|
1
|
Cardoso MF, Machado MV. The Changing Face of Hepatitis Delta Virus Associated Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:3723. [PMID: 39594679 PMCID: PMC11591730 DOI: 10.3390/cancers16223723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/22/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
Hepatitis delta virus (HDV) infection requires the presence of hepatitis B virus (HBV), and chronic HBV-HDV coinfection is considered the most severe form of viral hepatitis. When compared with HBV mono-infection, HBV-HDV coinfection is associated with higher rates of liver cirrhosis and hepatocellular carcinoma (HCC). In this review, we aim to elucidate the complex relationship between HDV infection and the development of HCC. The exact mechanisms underlying the carcinogenic potential of HDV remain to be fully elucidated. Evidence suggests that HDV has both indirect and direct oncogenic effects. Indirect effects promote accelerated progression to liver cirrhosis, which results in a different tumor microenvironment. Direct oncogenic effects are suggested by a distinct molecular signature. The recent epidemiological data regarding HBV-HDV coinfection should make us reconsider the HCC screening strategy, with special focus in younger non-cirrhotic patients. Finally, treating HCC in patients with chronic HDV poses unique challenges due to the complex interplay between HBV and HDV and the severity of liver disease. An in-depth understanding of the epidemiology and pathophysiology of HDV infection and carcinogenesis is essential to improve disease management in this high-risk population.
Collapse
Affiliation(s)
- Mariana Ferreira Cardoso
- Gastroenterology Department, Hospital Prof. Doutor Fernando Fonseca, 2720-276 Amadora, Portugal;
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
| | - Mariana Verdelho Machado
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
- Gastroenterology Department, Hospital de Vila Franca de Xira, 2600-009 Vila Franca de Xira, Portugal
| |
Collapse
|
|
2
|
Lombardo D, Franzè MS, Caminiti G, Pollicino T. Hepatitis Delta Virus and Hepatocellular Carcinoma. Pathogens 2024; 13:362. [PMID: 38787214 PMCID: PMC11124437 DOI: 10.3390/pathogens13050362] [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: 03/22/2024] [Revised: 04/14/2024] [Accepted: 04/20/2024] [Indexed: 05/25/2024] Open
Abstract
The hepatitis D virus (HDV) is a compact, enveloped, circular RNA virus that relies on hepatitis B virus (HBV) envelope proteins to initiate a primary infection in hepatocytes, assemble, and secrete new virions. Globally, HDV infection affects an estimated 12 million to 72 million people, carrying a significantly elevated risk of developing cirrhosis, liver failure, and hepatocellular carcinoma (HCC) compared to an HBV mono-infection. Furthermore, HDV-associated HCC often manifests at a younger age and exhibits more aggressive characteristics. The intricate mechanisms driving the synergistic carcinogenicity of the HDV and HBV are not fully elucidated but are believed to involve chronic inflammation, immune dysregulation, and the direct oncogenic effects of the HDV. Indeed, recent data highlight that the molecular profile of HCC associated with HDV is unique and distinct from that of HBV-induced HCC. However, the question of whether the HDV is an oncogenic virus remains unanswered. In this review, we comprehensively examined several crucial aspects of the HDV, encompassing its epidemiology, molecular biology, immunology, and the associated risks of liver disease progression and HCC development.
Collapse
Affiliation(s)
| | | | | | - Teresa Pollicino
- Department of Clinical and Experimental Medicine, University Hospital of Messina, 98124 Messina, Italy; (D.L.); (M.S.F.); (G.C.)
| |
Collapse
|
|
3
|
Martín-García D, García-Aranda M, Redondo M. Therapeutic Potential of Clusterin Inhibition in Human Cancer. Cells 2024; 13:665. [PMID: 38667280 PMCID: PMC11049052 DOI: 10.3390/cells13080665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/11/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Clusterin (CLU) protein is involved in various pathophysiological processes including carcinogenesis and tumor progression. In recent years, the role of the secretory isoform has been demonstrated in tumor cells, where it inhibits apoptosis and favors the acquisition of resistance to conventional treatments used to treat cancer. To determine the possible therapeutic potential of inhibiting this protein, numerous studies have been carried out in this field. In this article, we present the existing knowledge to date on the inhibition of this protein in different types of cancer and analyze the importance it could have in the development of new therapies targeted against this disease.
Collapse
Affiliation(s)
- Desirée Martín-García
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Málaga, Spain;
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Málaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
| | - Marilina García-Aranda
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Málaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
| | - Maximino Redondo
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Málaga, Spain;
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Málaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
| |
Collapse
|
|
4
|
Gross C, Guérin LP, Socol BG, Germain L, Guérin SL. The Ins and Outs of Clusterin: Its Role in Cancer, Eye Diseases and Wound Healing. Int J Mol Sci 2023; 24:13182. [PMID: 37685987 PMCID: PMC10488069 DOI: 10.3390/ijms241713182] [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: 06/30/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Clusterin (CLU) is a glycoprotein originally discovered in 1983 in ram testis fluid. Rapidly observed in other tissues, it was initially given various names based on its function in different tissues. In 1992, it was finally named CLU by consensus. Nearly omnipresent in human tissues, CLU is strongly expressed at fluid-tissue interfaces, including in the eye and in particular the cornea. Recent research has identified different forms of CLU, with the most prominent being a 75-80 kDa heterodimeric protein that is secreted. Another truncated version of CLU (55 kDa) is localized to the nucleus and exerts pro-apoptotic activities. CLU has been reported to be involved in various physiological processes such as sperm maturation, lipid transportation, complement inhibition and chaperone activity. CLU was also reported to exert important functions in tissue remodeling, cell-cell adhesion, cell-substratum interaction, cytoprotection, apoptotic cell death, cell proliferation and migration. Hence, this protein is sparking interest in tissue wound healing. Moreover, CLU gene expression is finely regulated by cytokines, growth factors and stress-inducing agents, leading to abnormally elevated levels of CLU in many states of cellular disturbance, including cancer and neurodegenerative conditions. In the eye, CLU expression has been reported as being severely increased in several pathologies, such as age-related macular degeneration and Fuch's corneal dystrophy, while it is depleted in others, such as pathologic keratinization. Nevertheless, the precise role of CLU in the development of ocular pathologies has yet to be deciphered. The question of whether CLU expression is influenced by these disorders or contributes to them remains open. In this article, we review the actual knowledge about CLU at both the protein and gene expression level in wound healing, and explore the possibility that CLU is a key factor in cancer and eye diseases. Understanding the expression and regulation of CLU could lead to the development of novel therapeutics for promoting wound healing.
Collapse
Affiliation(s)
- Christelle Gross
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
- Centre de Recherche du CHU de Québec, Axe Médecine Régénératrice, Québec City, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
| | | | - Bianca G. Socol
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
| | - Lucie Germain
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
- Centre de Recherche du CHU de Québec, Axe Médecine Régénératrice, Québec City, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
- Département de Chirurgie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
| | - Sylvain L. Guérin
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
- Centre de Recherche du CHU de Québec, Axe Médecine Régénératrice, Québec City, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
| |
Collapse
|
|
5
|
Thiyagarajah K, Basic M, Hildt E. Cellular Factors Involved in the Hepatitis D Virus Life Cycle. Viruses 2023; 15:1687. [PMID: 37632029 PMCID: PMC10459925 DOI: 10.3390/v15081687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/30/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatitis D virus (HDV) is a defective RNA virus with a negative-strand RNA genome encompassing less than 1700 nucleotides. The HDV genome encodes only for one protein, the hepatitis delta antigen (HDAg), which exists in two forms acting as nucleoproteins. HDV depends on the envelope proteins of the hepatitis B virus as a helper virus for packaging its ribonucleoprotein complex (RNP). HDV is considered the causative agent for the most severe form of viral hepatitis leading to liver fibrosis/cirrhosis and hepatocellular carcinoma. Many steps of the life cycle of HDV are still enigmatic. This review gives an overview of the complete life cycle of HDV and identifies gaps in knowledge. The focus is on the description of cellular factors being involved in the life cycle of HDV and the deregulation of cellular pathways by HDV with respect to their relevance for viral replication, morphogenesis and HDV-associated pathogenesis. Moreover, recent progress in antiviral strategies targeting cellular structures is summarized in this article.
Collapse
Affiliation(s)
| | | | - Eberhard Hildt
- Paul-Ehrlich-Institute, Department of Virology, D-63225 Langen, Germany; (K.T.); (M.B.)
| |
Collapse
|
|
6
|
Papatheodoridi A, Papatheodoridis G. Hepatocellular carcinoma: The virus or the liver? Liver Int 2023; 43 Suppl 1:22-30. [PMID: 35319167 DOI: 10.1111/liv.15253] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/28/2022] [Accepted: 03/19/2022] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) represents a major public health problem being one of the most common causes of cancer-related deaths worldwide. Hepatitis B (HBV) and C viruses have been classified as oncoviruses and are responsible for the majority of HCC cases, while the role of hepatitis D virus (HDV) in liver carcinogenesis has not been elucidated. HDV/HBV coinfection is related to more severe liver damage than HBV mono-infection and recent studies suggest that HDV/HBV patients are at increased risk of developing HCC compared to HBV mono-infected patients. HBV is known to promote hepatocarcinogenesis via DNA integration into host DNA, disruption of molecular pathways by regulatory HBV x (HBx) protein and excessive oxidative stress. Recently, several molecular mechanisms have been proposed to clarify the pathogenesis of HDV-related HCC including activation of signalling pathways by specific HDV antigens, epigenetic dysregulation and altered gene expression. Alongside, ongoing chronic inflammation and impaired immune responses have also been suggested to facilitate carcinogenesis. Finally, cellular senescence seems to play an important role in chronic viral infection and inflammation leading to hepatocarcinogenesis. In this review, we summarize the current literature on the impact of HDV in HCC development and discuss the potential interplay between HBV, HDV and neighbouring liver tissue in liver carcinogenesis.
Collapse
Affiliation(s)
- Alkistis Papatheodoridi
- Department of Clinical Therapeutics, Medical School of National and Kapodistrian University of Athens, "Alexandra" General Hospital of Athens, Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Laiko", Athens, Greece
| |
Collapse
|
|
7
|
Costante F, Stella L, Santopaolo F, Gasbarrini A, Pompili M, Asselah T, Ponziani FR. Molecular and Clinical Features of Hepatocellular Carcinoma in Patients with HBV-HDV Infection. J Hepatocell Carcinoma 2023; 10:713-724. [PMID: 37128594 PMCID: PMC10148646 DOI: 10.2147/jhc.s384751] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 04/06/2023] [Indexed: 05/03/2023] Open
Abstract
Hepatitis D virus (HDV) infection affects more than 10 million people worldwide, with an estimated prevalence of nearly 4.5% among HBsAg-positive individuals. Epidemiological studies have shown a significant increase in the prevalence of hepatocellular carcinoma (HCC) in patients with chronic HDV infection compared to those with chronic hepatitis B virus (HBV) mono-infection. Despite the clinical findings, data on molecular oncogenic mechanisms are limited and fragmentary. Moreover, the role of HDV in promoting the development of HCC has so far been controversial, because it is difficult to weigh the respective contributions of the two viruses. In this review, we focused on the direct oncogenic action of HDV, its role in modifying the tumor microenvironment, and the genetic signature of HDV-related HCC, comparing these features with HBV-related HCC.
Collapse
Affiliation(s)
- Federico Costante
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Leonardo Stella
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Tarik Asselah
- Service d’Hépatologie, Hôpital Beaujon UMR 1149 Inserm - Université de Paris, Clichy, France
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
- Correspondence: Francesca Romana Ponziani; Federico Costante, Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Francesco Vito 1, Rome, 00168, Italy, Tel +390630156264, Email ;
| |
Collapse
|
|
8
|
Zaki MYW, Fathi AM, Samir S, Eldafashi N, William KY, Nazmy MH, Fathy M, Gill US, Shetty S. Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:1255. [PMID: 35267563 PMCID: PMC8909759 DOI: 10.3390/cancers14051255] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 02/08/2023] Open
Abstract
Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.
Collapse
Affiliation(s)
- Marco Y. W. Zaki
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Ahmed M. Fathi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Samara Samir
- Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt;
| | - Nardeen Eldafashi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Kerolis Y. William
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 12613, Egypt;
| | - Maiiada Hassan Nazmy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Upkar S. Gill
- Barts Liver Centre, Centre for Immunobiology, Barts & The London School of Medicine & Dentistry, QMUL, London E1 2AT, UK;
| | - Shishir Shetty
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| |
Collapse
|
|
9
|
Russo FP, Zanetto A, Pinto E, Battistella S, Penzo B, Burra P, Farinati F. Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand? Int J Mol Sci 2022; 23:500. [PMID: 35008926 PMCID: PMC8745141 DOI: 10.3390/ijms23010500] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in "high-risk" patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient's risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Fabio Farinati
- Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy; (F.P.R.); (A.Z.); (E.P.); (S.B.); (B.P.); (P.B.)
| |
Collapse
|
|
10
|
Datfar T, Doulberis M, Papaefthymiou A, Hines IN, Manzini G. Viral Hepatitis and Hepatocellular Carcinoma: State of the Art. Pathogens 2021; 10:pathogens10111366. [PMID: 34832522 PMCID: PMC8619105 DOI: 10.3390/pathogens10111366] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/26/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis is one of the main causes leading to hepatocellular carcinoma (HCC). The continued rise in incidence of HCC suggests additional factors following infection may be involved. This review examines recent studies investigating the molecular mechanisms of chronic hepatitis and its association with hepatocarcinogenesis. Hepatitis B virus patients with genotype C display an aggressive disease course leading to HCC more than other genotypes. Furthermore, hepatitis B excretory antigen (HBeAg) seems to be a more sensitive predictive tumor marker exhibiting a six-fold higher relative risk in patients with positive HBsAg and HBeAg than those with HBsAg only. Single or combined mutations of viral genome can predict HCC development in up to 80% of patients. Several mutations in HBx-gene are related with higher HCC incidence. Overexpression of the core protein in HCV leads to hepatocellular lipid accumulation associated with oncogenesis. Reduced number and decreased functionality of natural killer cells in chronic HCV individuals dysregulate their surveillance function in tumor and viral cells resulting in HCC. Furthermore, high T-cell immunoglobulin and mucin 3 levels supress CD8+ T-cells, which lead to immunological dysregulation. Hepatitis D promotes HCC development indirectly via modifications to innate immunity, epigenetic alterations and production of reactive oxygen species with the LHDAg being the most highly associated with HCC development. Summarizing the results, HBV and HCV infection represent the most associated forms of viral hepatitis causing HCC. Further studies are warranted to further improve the prediction of high-risk patients and development of targeted therapeutics preventing the transition from hepatic inflammation–fibrosis to cancer.
Collapse
Affiliation(s)
- Toofan Datfar
- Department of General and Visceral Surgery, Hospital of Aarau, 5001 Aarau, Switzerland;
- Correspondence: ; Tel.: +41-76-4930834
| | - Michael Doulberis
- Department of Gastroenterology and Hepatology, Hospital of Aarau, 5001 Aarau, Switzerland;
| | | | - Ian N. Hines
- Department of Nutrition Science, East Carolina University, Greenville, NC 27858, USA;
| | - Giulia Manzini
- Department of General and Visceral Surgery, Hospital of Aarau, 5001 Aarau, Switzerland;
| |
Collapse
|
|
11
|
Abstract
Hepatitis D virus (HDV) is a small, defective RNA virus that depends on hepatitis B virus (HBV) for virion assembly and transmission. It replicates within the nucleus of hepatocytes and interacts with several cellular proteins. Chronic hepatitis D is a severe and progressive disease, leading to cirrhosis in up to 80% of cases. A high proportion of patients die of liver decompensation or hepatocellular carcinoma (HCC), but the lack of large prospective studies has made it difficult to precisely define the rate of these long-term complications. In particular, the question of whether HDV is an oncogenic virus has been a matter of debate. Studies conducted over the past decade provided evidence that HDV is associated with a significantly higher risk of developing HCC compared to HBV monoinfection. However, the mechanisms whereby HDV promotes liver cancer remain elusive. Recent data have demonstrated that the molecular profile of HCC-HDV is unique and distinct from that of HBV-HCC, with an enrichment of upregulated genes involved in cell-cycle/DNA replication, and DNA damage and repair, which point to genome instability as an important mechanism of HDV hepatocarcinogenesis. These data suggest that HBV and HDV promote carcinogenesis by distinct molecular mechanisms despite the obligatory dependence of HDV on HBV.
Collapse
|
|
12
|
HDV Pathogenesis: Unravelling Ariadne's Thread. Viruses 2021; 13:v13050778. [PMID: 33924806 PMCID: PMC8145675 DOI: 10.3390/v13050778] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatitis Delta virus (HDV) lies in between satellite viruses and viroids, as its unique molecular characteristics and life cycle cannot categorize it according to the standard taxonomy norms for viruses. Being a satellite virus of hepatitis B virus (HBV), HDV requires HBV envelope glycoproteins for its infection cycle and its transmission. HDV pathogenesis varies and depends on the mode of HDV and HBV infection; a simultaneous HDV and HBV infection will lead to an acute hepatitis that will resolve spontaneously in the majority of patients, whereas an HDV super-infection of a chronic HBV carrier will mainly result in the establishment of a chronic HDV infection that may progress towards cirrhosis, liver decompensation, and hepatocellular carcinoma (HCC). With this review, we aim to unravel Ariadne’s thread into the labyrinth of acute and chronic HDV infection pathogenesis and will provide insights into the complexity of this exciting topic by detailing the different players and mechanisms that shape the clinical outcome.
Collapse
|
|
13
|
Praharaj PP, Patra S, Panigrahi DP, Patra SK, Bhutia SK. Clusterin as modulator of carcinogenesis: A potential avenue for targeted cancer therapy. Biochim Biophys Acta Rev Cancer 2020; 1875:188500. [PMID: 33385484 DOI: 10.1016/j.bbcan.2020.188500] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/14/2020] [Accepted: 12/24/2020] [Indexed: 12/30/2022]
Abstract
Clusterin (CLU) is an evolutionary conserved molecular chaperone present in different human tissues and fluids and established to be a significant cancer regulator. It controls several cancer-associated cellular events, including cancer cell proliferation, stemness, survival, metastasis, epithelial-mesenchymal transition, therapy resistance, and inhibition of programmed cell death to support cancer growth and recurrence. This multifunctional role of CLU makes it an ideal target for cancer control. More importantly, genetic and antisense-mediated (OGX-011) inhibition of CLU enhances the anticancer potential of different FDA-approved chemotherapeutic drugs at the clinical level, improving patient's survival. In this review, we have discussed the detailed mechanism of CLU-mediated modulation of different cancer-associated signaling pathways. We have also provided updated information on the current preclinical and clinical findings that drive trials in various cancer types for potential targeted cancer therapy.
Collapse
Affiliation(s)
- Prakash Priyadarshi Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Debasna Pritimanjari Panigrahi
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India.
| |
Collapse
|
|
14
|
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: 152] [Impact Index Per Article: 30.4] [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.
Collapse
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
| |
Collapse
|
|
15
|
Donalisio M, Cirrincione S, Rittà M, Lamberti C, Civra A, Francese R, Tonetto P, Sottemano S, Manfredi M, Lorenzato A, Moro GE, Giribaldi M, Cavallarin L, Giuffrida MG, Bertino E, Coscia A, Lembo D. Extracellular Vesicles in Human Preterm Colostrum Inhibit Infection by Human Cytomegalovirus In Vitro. Microorganisms 2020; 8:microorganisms8071087. [PMID: 32708203 PMCID: PMC7409124 DOI: 10.3390/microorganisms8071087] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/08/2020] [Accepted: 07/17/2020] [Indexed: 11/16/2022] Open
Abstract
Breast milk is a complex biofluid that nourishes infants, supports their growth and protects them from diseases. However, at the same time, breastfeeding is a transmission route for human cytomegalovirus (HCMV), with preterm infants being at a great risk of congenital disease. The discrepancy between high HCMV transmission rates and the few reported cases of infants with severe clinical illness is likely due to the protective effect of breast milk. The aim of this study was to investigate the anti-HCMV activity of human preterm colostrum and clarify the role of colostrum-derived extracellular vesicles (EVs). Preterm colostrum samples were collected and the EVs were purified and characterized. The in vitro anti-HCMV activity of both colostrum and EVs was tested against HCMV, and the viral replication step inhibited by colostrum-purified EVs was examined. We investigated the putative role EV surface proteins play in impairing HCMV infection using shaving experiments and proteomic analysis. The obtained results confirmed the antiviral action of colostrum against HCMV and demonstrated a remarkable antiviral activity of colostrum-derived EVs. Furthermore, we demonstrated that EVs impair the attachment of HCMV to cells, with EV surface proteins playing a role in mediating this action. These findings contribute to clarifying the mechanisms that underlie the protective role of human colostrum against HCMV infection.
Collapse
Affiliation(s)
- Manuela Donalisio
- Laboratory of Molecular Virology, Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (M.R.); (A.C.); (R.F.); (D.L.)
- Correspondence: (M.D.); (A.C.); Tel.: +39-011-6705427 (M.D.); +39-011-3134437 (A.C.)
| | - Simona Cirrincione
- Consiglio Nazionale delle Ricerche-Istituto di Scienze delle Produzioni Alimentari, 10095 Grugliasco (TO), Italy; (S.C.); (C.L.); (L.C.); (M.G.G.)
| | - Massimo Rittà
- Laboratory of Molecular Virology, Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (M.R.); (A.C.); (R.F.); (D.L.)
| | - Cristina Lamberti
- Consiglio Nazionale delle Ricerche-Istituto di Scienze delle Produzioni Alimentari, 10095 Grugliasco (TO), Italy; (S.C.); (C.L.); (L.C.); (M.G.G.)
| | - Andrea Civra
- Laboratory of Molecular Virology, Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (M.R.); (A.C.); (R.F.); (D.L.)
| | - Rachele Francese
- Laboratory of Molecular Virology, Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (M.R.); (A.C.); (R.F.); (D.L.)
| | - Paola Tonetto
- Neonatal Intensive Care Unit, Department of Public Health and Pediatrics, University of Turin, 10126 Torino, Italy; (P.T.); (S.S.); (E.B.)
| | - Stefano Sottemano
- Neonatal Intensive Care Unit, Department of Public Health and Pediatrics, University of Turin, 10126 Torino, Italy; (P.T.); (S.S.); (E.B.)
| | - Marcello Manfredi
- Center for Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, 28100 Novara, Italy;
| | - Annalisa Lorenzato
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy;
- Department of Oncology, University of Turin, 10060 Candiolo (TO), Italy
| | - Guido E. Moro
- Italian Association of Human Milk Banks, 20126 Milano, Italy;
| | - Marzia Giribaldi
- Research Centre for Engineering and Agro-food Processing (CREA), 10135 Torino, Italy;
| | - Laura Cavallarin
- Consiglio Nazionale delle Ricerche-Istituto di Scienze delle Produzioni Alimentari, 10095 Grugliasco (TO), Italy; (S.C.); (C.L.); (L.C.); (M.G.G.)
| | - Maria Gabriella Giuffrida
- Consiglio Nazionale delle Ricerche-Istituto di Scienze delle Produzioni Alimentari, 10095 Grugliasco (TO), Italy; (S.C.); (C.L.); (L.C.); (M.G.G.)
| | - Enrico Bertino
- Neonatal Intensive Care Unit, Department of Public Health and Pediatrics, University of Turin, 10126 Torino, Italy; (P.T.); (S.S.); (E.B.)
| | - Alessandra Coscia
- Neonatal Intensive Care Unit, Department of Public Health and Pediatrics, University of Turin, 10126 Torino, Italy; (P.T.); (S.S.); (E.B.)
- Correspondence: (M.D.); (A.C.); Tel.: +39-011-6705427 (M.D.); +39-011-3134437 (A.C.)
| | - David Lembo
- Laboratory of Molecular Virology, Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (M.R.); (A.C.); (R.F.); (D.L.)
| |
Collapse
|
|
16
|
Coppola N, Alessio L, Onorato L, Sagnelli C, Sagnelli E, Pisaturo M. HDV infection in immigrant populations. J Med Virol 2019; 91:2049-2058. [PMID: 31429940 DOI: 10.1002/jmv.25570] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 08/10/2019] [Indexed: 12/16/2022]
Abstract
AIMS Little data have been published so far on the epidemiological aspects of hepatitis D virus (HDV) infection in immigrant populations and even poorer is the information on the virological, phylogenetic, and clinical aspects of this infection in these populations. This review article, aimed primarily at physicians caring for immigrants, summarizes the information available on HDV infection and analyzes data on this topic concerning the immigrant populations. METHODS AND RESULTS The prevalence of HDV infection in HBsAg-positive immigrants varies according to the country of origin. For example, in immigrants from sub-Saharan Africa, this prevalence is higher in those born in Equatorial Guinea (24.4%) than those from other African countries (10.3%). The epidemiological impact of HDV infection linked to migratory flows is a function of the different endemicity between countries of origin and countries in which a new existence has been established. This impact is high when immigrants from areas endemic to HDV infection (eg, Equatorial Guinea) settle in areas of low endemicity (eg, Germany or England, with a prevalence of around 4%), while the impact is lesser or nonexistent if the migratory flows are directed toward countries with intermediate endemicity (eg, Italy and Greece, with a prevalence of around 10%). CONCLUSION This impact of immigration on HDV epidemiology can be strong when HDV endemicity is high in the country of origin and low in the host country and slight when immigrants move to high or medium endemic countries.
Collapse
Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
- Infectious Disease Unit, AORN Caserta, Caserta, Italy
| | | | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
- Infectious Disease Unit, AORN Caserta, Caserta, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| |
Collapse
|
|
17
|
Puigvehí M, Moctezuma-Velázquez C, Villanueva A, Llovet JM. The oncogenic role of hepatitis delta virus in hepatocellular carcinoma. JHEP Rep 2019; 1:120-130. [PMID: 32039360 PMCID: PMC7001537 DOI: 10.1016/j.jhepr.2019.05.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/18/2019] [Accepted: 05/05/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis delta virus (HDV) is a small defective virus that needs hepatitis B virus (HBV) to replicate and propagate. HDV infection affects 20-40 million people worldwide and pegylated interferon (PegIFN) is the only recommended therapy. There is limited data on the contribution of HDV infection to HBV-related liver disease or liver cancer. Evidence from retrospective and cohort studies suggests that HBV/HDV coinfection accelerates progression to cirrhosis and is associated with an increased risk of hepatocellular carcinoma (HCC) development compared to HBV monoinfection. Although the life cycle of HDV is relatively well known, there is only ancillary information on the molecular mechanisms that can drive specific HDV-related oncogenesis. No thorough reports on the specific landscape of mutations or molecular classes of HDV-related HCC have been published. This information could be critical to better understand the uniqueness, if any, of HDV-related HCC and help identify novel targetable mutations. Herein, we review the evidence supporting an oncogenic role of HDV, the main reported mechanisms of HDV involvement and their impact on HCC development.
Collapse
Affiliation(s)
- Marc Puigvehí
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Hepatology Section, Gastroenterology Department, Hospital del Mar, IMIM, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - Carlos Moctezuma-Velázquez
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA.,Denotes co-senior authorship
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain.,Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.,Denotes co-senior authorship
| |
Collapse
|
|
18
|
Foster EM, Dangla-Valls A, Lovestone S, Ribe EM, Buckley NJ. Clusterin in Alzheimer's Disease: Mechanisms, Genetics, and Lessons From Other Pathologies. Front Neurosci 2019; 13:164. [PMID: 30872998 PMCID: PMC6403191 DOI: 10.3389/fnins.2019.00164] [Citation(s) in RCA: 245] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 02/12/2019] [Indexed: 01/10/2023] Open
Abstract
Clusterin (CLU) or APOJ is a multifunctional glycoprotein that has been implicated in several physiological and pathological states, including Alzheimer's disease (AD). With a prominent extracellular chaperone function, additional roles have been discussed for clusterin, including lipid transport and immune modulation, and it is involved in pathways common to several diseases such as cell death and survival, oxidative stress, and proteotoxic stress. Although clusterin is normally a secreted protein, it has also been found intracellularly under certain stress conditions. Multiple hypotheses have been proposed regarding the origin of intracellular clusterin, including specific biogenic processes leading to alternative transcripts and protein isoforms, but these lines of research are incomplete and contradictory. Current consensus is that intracellular clusterin is most likely to have exited the secretory pathway at some point or to have re-entered the cell after secretion. Clusterin's relationship with amyloid beta (Aβ) has been of great interest to the AD field, including clusterin's apparent role in altering Aβ aggregation and/or clearance. Additionally, clusterin has been more recently identified as a mediator of Aβ toxicity, as evidenced by the neuroprotective effect of CLU knockdown and knockout in rodent and human iPSC-derived neurons. CLU is also the third most significant genetic risk factor for late onset AD and several variants have been identified in CLU. Although the exact contribution of these variants to altered AD risk is unclear, some have been linked to altered CLU expression at both mRNA and protein levels, altered cognitive and memory function, and altered brain structure. The apparent complexity of clusterin's biogenesis, the lack of clarity over the origin of the intracellular clusterin species, and the number of pathophysiological functions attributed to clusterin have all contributed to the challenge of understanding the role of clusterin in AD pathophysiology. Here, we highlight clusterin's relevance to AD by discussing the evidence linking clusterin to AD, as well as drawing parallels on how the role of clusterin in other diseases and pathways may help us understand its biological function(s) in association with AD.
Collapse
Affiliation(s)
| | | | | | | | - Noel J. Buckley
- Department of Psychiatry, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
19
|
Goodrum G, Pelchat M. Insight into the Contribution and Disruption of Host Processes during HDV Replication. Viruses 2018; 11:v11010021. [PMID: 30602655 PMCID: PMC6356607 DOI: 10.3390/v11010021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 12/18/2018] [Accepted: 12/30/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatitis delta virus (HDV) is unique among animal viruses. HDV is a satellite virus of the hepatitis B virus (HBV), however it shares no sequence similarity with its helper virus and replicates independently in infected cells. HDV is the smallest human pathogenic RNA virus and shares numerous characteristics with viroids. Like viroids, HDV has a circular RNA genome which adopts a rod-like secondary structure, possesses ribozyme domains, replicates in the nucleus of infected cells by redirecting host DNA-dependent RNA polymerases (RNAP), and relies heavily on host proteins for its replication due to its small size and limited protein coding capacity. These similarities suggest an evolutionary relationship between HDV and viroids, and information on HDV could allow a better understanding of viroids and might globally help understanding the pathogenesis and molecular biology of these subviral RNAs. In this review, we discuss the host involvement in HDV replication and its implication for HDV pathogenesis.
Collapse
Affiliation(s)
- Gabrielle Goodrum
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
| | - Martin Pelchat
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
| |
Collapse
|
|
20
|
Sureau C, Negro F. The hepatitis delta virus: Replication and pathogenesis. J Hepatol 2016; 64:S102-S116. [PMID: 27084031 DOI: 10.1016/j.jhep.2016.02.013] [Citation(s) in RCA: 196] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 02/01/2016] [Accepted: 02/10/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis delta virus (HDV) is a defective virus and a satellite of the hepatitis B virus (HBV). Its RNA genome is unique among animal viruses, but it shares common features with some plant viroids, including a replication mechanism that uses a host RNA polymerase. In infected cells, HDV genome replication and formation of a nucleocapsid-like ribonucleoprotein (RNP) are independent of HBV. But the RNP cannot exit, and therefore propagate, in the absence of HBV, as the latter supplies the propagation mechanism, from coating the HDV RNP with the HBV envelope proteins for cell egress to delivery of the HDV virions to the human hepatocyte target. HDV is therefore an obligate satellite of HBV; it infects humans either concomitantly with HBV or after HBV infection. HDV affects an estimated 15 to 20 million individuals worldwide, and the clinical significance of HDV infection is more severe forms of viral hepatitis--acute or chronic--, and a higher risk of developing cirrhosis and hepatocellular carcinoma in comparison to HBV monoinfection. This review covers molecular aspects of HDV replication cycle, including its interaction with the helper HBV and the pathogenesis of infection in humans.
Collapse
Affiliation(s)
- Camille Sureau
- Molecular Virology laboratory, Institut National de la Transfusion Sanguine (INTS), CNRS INSERM U1134, Paris, France.
| | - Francesco Negro
- Division of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland; Division of Clinical Pathology, University Hospitals, Geneva, Switzerland.
| |
Collapse
|
|
21
|
Minarovits J, Demcsák A, Banati F, Niller HH. Epigenetic Dysregulation in Virus-Associated Neoplasms. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 879:71-90. [DOI: 10.1007/978-3-319-24738-0_4] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
|
|
22
|
Alfaiate D, Dény P, Durantel D. Hepatitis delta virus: From biological and medical aspects to current and investigational therapeutic options. Antiviral Res 2015; 122:112-29. [PMID: 26275800 DOI: 10.1016/j.antiviral.2015.08.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 08/10/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
|
|
23
|
Guo Z, King T. Therapeutic Strategies and New Intervention Points in Chronic Hepatitis Delta Virus Infection. Int J Mol Sci 2015; 16:19537-52. [PMID: 26295228 PMCID: PMC4581312 DOI: 10.3390/ijms160819537] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 08/05/2015] [Accepted: 08/07/2015] [Indexed: 12/18/2022] Open
Abstract
Chronic hepatitis delta virus infection (CHD) is a condition arising from super-infection of hepatitis B virus (HBV)-infected patients, resulting in a more rapid advance in liver pathology and hepatocellular carcinoma than is observed for HBV mono-infection. Although hepatitis delta virus (HDV) is structurally simple, its life cycle involves the complex participation of host enzymes, HBV-derived surface antigen (HBsAg), and HDV-auto-ribozyme and hepatitis delta antigen (HDAg) activities. Unsatisfactory clinical trial results with interferon-based therapies are motivating researchers to adjust and redirect the approach to CHD drug development. This new effort will likely require additional structural and functional studies of the viral and cellular/host components involved in the HDV replication cycle. This review highlights recent work aimed at new drug interventions for CHD, with interpretation of key pre-clinical- and clinical trial outcomes and a discussion of promising new technological approaches to antiviral drug design.
Collapse
Affiliation(s)
- Zhimin Guo
- Huron Peak Ave., Superior, CO 80027, USA.
| | - Thomas King
- Allevagen, LLC, 4105 Perry St., Denver, CO 80212, USA.
| |
Collapse
|
|
24
|
Abbas Z, Abbas M, Abbas S, Shazi L. Hepatitis D and hepatocellular carcinoma. World J Hepatol 2015; 7:777-786. [PMID: 25914778 PMCID: PMC4404383 DOI: 10.4254/wjh.v7.i5.777] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 12/21/2014] [Accepted: 01/15/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D virus (HDV) is a defective circular shape single stranded HDV RNA virus with two types of viral proteins, small and large hepatitis D antigens, surrounded by hepatitis B surface antigen. Superinfection with HDV in chronic hepatitis B is associated with a more threatening form of liver disease leading to rapid progression to cirrhosis. In spite of some controversy in the epidemiological studies, HDV infection does increase the risk of hepatocellular carcinoma (HCC) compared to hepatitis B virus (HBV) monoinfection. Hepatic decompensation, rather than development of HCC, is the first usual clinical endpoint during the course of HDV infection. Oxidative stress as a result of severe necroinflammation may progress to HCC. The large hepatitis D antigen is a regulator of various cellular functions and an activator of signal transducer and activator of transcription (STAT)3 and the nuclear factor kappa B pathway. Another proposed epigenetic mechanism by which HCC may form is the aberrant silencing of tumor suppressor genes by DNA Methyltransferases. HDV antigens have also been associated with increased histone H3 acetylation of the clusterin promoter. This enhances the expression of clusterin in infected cells, increasing cell survival potential. Any contribution of HBV DNA integration with chromosomes of infected hepatocytes is not clear at this stage. The targeted inhibition of STAT3 and cyclophilin, and augmentation of peroxisome proliferator-activated receptor γ have a potential therapeutic role in HCC.
Collapse
Affiliation(s)
- Zaigham Abbas
- Zaigham Abbas, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 74200, Pakistan
| | - Minaam Abbas
- Zaigham Abbas, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 74200, Pakistan
| | - Sarim Abbas
- Zaigham Abbas, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 74200, Pakistan
| | - Lubna Shazi
- Zaigham Abbas, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 74200, Pakistan
| |
Collapse
|
|
25
|
Aldabe R, Suárez-Amarán L, Usai C, González-Aseguinolaza G. Animal models of chronic hepatitis delta virus infection host-virus immunologic interactions. Pathogens 2015; 4:46-65. [PMID: 25686091 PMCID: PMC4384072 DOI: 10.3390/pathogens4010046] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 02/05/2015] [Indexed: 02/08/2023] Open
Abstract
Hepatitis delta virus (HDV) is a defective RNA virus that has an absolute requirement for a virus belonging to the hepadnaviridae family like hepatitis B virus (HBV) for its replication and formation of new virions. HDV infection is usually associated with a worsening of HBV-induced liver pathogenesis, which leads to more frequent cirrhosis, increased risk of hepatocellular carcinoma (HCC), and fulminant hepatitis. Importantly, no selective therapies are available for HDV infection. The mainstay of treatment for HDV infection is pegylated interferon alpha; however, response rates to this therapy are poor. A better knowledge of HDV–host cell interaction will help with the identification of novel therapeutic targets, which are urgently needed. Animal models like hepadnavirus-infected chimpanzees or the eastern woodchuck have been of great value for the characterization of HDV chronic infection. Recently, more practical animal models in which to perform a deeper study of host virus interactions and to evaluate new therapeutic strategies have been developed. Therefore, the main focus of this review is to discuss the current knowledge about HDV host interactions obtained from cell culture and animal models.
Collapse
Affiliation(s)
- Rafael Aldabe
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain.
| | - Lester Suárez-Amarán
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain
| | - Carla Usai
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain.
| | - Gloria González-Aseguinolaza
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain.
| |
Collapse
|
|
26
|
Abstract
HDV is a defective RNA pathogen requiring the simultaneous presence of HBV to complete its life cycle. Two major specific patterns of infection have been described: the coinfection with HDV and HBV of a susceptible, anti-HBs-negative individual, or the HDV superinfection of a chronic HBV carrier. Coinfection mostly leads to the eradication of both agents, whereas the majority of patients with HDV superinfection evolve to chronic HDV infection and hepatitis. Chronic HDV infection worsens the preexisting HBV-related liver damage. HDV-associated chronic liver disease (chronic hepatitis D) is characterized by necroinflammation and the relentless deposition of collagen culminating, within a few decades, into the development of cirrhosis and hepatocellular carcinoma.
Collapse
|
|
27
|
Wan M, Jin X, Xia J, Rosenberg JN, Yu G, Nie Z, Oyler GA, Betenbaugh MJ. The effect of iron on growth, lipid accumulation, and gene expression profile of the freshwater microalga Chlorella sorokiniana. Appl Microbiol Biotechnol 2014; 98:9473-81. [PMID: 25248441 DOI: 10.1007/s00253-014-6088-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 09/02/2014] [Accepted: 09/09/2014] [Indexed: 10/24/2022]
Abstract
The effects of iron on the growth, lipid accumulation, and gene expression profiles of the limnetic Chlorella sorokiniana CCTCC M209220 under photoautotrophy were investigated. The addition of iron up to 10(-5) mol l(-l) increased final cell densities by nearly 2-fold at 2.3 × 10(7) cells/ml, growth rate by 2-fold, and the length of the exponential phase by 5 days as compared to unsupplemented controls while 10(-3) mol l(-1) iron was toxic. The lipid content increased from 12 % for unsupplemented cultures to 33 % at 10(-4) mol l(-1) iron while the highest overall lipid yield reached 179 mg l(-1). A genefishing and qPCR comparison between the C. sorokiniana at low and high iron levels indicated increases in the expression of several genes, including carbonic anhydrase involved in microalgal cell growth, as well as acc1 and choline transporter related to lipid synthesis. This study provides insights into changes in gene expression and metabolism that accompany iron supplementation to Chlorella as well as potential metabolic engineering targets for improving growth and lipid synthesis in microalgae.
Collapse
Affiliation(s)
- Minxi Wan
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Park J, Park SY, Shin E, Lee SH, Kim YS, Lee DH, Roh GS, Kim HJ, Kang SS, Cho GJ, Jeong BY, Kim H, Choi WS. Hypoxia inducible factor-1α directly regulates nuclear clusterin transcription by interacting with hypoxia response elements in the clusterin promoter. Mol Cells 2014; 37:178-86. [PMID: 24599003 PMCID: PMC3935631 DOI: 10.14348/molcells.2014.2349] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 12/29/2013] [Accepted: 12/30/2013] [Indexed: 11/27/2022] Open
Abstract
Differential transcription of the clusterin (CLU) gene yields two CLU isoforms, a nuclear form (nCLU) and a secretory form (sCLU), which play crucial roles in prostate tumorigenesis. Pro-apoptotic nCLU and anti-apoptotic sCLU have opposite effects and are differentially expressed in normal and cancer cells; however, their regulatory mechanisms at the transcriptional level are not yet known. Here, we examined the transcriptional regulation of nCLU in response to hypoxia. We identified three putative hypoxia response elements (HREs) in the human CLU promoter between positions -806 and +51 bp. Using a luciferase reporter, electrophoretic gel mobility shift, and chromatin immunoprecipitation assays, we further showed that hypoxia-inducible factor-1α (HIF-1α) bound directly to these sites and activated transcription. Exposure to the hypoxiamimetic compound CoCl₂, incubation under 1% O₂ conditions, or overexpression of HIF-1α enhanced nCLU expression and induced apoptosis in human prostate cancer PC3M cells. However, LNCaP prostate cancer cells were resistant to hypoxia-induced cell death. Methylation-specific PCR analysis revealed that the CLU promoter in PC3M cells was not methylated; in contrast, the CLU promoter in LNCap cells was methylated. Co-treatment of LNCaP cells with CoCl₂ and a demethylating agent promoted apoptotic cell death through the induction of nCLU. We conclude that nCLU expression is regulated by direct binding of HIF-1α to HRE sites and is epigenetically controlled by methylation of its promoter region.
Collapse
Affiliation(s)
- Jeongsook Park
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
- Department of Food & Nutrition, College of Natural Sciences, Gyeong-sang National University, Jinju 660-290,
Korea
| | - So Yun Park
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Eunkyung Shin
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Sun Hee Lee
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Yoon Sook Kim
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Dong Hoon Lee
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Gu Seob Roh
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Hyun Joon Kim
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Sang Soo Kang
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Gyeong Jae Cho
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Bo-Young Jeong
- Department of Food & Nutrition, College of Natural Sciences, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Hwajin Kim
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| | - Wan Sung Choi
- Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeong-sang National University, Jinju 660-290,
Korea
| |
Collapse
|
|
29
|
Kaposi's sarcoma-associated herpesvirus-encoded LANA contributes to viral latent replication by activating phosphorylation of survivin. J Virol 2014; 88:4204-17. [PMID: 24478433 DOI: 10.1128/jvi.03855-13] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus casually linked to Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). Previously, we showed that LANA encoded by KSHV upregulates expression of survivin, a member of the inhibitor of apoptosis (IAP) family. This leads to an increase in the rate of cell proliferation of KSHV-infected B cells. LANA is required for tethering of the KSHV episome to the host chromosomes and efficiently segregates the viral genomes into dividing tumor cells. Here we show that LANA interacts with Aurora kinase B (AK-B) and induces phosphorylation of survivin at residue T34. Phosphorylation of survivin specifically on residue T34 enhances the activity of p300 and inhibits the activity of histone deacetylase 1 (HDAC-1), which then leads to an increase in acetylation of histone H3 on the viral genome. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases, which then leads to an increase in viral copy number in KSHV-infected B cells. This results in a boost of KSHV replication in latently infected B-lymphoma cells. The studies showed that LANA can also function to regulate viral replication prior to mitosis of the latently infected cells, suggesting that LANA possesses a novel role in regulating KSHV replication in infected B cells. IMPORTANCE This work represents a report of KSHV latent protein LANA and its interactions with AK-B leading to induction of phosphorylation of the oncoprotein survivin at residue T34. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases. This leads to an increase in viral copy number in KSHV-infected B cells. These studies support a role for LANA in regulating KSHV replication through posttranslation modification in KSHV-infected B cells.
Collapse
|
|
30
|
Abbas Z, Afzal R. Life cycle and pathogenesis of hepatitis D virus: A review. World J Hepatol 2013; 5:666-675. [PMID: 24409335 PMCID: PMC3879688 DOI: 10.4254/wjh.v5.i12.666] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 11/06/2013] [Accepted: 11/15/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D virus (HDV) is a defective RNA virus which requires the help of hepatitis B virus (HBV) virus for its replication and assembly of new virions. HDV genome contains only one actively transcribed open reading frame which encodes for two isoforms of hepatitis delta antigen. Post-translational modifications of small and large delta antigens (S-HDAg and L-HDAg) involving phosphorylation and isoprenylation respectively confer these antigens their specific properties. S-HDAg is required for the initiation of the viral genome replication, whereas L-HDAg serves as a principal inhibitor of replication and is essential for the assembly of new virion particles. Immune mediation has usually been implicated in HDV-associated liver damage. The pathogenesis of HDV mainly involves interferon-α signaling inhibition, HDV-specific T-lymphocyte activation and cytokine responses, and tumor necrosis factor-alpha and nuclear factor kappa B signaling. Due to limited protein coding capacity, HDV makes use of host cellular proteins to accomplish their life cycle processes, including transcription, replication, post-transcriptional and translational modifications. This intimate host-pathogen interaction significantly alters cell proteome and is associated with an augmented expression of pro-inflammatory, growth and anti-apoptotic factors which explains severe necroinflammation and increased cell survival and an early progression to hepatocellular carcinoma in HDV patients. The understanding of the process of viral replication, HBV-HDV interactions, and etio-pathogenesis of the severe course of HDV infection is helpful in identifying the potential therapeutic targets in the virus life cycle for the prophylaxis and treatment of HDV infection and complications.
Collapse
Affiliation(s)
- Zaigham Abbas
- Zaigham Abbas, Rafia Afzal, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 75500, Pakistan
| | - Rafia Afzal
- Zaigham Abbas, Rafia Afzal, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 75500, Pakistan
| |
Collapse
|
|
31
|
Trougakos IP. The molecular chaperone apolipoprotein J/clusterin as a sensor of oxidative stress: implications in therapeutic approaches - a mini-review. Gerontology 2013; 59:514-23. [PMID: 23689375 DOI: 10.1159/000351207] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Accepted: 04/03/2013] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Organisms are constantly exposed to physiological and environmental stresses and therefore require an efficient surveillance of genome and proteome quality in order to prevent disruption of homeostasis. Central to the intra- and extracellular proteome surveillance system are the molecular chaperones that contribute to both proteome maintenance and clearance. The conventional protein product of the apolipoprotein J/clusterin (CLU) gene is a heterodimeric secreted glycoprotein (also termed as sCLU) with a ubiquitous expression in human tissues. CLU exerts a small heat shock protein-like stress-induced chaperone activity and has been functionally implicated in numerous physiological processes as well as in ageing and most age-related diseases including tumorigenesis, neurodegeneration, and cardiovascular and metabolic syndromes. OBJECTIVE The CLU gene is differentially regulated by a wide variety of stimuli due to the combined presence of many distinct regulatory elements in its promoter that make it an extremely sensitive cellular biosensor of environmental and/or oxidative stress. Downstream to CLU gene induction, the CLU protein seems to actively intervene in pathological states of increased oxidative injury due to its chaperone-related property to inhibit protein aggregation and precipitation (a main feature of oxidant injury), as well as due to its reported distribution in both extra- and, most likely, intracellular compartments. CONCLUSION On the basis of these findings, CLU has emerged as a unique regulator of cellular proteostasis. Nevertheless, it seemingly exerts a dual function in pathology. For instance, in normal cells and during early phases of carcinogenesis, CLU may inhibit tumor progression as it contributes to suppression of proteotoxic stress. In advanced neoplasia, however, it may offer a significant survival advantage in the tumor by suppressing many therapeutic stressors and enhancing metastasis. This review will critically present a synopsis of recent novel findings that relate to the function of this amazing molecule and support the notion that CLU is a biosensor of oxidative injury; a common link between ageing and all pathologies where CLU has been implicated. Potential future perspectives, implications and opportunities for translational research and the development of new therapies will be discussed.
Collapse
Affiliation(s)
- Ioannis P Trougakos
- Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Athens, Greece
| |
Collapse
|
|
32
|
Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: implications of a novel interaction between nucleoprotein and host protein Clusterin. Cell Death Dis 2013; 4:e562. [PMID: 23538443 PMCID: PMC3615740 DOI: 10.1038/cddis.2013.89] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Apoptosis induction is an antiviral host response, however, influenza A virus (IAV) infection promotes host cell death. The nucleoprotein (NP) of IAV is known to contribute to viral pathogenesis, but its role in virus-induced host cell death was hitherto unknown. We observed that NP contributes to IAV infection induced cell death and heterologous expression of NP alone can induce apoptosis in human airway epithelial cells. The apoptotic effect of IAV NP was significant when compared with other known proapoptotic proteins of IAV. The cell death induced by IAV NP was executed through the intrinsic apoptosis pathway. We screened host cellular factors for those that may be targeted by NP for inducing apoptosis and identified human antiapoptotic protein Clusterin (CLU) as a novel interacting partner. The interaction between IAV NP and CLU was highly conserved and mediated through β-chain of the CLU protein. Also CLU was found to interact specifically with IAV NP and not with any other known apoptosis modulatory protein of IAV. CLU prevents induction of the intrinsic apoptosis pathway by binding to Bax and inhibiting its movement into the mitochondria. We found that the expression of IAV NP reduced the association between CLU and Bax in mammalian cells. Further, we observed that CLU overexpression attenuated NP-induced cell death and had a negative effect on IAV replication. Collectively, these findings indicate a new function for IAV NP in inducing host cell death and suggest a role for the host antiapoptotic protein CLU in this process.
Collapse
|
|
33
|
Abstract
Hepatitis delta virus (HDV) is a unique human virus, showing similarities with plant viroids. Although impressive knowledge on virus structure and replication has been achieved, several questions like HBV/HDV interaction and post translational modifications of HD antigens remain to be answered. Potential targets for therapeutic strategies are now emerging. To date, eight major genotypes of the HDV have been identified. The HDV-1 is the prevailing genotype in Europe, but migration phenomena may change this profile. Immune response is likely to play an important role in the pathogenesis of HDV-induced liver disease; few data are available on T cells response either during infection and therapy. HDV usually suppresses HBV replication; recent studies show as viral dominances may change over time. Delta infection leads to severe liver disease, with different patterns of progression to liver fibrosis and decompensation. Beside the association between HDV/HBV and HCC is demonstrated a risk specifically related to HDV remains controversial.
Collapse
|
|
34
|
Liao FT, Hsu LS, Ko JL, Lin CC, Sheu GT. Multiple genomic sequences of hepatitis delta virus are associated with cDNA promoter activity and RNA double rolling-circle replication. J Gen Virol 2012; 93:577-587. [DOI: 10.1099/vir.0.037507-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
To understand how DNA-dependent RNA polymerase II (pol II) recognizes hepatitis delta virus (HDV) RNA as a template, it is first necessary to identify the HDV sequence that acts as a promoter of pol II-initiated RNA synthesis. Therefore, we isolated the pol II-response element from HDV cDNA and examined the regulation by hepatitis delta antigens (HDAgs). Two HDV cDNA fragments containing bidirectional promoter activity were identified. One was located at nt 1582–1683 (transcription-promoter region 1, TR-P1) and the other at nt 1223–1363 (transcription-internal region 5, TR-I5). The promoter activities of these two regions were enhanced by HDAgs to differing degrees. Next, the role of these sequences in an HDV cDNA-free RNA replication system was characterized by site-directed mutagenesis. Our data showed that: (i) the AUG codon at the HDAg ORF of HDV RNA (nt 1599–1601) that mutates to UAG (amber stop codon) results in loss of dimeric but not monomeric HDV RNA synthesis. (ii) A 5 nt mutation of TR-P1 (P1-m5, nt 1670–1674) abolishes RNA replication completely. Two-nucleotide-mutated RNA (P1-m2, nt 1662–1663) is able to synthesize short RNAs but not monomeric HDV RNA. (iii) A mutation in 5 nt at the TR-I5 region (I5-m5, nt 1351–1355) also abolishes HDV replication. Mutants with 2 nt mutations (I5-m2, nt 1351–1352) or 3 nt mutations (I5-m3, nt 1353–1355) inhibit HDV dimeric but not monomeric RNA synthesis. Furthermore, large HDAg is expressed in cells transfected with I5-m3 and I5-m2 RNAs and that demonstrate the RNA-editing event in the monomeric HDV RNA. These results provide further understanding of the double rolling-circle mechanism in HDV RNA replication.
Collapse
Affiliation(s)
- Fu-Tien Liao
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Li-Sung Hsu
- Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Jiunn-Liang Ko
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Chun-Che Lin
- Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Gwo-Tarng Sheu
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
| |
Collapse
|
|
35
|
Lutz HH, Trautwein C. Reviving pegylated interferon as a therapeutic agent for hepatitis D: no more room for nucleos(t)ides? Hepatology 2011; 53:2131-3. [PMID: 21618261 DOI: 10.1002/hep.24311] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results in the most severe form of viral hepatitis. There is no currently approved treatment. We investigated the safety and efficacy of 48 weeks of treatment with peginterferon alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone,and adefovir dipivoxil alone. METHODS We conducted a randomized trial in which 31 patients with HDV infection received treatment with 180 lg of peginterferon alfa-2a weekly plus 10 mgof adefovir daily, 29 received 180 lg of peginterferon alfa-2a weekly plus placebo, and 30 received 10 mg of adefovir alone weekly for 48 weeks. Follow-up was conducted for an additional 24 weeks. Efficacy end points included clearance of HDV RNA,normalization of alanine aminotransferase levels, and a decline in levels of hepatitis B surface antigen (HBsAg). RESULTS The primary endpoint—normalization of alanine aminotransferase levels and clearance of HDV RNA at week 48--was achieved in two patients in the group receiving peginterferon alfa-2a plus adefovir and two patients in the group receiving peginterferon alfa-2a plus placebo but in none of the patients in the group receiving adefovir alone. At week 48, the test for HDV RNA was negative in 23% of patients in the first group, 24% of patients in the second, and none of those in the third (P¼ 0.006 for the comparison of the first and third groups; P¼ 0.004 for the comparison of the second and third). The efficacy of peginterferon alfa-2a was sustained for 24 weeks after treatment, with 28% of the patients receiving peginterferon alfa-2a plus adefovir or peginterferon alfa-2a alone having negative results on HDV-RNA tests; none of the patients receiving adefovir alone had negative results. A decline in HBsAg levels of more than 1 log10 IU per milliliter from baseline to week 48 was observed in 10 patients in the first group, 2 in the second, and none in the third (P<0.001 for the comparison of the first and third groups and P¼0.01 for the comparison of the first and second). CONCLUSIONS Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir, resulted in sustained HDV RNA clearance in about one quarter of patients with HDV infection.
Collapse
Affiliation(s)
- Holger H Lutz
- Department of Medicine III, University Hospital Aachen Aachen, Germany
| | | |
Collapse
|
|
36
|
Comunale MA, Wang M, Rodemich-Betesh L, Hafner J, Lamontagne A, Klein A, Marrero J, Di Bisceglie AM, Gish R, Block T, Mehta A. Novel changes in glycosylation of serum Apo-J in patients with hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev 2011; 20:1222-9. [PMID: 21467232 PMCID: PMC3111882 DOI: 10.1158/1055-9965.epi-10-1047] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the occurrence of HCC has more than doubled in the United States in the past decade. Early detection is considered key to reducing the mortality of HCC. METHODS Using two-dimensional gel electrophoresis and high-performance liquid chromatography we have analyzed the glycosylation of Apo-J from healthy controls, patients with liver cirrhosis, or those with HCC. RESULTS Apo-J in the serum from patients with HCC had decreased levels of (β-1,4) triantennary N-linked glycan compared with the healthy controls or patients with liver cirrhosis. We analyzed this change in an independent cohort of 76 patients with HCC, 32 with cirrhosis, and 43 infected with hepatitis C virus using the Datura stramonium lectin (DSL), which binds to (β-1,4) triantennary N-linked glycan. The level of DSL-reactive Apo-J allowed us to differentiate HCC from cirrhosis with an area under the receiver operating characteristic curve (AUROC) of 0.852. When Apo-J was combined with other serum biomarkers such as α-fetoprotein (AFP) and fucosylated kininogen by using a multivariate logistic regression model, the AUROC increased to 0.944, a value much greater than that observed with AFP alone (AUROC of 0.765). CONCLUSIONS The glycosylation of Apo-J is a useful marker when used alone or in combination with outer makers for the early detection of HCC. IMPACT The potential use of a combination of AFP, DSL-reactive Apo-J, and fucosylated kininogen as a biomarker of HCC would have great value in the management of patients with liver disease.
Collapse
Affiliation(s)
- Mary Ann Comunale
- Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virus Research, Drexel University College of Medicine, Doylestown, PA 18901
| | - Mengjun Wang
- Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virus Research, Drexel University College of Medicine, Doylestown, PA 18901
| | - Lucy Rodemich-Betesh
- Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virus Research, Drexel University College of Medicine, Doylestown, PA 18901
| | - Julie Hafner
- Institute for Hepatitis and Virus Research, Doylestown, PA 18901
| | - Anne Lamontagne
- Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virus Research, Drexel University College of Medicine, Doylestown, PA 18901
| | - Andrew Klein
- Institute for Hepatitis and Virus Research, Doylestown, PA 18901
| | - Jorge Marrero
- Division of Gastroenterology, University of Michigan, 3912 Taubman Center, Ann Arbor, MI 48109-0362
| | - Adrian M. Di Bisceglie
- Division of Gastroenterology and Hepatology, Saint Louis VA Medical Center, Saint Louis University School of Medicine, St Louis, MO 631110-0250
| | - Robert Gish
- California Pacific Medical Center, Liver Disease Management and Transplant Program 2340 Clay Street, 2nd Floor San Francisco, California 94115
| | - Timothy Block
- Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virus Research, Drexel University College of Medicine, Doylestown, PA 18901
| | - Anand Mehta
- Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virus Research, Drexel University College of Medicine, Doylestown, PA 18901
| |
Collapse
|
|
37
|
Abstract
Hepatitis D virus (HDV) infection involves a distinct subgroup of individuals simultaneously infected with the hepatitis B virus (HBV) and characterized by an often severe chronic liver disease. HDV is a defective RNA agent needing the presence of HBV for its life cycle. HDV is present worldwide, but the distribution pattern is not uniform. Different strains are classified into eight genotypes represented in specific regions and associated with peculiar disease outcome. Two major specific patterns of infection can occur, i.e. co-infection with HDV and HBV or HDV superinfection of a chronic HBV carrier. Co-infection often leads to eradication of both agents, whereas superinfection mostly evolves to HDV chronicity. HDV-associated chronic liver disease (chronic hepatitis D) is characterized by necro-inflammation and relentless deposition of fibrosis, which may, over decades, result in the development of cirrhosis. HDV has a single-stranded, circular RNA genome. The virion is composed of an envelope, provided by the helper HBV and surrounding the RNA genome and the HDV antigen (HDAg). Replication occurs in the hepatocyte nucleus using cellular polymerases and via a rolling circle process, during which the RNA genome is copied into a full-length, complementary RNA. HDV infection can be diagnosed by the presence of antibodies directed against HDAg (anti-HD) and HDV RNA in serum. Treatment involves the administration of pegylated interferon-α and is effective in only about 20% of patients. Liver transplantation is indicated in case of liver failure.
Collapse
Affiliation(s)
- Stéphanie Pascarella
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | | |
Collapse
|
|
38
|
Interaction of host cellular proteins with components of the hepatitis delta virus. Viruses 2010; 2:189-212. [PMID: 21994607 PMCID: PMC3185554 DOI: 10.3390/v2010189] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 01/13/2010] [Accepted: 01/14/2010] [Indexed: 12/18/2022] Open
Abstract
The hepatitis delta virus (HDV) is the smallest known RNA pathogen capable of propagation in the human host and causes substantial global morbidity and mortality. Due to its small size and limited protein coding capacity, HDV is exquisitely reliant upon host cellular proteins to facilitate its transcription and replication. Remarkably, HDV does not encode an RNA-dependent RNA polymerase which is traditionally required to catalyze RNA-templated RNA synthesis. Furthermore, HDV lacks enzymes responsible for post-transcriptional and -translational modification, processes which are integral to the HDV life cycle. This review summarizes the known HDV-interacting proteins and discusses their significance in HDV biology.
Collapse
|
|
39
|
|