver tissues of chronic hepatitis B patients. Inhibition of autophagy enhanced the susceptibility of HBx-infected hepatocytes to TNFSF10. These results identify the dual function of HBx in TNFRSF10B degradation: HBx plays a role as an autophagy receptor-like molecule, which promotes the association of TNFRSF10B with LC3B; HBx is also an autophagy inducer. Our data suggest a molecular mechanism for HBV evasion from TNFSF10-mediated antiviral immunity, which may contribute to chronic HBV infection.
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Affiliation(s)
- Gu-Choul Shin
- a Department of Pharmacology , Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University , Seoul , Korea.,b KU Open Innovation Center, Research Institute of Medical Sciences, Konkuk University , Seoul , Korea
| | - Hong Seok Kang
- a Department of Pharmacology , Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University , Seoul , Korea
| | - Ah Ram Lee
- a Department of Pharmacology , Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University , Seoul , Korea
| | - Kyun-Hwan Kim
- a Department of Pharmacology , Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University , Seoul , Korea.,b KU Open Innovation Center, Research Institute of Medical Sciences, Konkuk University , Seoul , Korea.,c Research Institute of Medical Sciences, Konkuk University , Seoul , Korea
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30
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Li J, Dai X, Zhang H, Zhang W, Sun S, Gao T, Kou Z, Yu H, Guo Y, Du L, Jiang S, Zhang J, Zhou Y. Up-regulation of human cervical cancer proto-oncogene contributes to hepatitis B virus-induced malignant transformation of hepatocyte by down-regulating E-cadherin. Oncotarget 2016; 6:29196-208. [PMID: 26470691 PMCID: PMC4745720 DOI: 10.18632/oncotarget.5039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 08/25/2015] [Indexed: 12/26/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most fatal human malignancies, Human cervical cancer proto-oncogene (HCCR) aberrantly expressed in a number of malignant tumors, including HCC. HCC is associated with Hepatitis B virus (HBV) infection in a large percentage of cases. To explore the regulation and function of HCCR expression in the development of HCC, we detected HCCR expression in HBV expressing hepatocytes. Results showed that the expression of HCCR was higher in HBV-expressing hepatocytes than that in control cells. Examining different components of HBV revealed that the HBx promotes HCCR expression in hepatocytes via the T-cell factor (TCF)/β-catenin pathway. HCCR expression in HBx transgenic mice increased with as the mice aged and developed tumors. We also found that overexpression of HCCR in hepatocytes promoted cell proliferation, migration, and invasion and reduced cell adhesion. Suppressing HCCR expression abolished the effect of HBx-induced hepatocyte growth. In addition, HCCR represses the expression of E-cadherin by inhibition its promoter activity, which might correlate with the effects of HCCR in hepatocytes. Taken together, these results demonstrate that HBx-HCCR-E-cadherin regulation pathway might play an important role in HBV-induced hepatocarcinogenesis. They also imply that HCCR is a potential risk marker for HCC and/or a potential therapeutic target.
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Affiliation(s)
- Junfeng Li
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Xiaopeng Dai
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Hongfei Zhang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Wei Zhang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Shihui Sun
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Tongtong Gao
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Zhihua Kou
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Hong Yu
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Yan Guo
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Lanying Du
- Laboratory of Viral Immunology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA
| | - Shibo Jiang
- Laboratory of Viral Immunology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA.,Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jianying Zhang
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
| | - Yusen Zhou
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
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HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling. Sci Rep 2016; 6:23521. [PMID: 27009634 PMCID: PMC4806364 DOI: 10.1038/srep23521] [Citation(s) in RCA: 119] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 03/09/2016] [Indexed: 12/11/2022] Open
Abstract
It is well accepted that HBx plays the major role in hepatocarcinogenesis associated with hepatitis B virus (HBV) infections. However, little was known about its role in regulating long noncoding RNAs (lncRNAs), a large group of transcripts regulating a variety of biological processes including carcinogenesis in mammalian cells. Here we report that HBx upregulates UCA1 genes and downregulates p27 genes in hepatic LO2 cells. Further studies show that the upregulated UCA1 promotes cell growth by facilitating G1/S transition through CDK2 in both hepatic and hepatoma cells. Knock down of UCA1 in HBx-expressing hepatic and hepatoma cells resulted in markedly increased apoptotic cells by elevating the cleaved caspase-3 and caspase-8. More importantly, UCA1 is found to be physically associated with enhancer of zeste homolog 2 (EZH2), which suppresses p27Kip1 through histone methylation (H3K27me3) on p27Kip1 promoter. We also show that knockdown of UCA1 in hepatoma cells inhibits tumorigenesis in nude mice. In a clinic study, UCA1 is found to be frequently up-regulated in HBx positive group tissues in comparison with the HBx negative group, and exhibits an inverse correlation between UCA1 and p27Kip1 levels. Our findings demonstrate an important mechanism of hepatocarcinogenesis through the signaling of HBx-UCA1/EZH2-p27Kip1 axis, and a potential target of HCC.
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32
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Tornesello ML, Buonaguro L, Buonaguro FM. An overview of new biomolecular pathways in pathogen-related cancers. Future Oncol 2016; 11:1625-39. [PMID: 26043216 DOI: 10.2217/fon.15.87] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cancer molecular pathways are combinations of metabolic processes deregulated in neoplastic cells. Besides pathways specific to tissues from which cancers originate, common neoplastic traits are present among most tumors. Hanahan and Weinberg have described the most critical 'hallmarks' shared by many cancer types. In recent years, cancer stem cell specific properties and pathways have also been identified. Other altered pathways are peculiar of cancer type and cancer stage, even in different cancer stem cell types. In pathogen-related tumors, the alteration of inflammatory and immunologic response along with impairment of cell cycle control represents key molecular events of tumor progression. This article summarizes the recent discoveries of new altered pathways in cancer and their importance in cancer diagnosis and tailored therapies.
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Mesri EA, Feitelson MA, Munger K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe 2014; 15:266-82. [PMID: 24629334 DOI: 10.1016/j.chom.2014.02.011] [Citation(s) in RCA: 459] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Approximately 12% of all human cancers are caused by oncoviruses. Human viral oncogenesis is complex, and only a small percentage of the infected individuals develop cancer, often many years to decades after the initial infection. This reflects the multistep nature of viral oncogenesis, host genetic variability, and the fact that viruses contribute to only a portion of the oncogenic events. In this review, the Hallmarks of Cancer framework of Hanahan and Weinberg (2000 and 2011) is used to dissect the viral, host, and environmental cofactors that contribute to the biology of multistep oncogenesis mediated by established human oncoviruses. The viruses discussed include Epstein-Barr virus (EBV), high-risk human papillomaviruses (HPVs), hepatitis B and C viruses (HBV and HCV, respectively), human T cell lymphotropic virus-1 (HTLV-1), and Kaposi's sarcoma herpesvirus (KSHV).
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Affiliation(s)
- Enrique A Mesri
- Viral Oncology Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; AIDS Malignancies Scientific Working Group, Miami Center for AIDS Research, Department and Graduate Program in Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Mark A Feitelson
- Department of Biology, Temple University, Philadelphia, PA 19122, USA.
| | - Karl Munger
- Division of Infectious Diseases, Department of Medicine, Brigham and Women Hospital and Harvard Medical School, Boston, MA 02115, USA.
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34
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Chung TW, Kim SJ, Choi HJ, Song KH, Jin UH, Yu DY, Seong JK, Kim JG, Kim KJ, Ko JH, Ha KT, Lee YC, Kim CH. Hepatitis B virus X protein specially regulates the sialyl lewis a synthesis among glycosylation events for metastasis. Mol Cancer 2014; 13:222. [PMID: 25255877 PMCID: PMC4190352 DOI: 10.1186/1476-4598-13-222] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 01/15/2014] [Indexed: 12/31/2022] Open
Abstract
Background The metastasis of hematogenous cancer cells is associated with abnormal glycosylation such as sialyl lewis antigens. Although the hepatitis B virus X protein (HBx) plays important role in liver disease, the precise function of HBx on aberrant glycosylation for metastasis remains unclear. Methods The human hepatocellular carcinoma tissues, HBx transgenic mice and HBx-transfected cells were used to check the correlation of expressions between HBx and Sialyl lewis antigen for cancer metastasis. To investigate whether expression levels of glycosyltransferases induced in HBx-transfected cells are specifically associated with sialyl lewis A (SLA) synthesis, which enhances metastasis by interaction of liver cancer cells with endothelial cells, ShRNA and siRNAs targeting specific glycosyltransferases were used. Results HBx expression in liver cancer region of HCC is associated with the specific synthesis of SLA. Furthermore, the SLA was specifically induced both in liver tissues from HBx-transgenic mice and in in vitro HBx-transfected cells. HBx increased transcription levels and activities of α2-3 sialyltransferases (ST3Gal III), α1-3/4 fucosyltransferases III and VII (FUT III and VII) genes, which were specific for SLA synthesis, allowing dramatic cell-cell adhesion for metastatic potential. Interestingly, HBx specifically induced expression of N-acetylglucosamine-β1-3 galactosyltransferase V (β1-3GalT 5) gene associated with the initial synthesis of sialyl lewis A, but not β1-4GalT I. The β1-3GalT 5 shRNA suppressed SLA expression by HBx, blocking the adhesion of HBx-transfected cells to the endothelial cells. Moreover, β1-3GalT 5 silencing suppressed lung metastasis of HBx-transfected cells in in vivo lung metastasis system. Conclusion HBx targets the specific glycosyltransferases for the SLA synthesis and this process regulates hematogenous cancer cell adhesion to endothelial cells for cancer metastasis. Electronic supplementary material The online version of this article (doi:10.1186/1476-4598-13-222) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Cheorl-Ho Kim
- Molecular and Cellular Glycobiology Laboratory, Department of Biological Science, SungKyunKwan University, 300 Chunchun-Dong, Jangan-Gu, Suwon, Kyunggi-Do 440-746, South Korea.
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35
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Abdel Mohsen MA, Hussein NA, Ghazal AA, El-Ghandour MK, Farouk M, Abd El-Wahab AE, Yousef AI. Angiogenic output in viral hepatitis, C and B, and HCV-associated hepatocellular carcinoma. ALEXANDRIA JOURNAL OF MEDICINE 2014. [DOI: 10.1016/j.ajme.2014.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Affiliation(s)
- Mohamed A. Abdel Mohsen
- Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, 165 El-Horria Ave., P.O. 21561, Alexandria, Egypt
| | - Neveen A. Hussein
- Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, 165 El-Horria Ave., P.O. 21561, Alexandria, Egypt
| | - Abeer A. Ghazal
- Microbiology Department, Medical Research Institute, Alexandria University, 165 El-Horria Ave., P.O. 21561, Alexandria, Egypt
| | - Marwa K. El-Ghandour
- Chemical Pathology Department, Medical Research Institute, Alexandria University, 165 El-Horria Ave., P.O. 21561, Alexandria, Egypt
| | - Mohamed Farouk
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Alexandria University, Egypt
| | - Abeer E. Abd El-Wahab
- Medical Biotechnology Department, City for Scientific Research & Technology Application, Egypt
| | - Amany I. Yousef
- Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, 165 El-Horria Ave., P.O. 21561, Alexandria, Egypt
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Sun Q, Wang R, Luo J, Wang P, Xiong S, Liu M, Cheng B. Notch1 promotes hepatitis B virus X protein-induced hepatocarcinogenesis via Wnt/β-catenin pathway. Int J Oncol 2014; 45:1638-48. [PMID: 25017705 DOI: 10.3892/ijo.2014.2537] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 06/24/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatocellular carcinoma (HCC) via a network of signaling pathways. Notch pathway is a major member of the network. Notch signaling may generate opposing effect in different steps of carcinogenesis, depending on the tumor cell type and the status of other signaling pathways, such as Wnt signaling pathway. Our previous studies have shown that activated Notch1 signaling is required for HBx to promote proliferation and survival of human hepatic cell line L02. However, the exact mechanisms remain vague. Here, we used L02/HBx cell lines as a cell model to study the relationship between Notch and Wnt/β-catenin pathways in promoting proliferation. We observed that activated Notch1 and Wnt/β-catenin signaling pathways and L02 cell malignant transformation were induced by HBx. Inhibition of the Notch1 pathway decreased the activation of Wnt/β-catenin pathway and cell proliferation, while inhibition of the Wnt/β-catenin pathway impaired cell proliferation, but did not significantly affect Notch1 signaling pathway in L02/HBx cells. Furthermore, inhibition of the Wnt/β-catenin pathway overcame the inhibition effect of knockdown Notch1 on proliferation and survival in L02/HBx cells. Additionally, the activity of Wnt/β-catenin signaling appears to be consistent with Fzd10 expression. Therefore, we demonstrate that Wnt signaling is downstream of the Notch pathway in regulating proliferation of L02/HBx cells, and which may be related to Fzd10 instead of Fzd7. These data suggest a new model of HBx-related HCC via cooperation between Wnt and Notch pathways.
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Affiliation(s)
- Qian Sun
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Ronghua Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Jing Luo
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Peng Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Si Xiong
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Man Liu
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Bin Cheng
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
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Involvement of DNA damage response pathways in hepatocellular carcinoma. BIOMED RESEARCH INTERNATIONAL 2014; 2014:153867. [PMID: 24877058 PMCID: PMC4022277 DOI: 10.1155/2014/153867] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 01/23/2014] [Accepted: 03/25/2014] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) has been known as one of the most lethal human malignancies, due to the difficulty of early detection, chemoresistance, and radioresistance, and is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. Its development has been closely associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Genetic alterations and genomic instability, probably resulted from unrepaired DNA lesions, are increasingly recognized as a common feature of human HCC. Dysregulation of DNA damage repair and signaling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. It has been demonstrated that various HCC-associated risk factors are able to promote DNA damages, formation of DNA adducts, and chromosomal aberrations. Hence, alterations in the DDR pathways may accumulate these lesions to trigger hepatocarcinogenesis and also to facilitate advanced HCC progression. This review collects some of the most known information about the link between HCC-associated risk factors and DDR pathways in HCC. Hopefully, the review will remind the researchers and clinicians of further characterizing and validating the roles of these DDR pathways in HCC.
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Huang JF, Guo YJ, Zhao CX, Yuan SX, Wang Y, Tang GN, Zhou WP, Sun SH. Hepatitis B virus X protein (HBx)-related long noncoding RNA (lncRNA) down-regulated expression by HBx (Dreh) inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin. Hepatology 2013; 57:1882-92. [PMID: 23239537 DOI: 10.1002/hep.26195] [Citation(s) in RCA: 275] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 12/01/2012] [Indexed: 12/11/2022]
Abstract
UNLABELLED The hepatitis B virus X protein (HBx) has been implicated as an oncogene in both epigenetic modifications and genetic regulation during hepatocarcinogenesis, but the underlying mechanisms are not entirely clear. Long noncoding RNAs (lncRNAs), which regulate gene expression with little or no protein-coding capacity, are involved in diverse biological processes and in carcinogenesis. We asked whether HBx could promote hepatocellular carcinoma (HCC) by regulating the expression of lncRNAs. In this study we investigated the alteration in expression of lncRNAs induced by HBx using microarrays and real-time quantitative polymerase chain reaction (PCR). Our results indicate that HBx transgenic mice have a specific profile of liver lncRNAs compared with wildtype mice. We identified an lncRNA, down-regulated expression by HBx (termed lncRNA-Dreh), which can inhibit HCC growth and metastasis in vitro and in vivo, act as a tumor suppressor in the development of hepatitis B virus (HBV)-HCC. LncRNA-Dreh could combine with the intermediate filament protein vimentin and repress its expression, and thus further change the normal cytoskeleton structure to inhibit tumor metastasis. We also identified a human ortholog RNA of Dreh (hDREH) and found that its expression level was frequently down-regulated in HBV-related HCC tissues in comparison with the adjacent noncancerous hepatic tissues, and its decrement significantly correlated with poor survival of HCC patients. CONCLUSION These findings support a role of lncRNA-Dreh in tumor suppression and survival prediction in HCC patients. This discovery contributes to a better understanding of the importance of the deregulated lncRNAs by HBx in HCC and provides a rationale for the potential development of lncRNA-based targeted approaches for the treatment of HBV-related HCC.
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Affiliation(s)
- Jin-feng Huang
- The Department of Medical Genetics, Second Military Medical University, Shanghai, China
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Kapoor NR, Ahuja R, Shukla SK, Kumar V. The HBx protein of hepatitis B virus confers resistance against nucleolar stress and anti-cancer drug-induced p53 expression. FEBS Lett 2013; 587:1287-92. [PMID: 23507139 DOI: 10.1016/j.febslet.2013.03.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 02/28/2013] [Accepted: 03/03/2013] [Indexed: 12/28/2022]
Abstract
The nucleolus is a stress sensor associated with cell cycle progression and a viral target. However, the role of the nucleolus during hepatitis B virus infection has not been studied. Here we show that under nucleolar stress, the HBx oncoprotein down-regulates p53 and p21(waf1) levels by disrupting the interaction between ribosomal protein L11 and MDM2. Further, HBx inhibited Act D-mediated down-regulation of proliferative factors such as c-Myc and cyclin E and revived RNA pol I-dependent transcription under these conditions. Importantly, HBx also countered the action of anticancer drug Paclitaxel suggesting its possible role in drug resistance. Thus, HBx not only can facilitate cell proliferation under stress conditions but can confer resistance against anticancer drugs.
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Affiliation(s)
- Neetu Rohit Kapoor
- Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
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40
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Wierstra I. FOXM1 (Forkhead box M1) in tumorigenesis: overexpression in human cancer, implication in tumorigenesis, oncogenic functions, tumor-suppressive properties, and target of anticancer therapy. Adv Cancer Res 2013; 119:191-419. [PMID: 23870513 DOI: 10.1016/b978-0-12-407190-2.00016-2] [Citation(s) in RCA: 138] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
FOXM1 (Forkhead box M1) is a typical proliferation-associated transcription factor and is also intimately involved in tumorigenesis. FOXM1 stimulates cell proliferation and cell cycle progression by promoting the entry into S-phase and M-phase. Additionally, FOXM1 is required for proper execution of mitosis. In accordance with its role in stimulation of cell proliferation, FOXM1 exhibits a proliferation-specific expression pattern and its expression is regulated by proliferation and anti-proliferation signals as well as by proto-oncoproteins and tumor suppressors. Since these factors are often mutated, overexpressed, or lost in human cancer, the normal control of the foxm1 expression by them provides the basis for deregulated FOXM1 expression in tumors. Accordingly, FOXM1 is overexpressed in many types of human cancer. FOXM1 is intimately involved in tumorigenesis, because it contributes to oncogenic transformation and participates in tumor initiation, growth, and progression, including positive effects on angiogenesis, migration, invasion, epithelial-mesenchymal transition, metastasis, recruitment of tumor-associated macrophages, tumor-associated lung inflammation, self-renewal capacity of cancer cells, prevention of premature cellular senescence, and chemotherapeutic drug resistance. However, in the context of urethane-induced lung tumorigenesis, FOXM1 has an unexpected tumor suppressor role in endothelial cells because it limits pulmonary inflammation and canonical Wnt signaling in epithelial lung cells, thereby restricting carcinogenesis. Accordingly, FOXM1 plays a role in homologous recombination repair of DNA double-strand breaks and maintenance of genomic stability, that is, prevention of polyploidy and aneuploidy. The implication of FOXM1 in tumorigenesis makes it an attractive target for anticancer therapy, and several antitumor drugs have been reported to decrease FOXM1 expression.
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Jung SY, Kim YJ. C-terminal region of HBx is crucial for mitochondrial DNA damage. Cancer Lett 2012; 331:76-83. [PMID: 23246371 DOI: 10.1016/j.canlet.2012.12.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 12/04/2012] [Accepted: 12/04/2012] [Indexed: 02/07/2023]
Abstract
HBx is strongly associated with hepatocellular carcinoma development through transcription factor activation and reactive oxygen species (ROSs) production. However, the exact role of HBx during hepatocellular carcinogenesis is not fully understood. Recently, it was reported that C-terminal truncated HBx is associated with tumor metastasis. In the present study, we confirmed that the C-terminal region of HBx is required for ROS production and 8-oxoguanine (8-oxoG) formation, which is considered as a reliable biomarker of oxidative stress. These results suggest ROS production induced by the C-terminal region of HBx leads to mitochondrial DNA damage, which may play a role in HCC development.
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Affiliation(s)
- Seung-Youn Jung
- Department of Molecular Biology, Pusan National University, Busan 609-735, Republic of Korea
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