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Ullah Khan N, Sadiq A, Khan J, Basharat N, Hassan ZU, Ali I, Shah TA, Bourhia M, Bin Jardan YA, Wondmie GF. Molecular characterization of plasma virome of hepatocellular carcinoma (HCC) patients. AMB Express 2024; 14:46. [PMID: 38664337 PMCID: PMC11045709 DOI: 10.1186/s13568-024-01696-2] [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: 01/23/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) stands as the most common cancer type, arising from various causes, and responsible for a substantial number of cancer-related fatalities. Recent advancements in viral metagenomics have empowered scientists to delve into the intricate diversity of the virosphere, viral evolution, interactions between viruses and their hosts, and the identification of viral causes behind disease outbreaks, the development of specific symptoms, and their potential role in altering the host's physiology. The present study had the objective of "Molecular Characterization of HBV, HCV, anelloviruses, CMV, SENV-D, SENV-H, HEV, and HPV viruses among individuals suffering from HCC." A total of 381 HCC patients contributed 10 cc of blood each for this study. The research encompassed the assessment of tumor markers, followed by molecular characterization of HBV, HCV, Anelloviruses (TTV, TTMV, and TTMDV), SENV-H and SENV-D viruses, HEV, CMV, and HPV, as well as histopathological examinations. The outcomes of this study revealed that majority of the HCC patients 72.4% (276/381) were male as compared to females. HCV infection, at 76.4% (291 out of 381), exhibited a significant association (p < 0.05) with HCC. Most patients displayed singular lesions in the liver, with Child Pugh Score Type B being the predominant finding in 45.2% of cases. Plasma virome analysis indicated the prevalence of TTMDV (75%), followed by TTMV (70%) and TTV (42.1%) among anelloviruses in HCC patients. Similarly, SENV-H (52%) was followed by SENV-D (20%), with co-infections at 15%. The presence of CMV and HEV among the HCC patients was recorded 5% each however 3.5% of the patients showed the presence of HPV. In conclusion, this study underscores that HCC patients serve as reservoirs for various pathogenic and non-pathogenic viruses, potentially contributing to the development, progression, and severity of the disease.
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Affiliation(s)
- Niamat Ullah Khan
- Molecular Virology Laboratory, Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | - Asma Sadiq
- Department of Microbiology, University of Jhang, Punjab, Pakistan
| | - Jadoon Khan
- Molecular Virology Laboratory, Department of Biosciences, COMSATS University, Islamabad, Pakistan.
- Department of Allied Health Sciences, Iqra University, Chak Shahzad Campus, Islamabad, Pakistan.
| | - Nosheen Basharat
- Department of Microbiology, University of Jhang, Punjab, Pakistan
| | - Zulfiqar Ul Hassan
- Department of Allied Health Sciences, Iqra University, Chak Shahzad Campus, Islamabad, Pakistan
| | - Ijaz Ali
- Molecular Virology Laboratory, Department of Biosciences, COMSATS University, Islamabad, Pakistan
- Center for Applied Mathematics and Bioinformatics (CAMB), Gulf University for Science and Technology, West Mishref, Kuwait
| | - Tawaf Ali Shah
- College of Agriculture Engineering and Food Science, Shandong University of Technology, Zibo, 255000, China
| | - Mohammed Bourhia
- Laboratory of Biotechnology and Natural Resources Valorization, Faculty of Sciences, Ibn Zohr University, Agadir, 80060, Morocco.
| | - Yousef A Bin Jardan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 11451, Riyadh, Saudi Arabia
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Catalano T, Selvaggi F, Esposito DL, Cotellese R, Aceto GM. Infectious Agents Induce Wnt/β-Catenin Pathway Deregulation in Primary Liver Cancers. Microorganisms 2023; 11:1632. [PMID: 37512809 PMCID: PMC10386003 DOI: 10.3390/microorganisms11071632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/18/2023] [Accepted: 06/20/2023] [Indexed: 07/30/2023] Open
Abstract
Interaction between infectious agents and liver tissue, as well as repeated and extreme biological events beyond adaptive capacities, may result in pathological conditions predisposing people to development of primary liver cancers (PLCs). In adults, PLCs mainly comprise hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Various infectious agents in the hepatic microenvironment can destabilize normal liver cell functions by modulating the Wnt/β-catenin pathway components. Among them, hepatotropic viruses B, C, and D are involved in Wnt/β-catenin signaling dysregulation. Other microbial agents, including oncogenic viruses such as Epstein-Barr virus (EBV) and human papilloma virus (HPV), bacteria, e.g., Mycoplasma hyorhinis and Salmonella Typhi, the protozoan parasite Toxoplasma gondii, the fungus Aspergillus flavus, and liver flukes such as Clonorchissinensis or Opisthorchis viverrini, may induce malignant transformation in hepatocytes or in target cells of the biliary tract through aberrant Wnt signaling activation. This review focuses on new insights into infectious agents implicated in the deregulation of Wnt signaling and PLC development. Since the Wnt/β-catenin pathway is a driver of cancer following viral and bacterial infections, molecules inhibiting the complex axis of Wnt signaling could represent novel therapeutic approaches in PLC treatment.
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Affiliation(s)
- Teresa Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy
| | - Federico Selvaggi
- Unit of General Surgery, ASL2 Lanciano-Vasto-Chieti, Ospedale Clinicizzato SS Annunziata, 66100 Chieti, Italy
| | - Diana Liberata Esposito
- Center for Advanced Studies and Technology (CAST), 66100 Chieti, Italy
- Department of Innovative Technologies in Medicine & Dentistry, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
| | - Roberto Cotellese
- Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
- Villa Serena Foundation for Research, 65013 Città Sant'Angelo, Italy
| | - Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
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Du Y, Yu X, Chang ET, Lian S, Wu B, Li F, Chu B, Wei K, Zhan J, Liang X, Ye W, Ji M. Pre-diagnostic anti-EBV antibodies and primary liver cancer risk: a population-based nested case-control study in southern China. BMC Cancer 2023; 23:250. [PMID: 36922768 PMCID: PMC10015780 DOI: 10.1186/s12885-023-10709-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 03/06/2023] [Indexed: 03/17/2023] Open
Abstract
BACKGROUND We aimed to investigate associations between pre-diagnostic anti-Epstein-Barr virus (EBV) antibodies, including interactions with hepatitis B virus (HBV), and risk of primary liver cancer in southern China. METHODS In a population-based nested case-control study, we measured pre-diagnostic immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA) in 125 primary liver cancer cases and 2077 matched controls. We also explored the interaction between HBV surface antigen (HBsAg) and anti-EBV antibodies. RESULTS Participants with positive EBNA1-IgA, positive VCA-IgA or single-positive anti-EBV antibodies had two-fold odds of developing liver cancer, compared with seronegative subjects. The odds ratios (ORs) between the relative optical density of EBNA1-IgA and VCA-IgA and primary cancer, controlling for age and HBsAg, were 1.59 (95% confidence interval (CI): 1.17, 2.14) and 1.60 (95% CI: 1.07, 2.41), respectively. Subjects with both HBsAg and anti-EBV antibody seropositivity were at 50-fold increased risk compared with those negative for both biomarkers (OR: 50.67, 95% CI: 18.28, 140.46), yielding a relative excess risk due to interaction of 30.81 (95% CI: 3.42, 114.93). CONCLUSION Pre-diagnostic seropositivity for EBNA1-IgA and/or VCA-IgA was positively associated with primary liver cancer risk, especially in combination with HBsAg positivity. EBV may interact with HBV in the development of primary liver cancer, and anti-EBV antibodies might be potential biomarkers for primary liver cancer in this high-risk population.
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Affiliation(s)
- Yun Du
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Xia Yu
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Ellen T Chang
- Department of Epidemiology and Biostatistics, University of California, California, USA
| | - Shifeng Lian
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Biaohua Wu
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Fugui Li
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Bing Chu
- Department of Pathology, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Kuangrong Wei
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Jiyun Zhan
- Xiaolan Public Health Service Center, Zhongshan, 528400, People's Republic of China
| | - Xuejun Liang
- Xiaolan Public Health Service Center, Zhongshan, 528400, People's Republic of China
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden.
| | - Mingfang Ji
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China.
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Marônek M, Link R, Monteleone G, Gardlík R, Stolfi C. Viruses in Cancers of the Digestive System: Active Contributors or Idle Bystanders? Int J Mol Sci 2020; 21:ijms21218133. [PMID: 33143318 PMCID: PMC7663754 DOI: 10.3390/ijms21218133] [Citation(s) in RCA: 8] [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: 09/30/2020] [Revised: 10/22/2020] [Accepted: 10/29/2020] [Indexed: 12/13/2022] Open
Abstract
The human virome, which is a collection of all the viruses that are present in the human body, is increasingly being recognized as an essential part of the human microbiota. The human gastrointestinal tract and related organs (e.g., liver, pancreas, and gallbladder)-composing the gastrointestinal (or digestive) system-contain a huge number of viral particles which contribute to maintaining tissue homeostasis and keeping our body healthy. However, perturbations of the virome steady-state may, both directly and indirectly, ignite/sustain oncogenic mechanisms contributing to the initiation of a dysplastic process and/or cancer progression. In this review, we summarize and discuss the available evidence on the association and role of viruses in the development of cancers of the digestive system.
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Affiliation(s)
- Martin Marônek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia; (M.M.); (R.G.)
| | - René Link
- Institute of Experimental Medicine, Faculty of Medicine, University of Pavol Jozef Šafárik, 040 11 Košice, Slovakia;
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
| | - Roman Gardlík
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia; (M.M.); (R.G.)
| | - Carmine Stolfi
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
- Division of Clinical Biochemistry and Clinical Molecular Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Correspondence: ; Tel.: +39-06-72596163
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Shimozuma Y, Ito T, Inokuchi M, Uchikoshi M, Miyashita M, Nozawa H, Shimazaki T, Hiroishi K, Imawari M. Reactivation of epstein-barr virus in B cells of patients with chronic hepatitis C. J Med Virol 2010; 82:2064-72. [DOI: 10.1002/jmv.21890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Kutok JL, Wang F. Spectrum of Epstein-Barr virus-associated diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2007; 1:375-404. [PMID: 18039120 DOI: 10.1146/annurev.pathol.1.110304.100209] [Citation(s) in RCA: 357] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The association between Epstein-Barr virus (EBV) and a large number of benign and malignant diseases is unique among DNA viruses. Within infected tissues, proteins that are expressed during the normal lytic and latent viral life cycle lead to cellular alterations that contribute to these EBV-associated diseases. Although the early events of EBV infection are poorly understood, increasing knowledge of the viral processes that govern viral latency has shed light upon the potential mechanisms by which EBV infection can lead to cellular transformation. Our current understanding of the role of EBV in the development of Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and other EBV-associated diseases is discussed.
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Affiliation(s)
- J L Kutok
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
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Delecluse HJ, Feederle R, O'Sullivan B, Taniere P. Epstein Barr virus-associated tumours: an update for the attention of the working pathologist. J Clin Pathol 2007; 60:1358-64. [PMID: 17873116 PMCID: PMC2095566 DOI: 10.1136/jcp.2006.044586] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Epstein-Barr virus (EBV) is a herpesvirus associated with approximately 1% of tumours worldwide. EBV is the epitome of B lymphotropic viruses, but the spectrum of tumours it is associated with extends to T lymphocyte and NK cell malignancies, various types of carcinomas and smooth muscle tumours. Ubiquitous EBV infection in humans implies that most individuals carry EBV-infected cells. Therefore, mere detection of the virus in individuals with a tumour is not sufficient for establishing a causal relationship between both events, but instead requires unequivocal detection of viral nucleic acids or viral proteins in the tumour cells. Recent controversies about EBV infection in several carcinomas mainly resulted from such technical issues. The gold standard remains in situ EBER detection, but detection of EBNA1 would be an interesting alternative. EBV detection can be helpful for diagnostic, prognostic and therapeutic purposes. The rate of EBV association with entities such as NK/T cell tumours of the nasal type is so high that absence of detection of the virus in such a lesion should cast doubt of the accuracy of the diagnosis. Similarly, diagnosis of EBV-associated follicular pseudo-tumour obviously requires detection of the virus. EBV-positive common gastric adenocarcinomas seem to have a better prognosis than their EBV-negative counterparts and identification of the virus in B cell lymphoproliferations in immunocompromised individuals will guide therapeutic options. In conclusion, EBV-associated tumours are common enough to be relevant for the pathologist in everyday practice, but there is a need to facilitate detection of the virus (eg EBNA1 antibody).
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Affiliation(s)
- H-J Delecluse
- German Research Cancer Centre, Department of Virus Associated Tumours, Heidelberg, Germany.
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Abstract
Epstein Barr virus (EBV) infection causes asymptomatic liver-associated enzyme abnormalities in 80 to 90% of cases which are often unrecognized. Patients with acute EBV infections may also develop cholestatic hepatitis with associated jaundice and hepatitis with moderate elevations in the transaminase levels. Other gastrointestinal complications associated with EBV may include splenic rupture, liver failure due to acute and/or chronic EBV infection, and perhaps, autoimmune hepatitis and hepatocellular carcinoma. This article presents a case series of EBV infections with clinically significant hepatitis and reviews the literature on the gastrointestinal complications of EBV.
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Affiliation(s)
- Nancy F Crum
- Department of Internal Medicine, Infectious Diseases Division, Naval Medical Center San Diego, San Diego, CA 92134-1005, USA.
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Dash S, Haque S, Joshi V, Prabhu R, Hazari S, Fermin C, Garry R. HCV-hepatocellular carcinoma: new findings and hope for effective treatment. Microsc Res Tech 2006; 68:130-48. [PMID: 16276514 DOI: 10.1002/jemt.20227] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We present here a comprehensive review of the current literature plus our own findings about in vivo and in vitro analysis of hepatitis C virus (HCV) infection, viral pathogenesis, mechanisms of interferon action, interferon resistance, and development of new therapeutics. Chronic HCV infection is a major risk factor for the development of human hepatocellular carcinoma. Standard therapy for chronic HCV infection is the combination of interferon alpha and ribavirin. A significant number of chronic HCV patients who cannot get rid of the virus infection by interferon therapy experience long-term inflammation of the liver and scarring of liver tissue. Patients who develop cirrhosis usually have increased risk of developing liver cancer. The molecular details of why some patients do not respond to standard interferon therapy are not known. Availability of HCV cell culture model has increased our understanding on the antiviral action of interferon alpha and mechanisms of interferon resistance. Interferons alpha, beta, and gamma each inhibit replication of HCV, and the antiviral action of interferon is targeted to the highly conserved 5'UTR used by the virus to translate protein by internal ribosome entry site mechanism. Studies from different laboratories including ours suggest that HCV replication in selected clones of cells can escape interferon action. Both viral and host factors appear to be involved in the mechanisms of interferon resistance against HCV. Since interferon therapy is not effective in all chronic hepatitis C patients, alternative therapeutic strategies are needed to treat chronic hepatitis C patients not responding to interferon therapy. We also reviewed the recent development of new alternative therapeutic strategies for chronic hepatitis C, which may be available in clinical use within the next decade. There is hope that these new agents along with interferon will prevent the occurrence of hepatocellular carcinoma due to chronic persistent hepatitis C virus infection. This review is not inclusive of all important scientific publications due to space limitation.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.
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Pujol FH, Devesa M. Genotypic variability of hepatitis viruses associated with chronic infection and the development of hepatocellular carcinoma. J Clin Gastroenterol 2005; 39:611-8. [PMID: 16000930 DOI: 10.1097/01.mcg.0000170770.49394.92] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
At least five hepatitis viruses are known to date. Infection by enterically transmitted viruses (HAV and HEV) is generally benign compared with the disease caused by parenterally transmitted viruses (HBV, HCV, and HDV). Chronic infection by HBV is common and may evolve to cirrhosis and hepatocellular carcinoma (HCC). Eight HBV genotypes (A-H) have been described, with the South American genotype F being the most divergent. Seven clades of HDV have been described; among them, the South American genotype III is associated to a high frequency of fulminant hepatitis. HCV infection leads to a high rate of chronicity and HCC. From the six HCV genotypes, infection with genotype 1 might have the worst prognostic. Chronic infection by HCV and HBV is the major risk factor for HCC, which occurs, in the majority of the cases, as a consequence of cirrhosis. However, there is growing evidence that some HBV and HCV proteins might contribute to the generation of HCC. Some HBV and HCV variants and specific mutations within the viral genomes might be more frequently associated with the evolution to HCC. Although more studies are needed, emerging evidence indicates that it might be important to address the genetic variability of these viruses and their contribution to the development of HCC.
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Affiliation(s)
- Flor H Pujol
- Laboratoria de Virología Molecular, Caracas, Venezuela.
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Si MW, Thorson JA, Lauwers GY, DalCin P, Furman J. Hepatocellular lymphoepithelioma-like carcinoma associated with epstein barr virus: a hitherto unrecognized entity. ACTA ACUST UNITED AC 2005; 13:183-9. [PMID: 15322431 DOI: 10.1097/01.pas.0000124336.90615.8d] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Lymphoepithelioma-like carcinoma (LELC) is an undifferentiated carcinoma with a dense lymphoid stroma. It has been reported in diverse organs and shows variable association with Epstein-Barr virus (EBV). Only a few EBV positive cases have been observed in the hepatobiliary system, all of which were considered to be cholangiocarcinomas. We report a unique case of hepatocellular LELC arising in a cirrhotic liver with EBV demonstrated in the tumor cells. METHODS AND RESULTS A 39-year-old Hispanic female underwent an orthotopic liver transplant for end stage liver disease secondary to chronic hepatitis C. A high-grade hepatocellular carcinoma with a dense lymphocytic infiltrate was found in the explant as well as in a portal lymph node. Three months posttransplant, the patient developed numerous hepatic nodules with enlarged periaortic and portacaval lymph nodes. Biopsy of the hepatic nodules showed a recurrent hepatocellular carcinoma devoid of a dense lymphocytic infiltrate. Both the primary and recurrent tumors were positive for EBV by molecular studies. The patient eventually expired from liver failure over a 6-week period. CONCLUSION This case represents the first report of EBV-positive hepatocellular LELC. It is particularly interesting given the precipitous clinical outcome, which was possibly related to immunosuppresive therapy.
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MESH Headings
- Adult
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/virology
- Chromosomes, Human, Pair 11/genetics
- Epstein-Barr Virus Infections/complications
- Epstein-Barr Virus Infections/pathology
- Female
- Gene Dosage
- Herpesvirus 4, Human/isolation & purification
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Liver Cirrhosis/virology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Liver Transplantation
- Lymphatic Metastasis/pathology
- Polymerase Chain Reaction
- Tumor Virus Infections/complications
- Tumor Virus Infections/pathology
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Affiliation(s)
- Michael W Si
- Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA
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Li W, Wu BA, Zeng YM, Chen GC, Li XX, Chen JT, Guo YW, Li MH, Zeng Y. Epstein-Barr virus in hepatocellular carcinogenesis. World J Gastroenterol 2004; 10:3409-13. [PMID: 15526357 PMCID: PMC4576219 DOI: 10.3748/wjg.v10.i23.3409] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: In recent years, studies have suggested that Epstein-Barr virus (EBV) is associated with HCC. The present study was to determine the prevalence of EBV in HCC patients, and whether EBV acted synergistically with hepatitis viruses in HCC carcinogenesis.
METHODS: Liver tissue 115 HCC patients and 26 non-carcinoma patients were studied. Polymerase chain reaction (PCR) was performed to detect EBV BamHI W DNA, EBV LMP1 DNA, HBV X DNA, and HBV S DNA. Reverse transcription PCR (RT-PCR) was performed to detect HCV RNA and HDV RNA. Immunohistochemistry was performed to detect LMP1, HBsAg, HBcAg and HCV. The positive ratios were compared between HCC group and control group by χ2 test.
RESULTS: Totally, 78 HCC samples whose β -globulin DNA was positively detected by amplified PCR were selected. PCR was performed in all cases for EBV DNA and HBV DNA. RT-PCR was performed in 18 cases for HCV RNA and HDV RNA. EBV BamHI W and EBV LMP1 were positive in 18 and 6 cases, respectively. HBV X gene and HBV S gene were positive in 42 and 27 cases respectively. HCV was positive in one of the 18 cases, and none was positive for HDV. The positive rates were 28.2% (22 of 78) for EBV DNA (BamHI W and/or LMP1) and 56.4% (44 of 78) for HBV DNA (X gene and/or S gene) respectively. In addition, 12 cases were positive for both EBV DNA and HBV DNA. Among the 26 cases in the control group, 2 cases were positive for EBV BamHI W, 4 positive for HBV X gene and 3 positive for HBV S gene. The positive rates were 8.0% (2 of 26) and 23.1% (6 of 26), respectively, for EBV DNA and HBV DNA. The result of DNA sequencing of BamHI W was 100% homologous with the corresponding sequence of B95-8. There was significant difference in EBV infection rate between HCC patients and controls (χ2 = 4.622, P < 0.05). The difference in HBV infection rate was also significant (χ2 = 8.681, P < 0.05). However, there was no obvious correlation between HBV and EBV in HCC patients (χ2 = 0.835, P > 0.05). LMP1, HBV (HBsAg, HBcAg) and HCV were detected positively in 25, 45 and 6 of 78 cases of HCC tissues respectively. In the 26 control cases, the corresponding positive cases were 2, 4 and 0. The difference in EBV infection rate between HCC patients and control cases was statistically significant (χ2 = 6.02, P < 0.05). The difference in HBV infection rate was also statistically significant (χ2 = 10.03, P < 0.05). In the 25 cases with positive LMP1 expression, 6 were in the nuclei of tumor cells, 9 in the cytoplasm of tumor cells and 10 in mesenchymal lymphocyte cytoplasm.
CONCLUSION: The existence of EBV infection in HCC tissues suggests that EBV may be involved in the hepatocellular carcinogenesis in China. HBV infection may be a major cause of HCC. There is no correlation between EBV and HBV in the development of HCC. The prevalence of HCV infection is low in our area, and HDV appears not to play a direct role in hepatocellular carcinogenesis.
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Affiliation(s)
- Wei Li
- Department of General Surgery, the First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China.
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Glaser SL, Hsu JL, Gulley ML. Epstein-Barr Virus and Breast Cancer: State of the Evidence for Viral Carcinogenesis. Cancer Epidemiol Biomarkers Prev 2004. [DOI: 10.1158/1055-9965.688.13.5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Abstract
As the etiology and progression of breast cancer remain incompletely understood, novel routes of disease pathogenesis are important to consider. Viral pathogens have not been much explored, but recent interest has focused on Epstein-Barr virus (EBV). Studies of an association of this ubiquitous herpesvirus with breast cancer have had notably inconsistent results, marked by varying EBV presence (from 0% to 50% of tumors) and the absence of certain viral characteristics found in other EBV-related malignancies. The research has been plagued by the technical challenges of localizing EBV to tumor cells and by a tendency to overlook epidemiological cofactors, shown in all other EBV-related cancers to impact the EBV association. Breast cancer studies to date have used several viral detection methods of varying or uncertain sensitivity and specificity; most have involved small and/or poorly characterized case series and paid insufficient attention to epidemiological cofactors relevant to breast cancer and to EBV-related malignancies. Given these limitations and the established complexity of the connection of EBV with other cancers, a definitive judgment regarding the presence of this virus in breast cancer cannot yet be rendered. Recent advances in laboratory methodologies should help overcome the challenges of EBV detection in breast cancers. Further research is warranted, given the potential for an EBV association to inform not only breast cancer etiology but also early detection, treatment, and prevention.
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Affiliation(s)
| | - Joe L. Hsu
- 2Stanford University Medical Center, Stanford, California
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Chu PG, Cerilli L, Chen YY, Mills SE, Weiss LM. Epstein-Barr virus plays no role in the tumorigenesis of small-cell carcinoma of the lung. Mod Pathol 2004; 17:158-64. [PMID: 14752524 DOI: 10.1038/modpathol.3800024] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Epstein-Barr virus infection has been associated with lymphoepithelioma-like carcinoma of the lung in Asian patients. Recently, Epstein-Barr virus proteins or genomic DNAs were detected in pulmonary squamous-cell carcinoma, adenocarcinoma, and undifferentiated small-cell carcinoma in American patients. We studied 23 cases of small-cell carcinoma of the lung for evidence of Epstein-Barr virus infection by in situ hybridization, immunohistochemistry, and polymerase chain reaction methods. Of the 23 cases, 13 cases were primary small-cell carcinoma of the lung and 10 cases were metastatic small-cell carcinoma of the lung to the brain (one case), liver (two cases), and lymph nodes (seven cases). None of the 23 cases was positive for Epstein-Barr virus-encoded small nonpolyadenylated RNA (EBER)-1 by in situ hybridization. By immunohistochemistry, eight cases showed focal positivity for Epstein-Barr virus nuclear antigen-1. The positive immunostaining was focal and was observed in tumor cells, vascular endothelial cells, and lymphocytes, suggesting nonspecific staining. None of the 23 cases was positive for the transactivating immediate-early BZLF1 (ZEBRA) and latent membrane protein (LMP-1). Only one case was positive for the BamHI W region and LMP-1 gene by polymerase chain reaction assay. Some tumor cells in the BamHI W region positive case were also positive for Epstein-Barr virus nuclear antigen-1. Our study indicates that rare cases of American small-cell carcinoma of the lung may contain Epstein-Barr virus-infected cells, but it is unlikely that Epstein-Barr virus plays a role in the tumorigenesis of small-cell carcinoma of the lung.
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Affiliation(s)
- Peiguo G Chu
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
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15
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Kaplan DE, Reddy KR. Rising incidence of hepatocellular carcinoma: the role of hepatitis B and C; the impact on transplantation and outcomes. Clin Liver Dis 2003; 7:683-714. [PMID: 14509534 DOI: 10.1016/s1089-3261(03)00060-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma caused by hepatitis B and hepatitis C are global scourges but are likely to peak in incidence in the next 2 decades and then decline. Universal vaccination has been effective in stemming the incidence of chronic hepatitis B and early-onset HCC in regions of high endemicity where implemented, but preventive measures in HCV are not yet available. After the attrition of older affected generations, the incidence of HCC will likely decline rapidly. While no vaccine is currently available for hepatitis C, cases are projected to peak and decline because of a marked reduction in transmission as a result of behavioral modification and safeguarding of blood supplies. Until these epidemiologic projections come to pass, management of hepatocellular carcinoma will continue to become a progressively more frequently encountered clinical challenge. Therapy for chronic hepatitis may ameliorate but will not eliminate the development of tumors. The demand for orthotopic liver transplantation will continue to climb, and palliative therapies for non-resectable cases will require studies aimed at optimization of benefit. LDLT may remain an option for high-risk patients affording tumor-free survival for some otherwise terminal patients.
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Affiliation(s)
- David E Kaplan
- Division of Gastroenterology and Hepatology, University of Pennsylvania School of Medicine, 3 Raydin, 3400 Spruce Street, Philadelphia, PA 19104, USA
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16
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Zur Hausen A, van Beek J, Bloemena E, Ten Kate FJ, Meijer CJLM, van den Brule AJC. No role for Epstein-Barr virus in Dutch hepatocellular carcinoma: a study at the DNA, RNA and protein levels. J Gen Virol 2003; 84:1863-1869. [PMID: 12810881 DOI: 10.1099/vir.0.19217-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) has been suggested to play a role in hepatocellular carcinoma (HCC). However, reports on detailed EBV transcript analyses in HCCs are limited. It was shown recently that expression of the transforming BARF1 (BamHI A rightward open reading frame 1) gene of EBV is restricted to latently EBV-infected epithelial malignancies, i.e. nasopharyngeal carcinoma and gastric carcinoma. The aim of this study was to test the presence of EBV in Dutch HCCs. A semiquantitative DNA PCR-enzyme immunoassay (PCR-EIA) for the BamHI W fragment of EBV was used to assess the presence of EBV in frozen and paraffin-embedded tissues of 16 HCCs. In addition, several RNA detection techniques, i.e. nucleic acid sequence-based amplification (NASBA), RT-PCR, RNA in situ hybridization (RISH) and immunohistochemistry (IHC), were applied. Five of 16 HCCs and two of four hepatitis C virus hepatitis samples were weakly positive for EBV DNA by PCR-EIA. Using sensitive RNA transcription techniques, no transcripts were found for BARF1, EBNA-1 and BARTs (BamHI A rightward transcripts) in any of the liver tissues tested. In addition, RISH for EBER1/2 and BARTs and IHC for EBNA-1, LMP-1 and ZEBRA, performed on the paraffin-embedded tissue of the PCR-EIA-positive cases and on adjacent non-neoplastic liver tissues, were negative. The absence of epithelial-specific BARF1 transcripts and other EBV transcripts and proteins in the EBV DNA PCR-positive cases argues strongly against a role for EBV in HCC.
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Affiliation(s)
- Axel Zur Hausen
- Department of Pathology, Section Molecular Pathology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Josine van Beek
- Department of Pathology, Section Molecular Pathology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Elisabeth Bloemena
- Department of Pathology, Section Molecular Pathology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Fiebo J Ten Kate
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - Chris J L M Meijer
- Department of Pathology, Section Molecular Pathology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Adriaan J C van den Brule
- Department of Pathology, Section Molecular Pathology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
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17
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Akhter S, Liu H, Prabhu R, DeLucca C, Bastian F, Garry RF, Schwartz M, Thung SN, Dash S. Epstein-Barr virus and human hepatocellular carcinoma. Cancer Lett 2003; 192:49-57. [PMID: 12637152 DOI: 10.1016/s0304-3835(02)00695-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recent studies suggest that Epstein-Barr virus (EBV) may act as a helper virus for the development of hepatocellular carcinoma by promoting replication of the hepatitis C virus (HCV) in the infected liver. Detection of EBV DNA in a high percentage of HCV-positive human hepatocellular carcinomas (HCC) from Japanese patients has supported this concept. In order to determine whether EBV infection is associated with HCC, we examined paraffin-embedded tissues from 31 cases of non-cirrhotic livers with hepatocellular carcinoma for the presence of EBV, HCV and hepatitis B virus (HBV) infection. RNA prepared from tumor samples were used as a template for reverse transcription followed by double-nested PCR with primers for the 5' untranslated region (NT) of HCV. DNA extracts of tumor samples were tested by single polymerase chain reaction for the detection of EBV and HBV (X- and/or S-gene) DNA sequences. To control for nucleic acid integrity, all tumor samples were amplified for human beta-globin DNA by polymerase chain reaction and subjected to Southern blot hybridization. None of the cases was found to be positive for EBV. Ten HCC cases (32%) tested positive for HCV and 12 HCC cases (38%) tested positive for HBV. Six of the surveyed patients had nucleic acids of both HCV and HBV in their tumor tissue. All HCC tumor samples were positive for beta-globin. Our study shows that HCV and HBV infections, but not EBV infection, are associated with hepatocarcinogenesis in non-cirrhotic livers. Other unknown risk factors seem to be in effect in the development of hepatocellular carcinoma in non-cirrhotic livers.
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Affiliation(s)
- Shamim Akhter
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
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18
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Junying J, Herrmann K, Davies G, Lissauer D, Bell A, Timms J, Reynolds GM, Hubscher SG, Young LS, Niedobitek G, Murray PG. Absence of Epstein-Barr virus DNA in the tumor cells of European hepatocellular carcinoma. Virology 2003; 306:236-43. [PMID: 12642097 DOI: 10.1016/s0042-6822(02)00027-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The Epstein-Barr virus (EBV) has recently been associated with hepatocellular carcinoma (HCC) arising in Japanese patients. We analyzed 82 cases of HCC from Germany and the U.K. for the presence of EBV DNA and viral gene products within tumor cells. Initial screening of whole sections using quantitative (Q)-PCR detected EBV DNA in 9/58 U.K. cases and in 9/24 German cases; in positive cases viral load was very low, ranging between 1.4 and 49.1 copies of the EBV genome/1000 cell equivalents, compared to much higher values for EBV-positive Hodgkin's disease and nasopharyngeal carcinoma controls (range, 714-3259/1000 cells). EBV DNA was not detected in the tumor cells of any of the Q-PCR-positive cases either by Q-PCR of pure tumor cell populations isolated by laser capture microdissection or by isotopic in situ hybridization. Furthermore, none of the German or U.K. HCC tumors tested positive for EBER or EBNAI expression in tumor cells. Our results provide strong evidence that HCCs from the U.K. or Germany are not associated with EBV.
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Affiliation(s)
- Jia Junying
- Department of Pathology, University of Birmingham, B15 2TT, Edgbaston, Birmingham, UK
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Abstract
The Epstein-Barr virus (EBV) is associated with several human tumours including lymphoid and epithelial malignancies. Most EBV-associated tumours are rare or occur at higher incidence only in certain geographical regions. The recently reported detection of EBV in gastric, breast, and hepatocellular carcinomas raises the possibility of involvement of the virus in the pathogenesis of common cancers. This article reviews the evidence linking EBV infection to epithelial tumours. It is concluded that at present, there is no convincing evidence to suggest that breast carcinoma and hepatocellular carcinoma are EBV-associated tumours.
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Affiliation(s)
- Kathrin Herrmann
- Pathologisches Institut, Friedrich-Alexander-Universität, Erlangen, Germany
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