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Gómez-Moreno A, Garaigorta U. Hepatitis B Virus and DNA Damage Response: Interactions and Consequences for the Infection. Viruses 2017; 9:v9100304. [PMID: 29048354 PMCID: PMC5691655 DOI: 10.3390/v9100304] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 10/13/2017] [Accepted: 10/18/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is a major etiologic agent of acute and chronic hepatitis, and end-stage liver disease. Establishment of HBV infection, progression to persistency and pathogenesis are determined by viral and cellular factors, some of which remain still undefined. Key steps of HBV life cycle e.g., transformation of genomic viral DNA into transcriptionally active episomal DNA (cccDNA) or transcription of viral mRNAs from cccDNA, take place in the nucleus of infected cells and strongly depend on enzymatic activities provided by cellular proteins. In this regard, DNA damage response (DDR) pathways and some DDR proteins are being recognized as important factors regulating the infection. On one hand, HBV highjacks specific DDR proteins to successfully complete some of the steps of its life cycle. On the other hand, HBV subverts DDR pathways to presumably create a cellular environment that favours its replication. Direct consequences of these interactions are: HBV DNA integration into host chromosomal DNA, and accumulation of mutations in host chromosomal DNA that could eventually trigger carcinogenic processes, which would explain in part the incidence of hepatocellular carcinoma in chronically infected patients. Unravelling the interactions that HBV establishes with DDR pathways might help identify new molecular targets for therapeutic intervention.
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Affiliation(s)
- Andoni Gómez-Moreno
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
| | - Urtzi Garaigorta
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Darwin 3, 28049 Madrid, Spain.
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain.
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Fu S, Li N, Zhou PC, Huang Y, Zhou RR, Fan XG. Detection of HBV DNA and antigens in HBsAg-positive patients with primary hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2017; 41:415-423. [PMID: 28286056 DOI: 10.1016/j.clinre.2017.01.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 12/16/2016] [Accepted: 01/23/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) markers include HBV deoxyribonucleic acid (DNA) and HBV antigens. The former involves HBV covalently closed circular DNA (cccDNA) as well as total HBV DNA, whereas the latter involves HBsAg, HBcAg, and HBx. METHODS Samples of tumor and adjacent non-tumor liver tissue were collected from 28 HBV-associated HCC patients. Intrahepatic total HBV DNA and cccDNA were measured using the real-time PCR Taqman assay. HBV antigens in hepatocytes were detected using immunohistochemical staining. Intrahepatic levels of total HBV DNA or cccDNA in HCC patients with different intrahepatic HBV antigen expression patterns were compared, and the correlation between serum HBV DNA and intrahepatic HBV DNA was analyzed. RESULTS No significant differences in intrahepatic cccDNA levels were observed between tumor and non-tumor liver tissue (median -3.00 vs. -2.30 log copies/cell, P=0.298). However, the tumor tissue had significantly higher levels of total HBV DNA (median -0.60 vs. -1.24 log copies/cell, P=0.045) but significantly lower proportion of intrahepatic HBV DNA in the form of cccDNA (median 0.25% vs. 4%, P=0.023) than the corresponding values in the non-tumor tissue. Also, HBV antigen levels were lower in the tumor tissue than in the non-tumor tissue. Analysis of the correlation between serum HBV DNA and intrahepatic HBV DNA indicated that the viral status in the tumor tissue was more complicated in HBV-HCC patients-the detected serum HBV DNA failed to accurately reflect intrahepatic viral load. CONCLUSION HBV DNA may play an important role in hepatocarcinogenesis, and cccDNA was not the predominant form of HBV DNA in the tumor tissue.
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Affiliation(s)
- Sha Fu
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan Province, Xiangya Hospital, Central South University, PO Box 410008, Changsha, China
| | - Ning Li
- Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha, China
| | - Peng-Cheng Zhou
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan Province, Xiangya Hospital, Central South University, PO Box 410008, Changsha, China
| | - Yan Huang
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan Province, Xiangya Hospital, Central South University, PO Box 410008, Changsha, China
| | - Rong-Rong Zhou
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan Province, Xiangya Hospital, Central South University, PO Box 410008, Changsha, China.
| | - Xue-Gong Fan
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan Province, Xiangya Hospital, Central South University, PO Box 410008, Changsha, China.
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3
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Safaie P, Poongkunran M, Kuang PP, Javaid A, Jacobs C, Pohlmann R, Nasser I, Lau DTY. Intrahepatic distribution of hepatitis B virus antigens in patients with and without hepatocellular carcinoma. World J Gastroenterol 2016; 22:3404-3411. [PMID: 27022222 PMCID: PMC4806198 DOI: 10.3748/wjg.v22.i12.3404] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 11/09/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the intrahepatic expression of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) in chronic hepatitis B patients with and without hepatocellular carcinoma.
METHODS: A total of 33 chronic hepatitis B patients (mean age of 40.3 ± 2.5 years), comprising of 14 HBeAg positive and 19 HBeAg negative patients; and 13 patients with hepatitis B virus related hepatocellular carcinoma (mean age of 49.6 ± 4.7 years), were included in our study. Immunohistochemical staining for HBcAg and HBsAg was done using standard streptavidin-biotin-immunoperoxidase technique on paraffin-embedded liver biopsies. The HBcAg and HBsAg staining distributions and patterns were described according to a modified classification system.
RESULTS: Compared to the HBeAg negative patients, the HBeAg positive patients were younger, had higher mean HBV DNA and alanine transaminases levels. All the HBeAg positive patients had intrahepatic HBcAg staining; predominantly with “diffuse” distribution (79%) and “mixed cytoplasmic/nuclear” pattern (79%). In comparison, only 5% of the HBeAg-negative patients had intrahepatic HBcAg staining. However, the intrahepatic HBsAg staining has wider distribution among the HBeAg negative patients, namely; majority of the HBeAg negative cases had “patchy” HBsAg distribution compared to “rare” distribution among the HBeAg positive cases. All but one patient with HCC were HBeAg negative with either undetectable HBV DNA or very low level of viremia. Intrahepatic HBcAg and HBsAg were seen in 13 (100%) and 10 (77%) of the HCC patients respectively. Interestingly, among the 9 HCC patients on anti-viral therapy with suppressed HBV DNA, HBcAg and HBsAg were detected in tumor tissues but not the adjacent liver in 4 (44%) and 1 (11%) patient respectively.
CONCLUSION: Isolated intrahepatic HBcAg and HBsAg can be present in tumors of patients with suppressed HBV DNA on antiviral therapy; that may predispose them to cancer development.
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Blackadar CB. Historical review of the causes of cancer. World J Clin Oncol 2016; 7:54-86. [PMID: 26862491 PMCID: PMC4734938 DOI: 10.5306/wjco.v7.i1.54] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 10/31/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
In the early 1900s, numerous seminal publications reported that high rates of cancer occurred in certain occupations. During this period, work with infectious agents produced only meager results which seemed irrelevant to humans. Then in the 1980s ground breaking evidence began to emerge that a variety of viruses also cause cancer in humans. There is now sufficient evidence of carcinogenicity in humans for human T-cell lymphotrophic virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, human papillomavirus, Epstein-Barr virus, and human herpes virus 8 according to the International Agency for Research on Cancer (IARC). Many other causes of cancer have also been identified by the IARC, which include: Sunlight, tobacco, pharmaceuticals, hormones, alcohol, parasites, fungi, bacteria, salted fish, wood dust, and herbs. The World Cancer Research Fund and the American Institute for Cancer Research have determined additional causes of cancer, which include beta carotene, red meat, processed meats, low fibre diets, not breast feeding, obesity, increased adult height and sedentary lifestyles. In brief, a historical review of the discoveries of the causes of human cancer is presented with extended discussions of the difficulties encountered in identifying viral causes of cancer.
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6
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Oncogenic potential of hepatitis B virus encoded proteins. Curr Opin Virol 2015; 14:109-15. [PMID: 26426688 DOI: 10.1016/j.coviro.2015.08.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 08/27/2015] [Accepted: 08/28/2015] [Indexed: 12/20/2022]
Abstract
Due to the limited treatment options hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death, and hepatitis B virus (HBV) infection is the major risk factor for development of HCC worldwide. HCC is typically preceded by chronic inflammation, but may also develop in the absence of liver disease on the basis of HBV infection and even when virus replication is controlled by antivirals. In this situation, HBV antigen expression persists and direct oncogenic effects of HBV are integration of the viral DNA into the host genome as well as direct effects of viral proteins. These factors have to be taken into account in order to personalize HCC surveillance in CHB and unravel novel therapeutic approaches.
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7
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Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology 2015; 479-480:672-86. [PMID: 25759099 PMCID: PMC4424072 DOI: 10.1016/j.virol.2015.02.031] [Citation(s) in RCA: 605] [Impact Index Per Article: 60.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Revised: 02/09/2015] [Accepted: 02/16/2015] [Indexed: 02/06/2023]
Abstract
Human hepatitis B virus (HBV) is the prototype of a family of small DNA viruses that productively infect hepatocytes, the major cell of the liver, and replicate by reverse transcription of a terminally redundant viral RNA, the pregenome. Upon infection, the circular, partially double-stranded virion DNA is converted in the nucleus to a covalently closed circular DNA (cccDNA) that assembles into a minichromosome, the template for viral mRNA synthesis. Infection of hepatocytes is non-cytopathic. Infection of the liver may be either transient (<6 months) or chronic and lifelong, depending on the ability of the host immune response to clear the infection. Chronic infections can cause immune-mediated liver damage progressing to cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of carcinogenesis are unclear. Antiviral therapies with nucleoside analog inhibitors of viral DNA synthesis delay sequelae, but cannot cure HBV infections due to the persistence of cccDNA in hepatocytes.
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8
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Mason WS. Hepadnaviruses and Hepatocellular Carcinoma. CANCER ASSOCIATED VIRUSES 2012:531-569. [DOI: 10.1007/978-1-4614-0016-5_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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9
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Su WJ, Ho MC, Ni YH, Wu JF, Jeng YM, Chen HL, Wu YM, Hu RH, Chang MH, Lee PH. Clinical course of de novo hepatitis B infection after pediatric liver transplantation. Liver Transpl 2010; 16:215-21. [PMID: 20104496 DOI: 10.1002/lt.21980] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The characteristics of hepatitis B virus (HBV) in vaccinated children who acquire de novo HBV infections after orthotopic liver transplantation (OLT) remain largely unknown. The aim of this study was to explore HBV mutants in pediatric OLT recipients with de novo HBV infections. In all, 50 recipients underwent OLT between December 1997 and October 2005, and they were regularly checked for HBV serum markers from November 2005 to April 2009. Before OLT, all were hepatitis B surface antigen (HBsAg)-negative and under the coverage of the universal infant HBV vaccination program. Those who became HBsAg-positive after OLT were diagnosed with de novo HBV infection. HBV viral loads and full-length genome sequencing were determined when the diagnosis of de novo HBV infection was established. Nine patients (9/50, 18%) acquired de novo HBV infections after OLT. None had graft loss or fulminant hepatitis. Five cleared HBsAg, and 4 of the 5 even recovered with antibody to hepatitis B surface antigen (anti-HBs) formation. The other 4 were persistently HBsAg-positive. Mutations in the major S gene (681 base pairs) were discovered in 8 (88.9%) of the de novo HBV-infected children. Six of them harbored mutations within the "a" determinant region (codons 124-147), whereas the other 2 had mutations outside this region. These 2 cleared HBsAg and recovered with anti-HBs formation. HBV DNA levels were not different between those who cleared HBsAg and those who did not. In conclusion, surface mutants are frequent among pediatric liver transplant recipients with de novo HBV infections, but their clinical relevance requires further study.
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Affiliation(s)
- Wei-Ju Su
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei 100, Taiwan
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10
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Crawford DR, Ostrowski S, Vakharia D, Ilic Z, Sell S. Separate origins of hepatitis B virus surface antigen-negative foci and hepatocellular carcinomas in transgenic HBsAg (alb/psx) mice. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 169:223-32. [PMID: 16816375 PMCID: PMC1698773 DOI: 10.2353/ajpath.2006.051284] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
We have examined the development and transgene expression in liver lesions of transgenic mice bearing the hepatitis B surface antigen (HBsAg) gene of hepatitis B virus under the control of the albumin promoter (alb/psx) to study liver regeneration and hepatocellular carcinoma (HCC) associated with hepatitis B virus infection. Storage of the HBsAg in the endoplasmic reticulum precedes loss of liver cells and regenerative hyperplastic nodules that do not express HBsAg. Histological analysis indicated that HBsAg-negative foci and nodules arose from liver progenitor cells in the portal zone and lacked mRNA expression. Genomic DNA from eight of nine HBsAg-negative laser capture-excised liver foci showed loss of part of the alb/psx gene, whereas no loss of the actin gene was observed. The alb/psx DNA was intact in adjacent HBsAg-positive tissue. Sequencing of polymerase chain reaction products suggested that alterations in the HBsAg transgene in HBsAg-negative foci occurred via large-scale deletions as opposed to single-site mutations. Southern blot analysis of HCC from 2-year-old transgenic HBsAg mice, however, revealed an intact alb/psx gene. Thus, HBsAg-negative progenitor cells with deletions in the transgene appear to be responsible for compensatory regeneration of the liver, whereas HCCs arise from clonal expansion of hepatocytes with intact alb/psx transgenes.
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Affiliation(s)
- Dana R Crawford
- Center for Immunology and Microbial Disease, The Albany Medical College, Albany, New York, USA
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11
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Chen HW, Liao CH, Ying C, Chang CJ, Lin CM. Ex vivo expansion of dendritic-cell-activated antigen-specific CD4+ T cells with anti-CD3/CD28, interleukin-7, and interleukin-15: Potential for adoptive T cell immunotherapy. Clin Immunol 2006; 119:21-31. [PMID: 16406844 DOI: 10.1016/j.clim.2005.11.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2004] [Revised: 10/31/2005] [Accepted: 11/03/2005] [Indexed: 11/17/2022]
Abstract
There is an increasing realization that the failure of adoptive therapy with cytotoxic T lymphocytes in the autologous setting, at least in part, results from the lack of help from antigen-specific CD4+ T cells. To incorporate these cells into this treatment strategy, it is not known whether currently used ex vivo culture conditions are adequate for expanding and charting these T cells with the desired qualities for optimal in vivo activity. In this study, we show that stimulation with agonistic antibodies to CD3 plus CD28 (anti-CD3/CD28), a commonly used method for CD4+ T cell expansion, is unable to expand dendritic-cell-activated hepatitis B virus (HBV)-specific CD4+ T cells to clinical relevant numbers. Whereas, in combination with interleukin(IL)-7 and IL-15, it leads to a 4000-fold expansion of HBV-specific CD4+ T cells in 2 weeks. This outcome is correlated with the anti-apoptosis effect of IL-7 and IL-15. Importantly, antigen specificity is preserved during expansion. Although a late addition of IL-2 to the anti-CD3/CD28-expanding cultures also results in robust expansion, this expansion condition renders HBV-specific CD4+ T cells more sensitive to cytokine withdrawal-, activation-, and transforming growth factor-beta-induced cell death compared to those expanded in IL-7 and IL-15. Moreover, NKG2D rather than 4-1BB, whose ligands are constitutively expressed on tumor cells, is significantly up-regulated on IL-7/IL-15-expanded HBV-specific CD4+ T cells, and its engagement promotes expansion and interferon-gamma production by these cells and thus may serve to provide co-stimulation to T cells once they reach tumor tissues. Collectively, these results may have important therapeutic implications for adoptive T cell therapy.
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MESH Headings
- Antibodies/pharmacology
- Antigens, CD/immunology
- Antigens, CD/metabolism
- Apoptosis/drug effects
- Apoptosis/immunology
- CD28 Antigens/immunology
- CD3 Complex/immunology
- CD4-Positive T-Lymphocytes/drug effects
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- Cell Culture Techniques/methods
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Coculture Techniques
- Dendritic Cells/immunology
- Hepatitis B Surface Antigens/genetics
- Hepatitis B Surface Antigens/immunology
- Humans
- Immunotherapy, Adoptive/methods
- Interferon-gamma/metabolism
- Interleukin-15/pharmacology
- Interleukin-2/pharmacology
- Interleukin-7/pharmacology
- Interleukins/pharmacology
- Lymphocyte Activation/immunology
- NK Cell Lectin-Like Receptor Subfamily K
- Receptors, Immunologic/immunology
- Receptors, Immunologic/metabolism
- Receptors, Interleukin-2/metabolism
- Receptors, Natural Killer Cell
- Receptors, Nerve Growth Factor/metabolism
- Receptors, Tumor Necrosis Factor/metabolism
- Transfection
- Transforming Growth Factor beta/pharmacology
- Tumor Necrosis Factor Receptor Superfamily, Member 9
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Affiliation(s)
- Hao-Wei Chen
- Department of Microbiology, Soochow University, Wai Shuang Hsi, Shih Lin, Taipei 11102, Taiwan, Republic of China
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12
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Chang CJ, Liao CH, Wang FH, Lin CM. Transforming growth factor-beta induces apoptosis in antigen-specific CD4+ T cells prepared for adoptive immunotherapy. Immunol Lett 2003; 86:37-43. [PMID: 12600743 DOI: 10.1016/s0165-2478(02)00307-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Transforming growth factor-beta (TGF-beta), found at the site of most tumors, has been recognized as one of the mechanisms involved in tumor immunological escape. To evaluate its impact on adoptive immunotherapy against cancer, we examined the susceptibility of tumor-specific T cells to TGF-beta in the setting of these T cells being prepared for adoptive transfer. Hepatitis B virus (HBV)-specific CD4(+) T cells were ex vivo generated by activating with HBV-transfected dendritic cells and selecting with antibodies to CD25 activation molecules, and then expanded with antibodies to CD3/CD28. These T cells expressed higher levels of the type II TGF-beta receptor than nai;ve T cells and exhibited enhanced apoptosis when exposed to TGF-beta. The underlying apoptotic pathway was linked to the dissipation of the mitochondrial inner membrane potential and activation of caspase-9. The absence of caspase-8 activity in TGF-beta-treated T cells suggests that the death receptor system may not be involved in this type of apoptosis. Interleukin-2 (IL-2), which is concomitantly administered with tumor-specific T cells in adoptive immunotherapy, was unable to protect HBV-specific CD4(+) T cells from the pro-apoptotic effect of TGF-beta when added simultaneously with TGF-beta. Interesting, IL-2-pretreated T cells displayed the type II TGF-beta receptor at lower levels and were more resistant to TGF-beta. Together, our findings indicate that the effectiveness of adoptive cancer immunotherapy may be impaired by tumor-derived TGF-beta and appropriate manipulation of exogenous IL-2 might overcome this hurdle.
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Affiliation(s)
- Chun-Jung Chang
- Department of Microbiology, Soochow University Taipei, Wai Shuang Hsi, Shih Lin, Taipei 11102, Taiwan, ROC
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13
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Farza H, Dragani TA, Metzler T, Manenti G, Tiollais P, Della Porta G, Pourcel C. Inhibition of hepatitis B virus surface antigen gene expression in carcinogen-induced liver tumors from transgenic mice. Mol Carcinog 1994; 9:185-92. [PMID: 8148051 DOI: 10.1002/mc.2940090402] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
We previously showed that hepatitis B surface antigen (HBsAg)-producing transgenic mice were more sensitive to hepatocarcinogens than their normal littermates were. We have now investigated the regulation of hepatitis B virus (HBV) gene expression in carcinogen-induced liver tumors of HBV-carrier transgenic mice and in three cell lines derived from tumor samples. Transcription of the S gene was repressed in 17 tumors even though they had normal levels of liver-specific mRNAs such as albumin and transferrin. Three hepatoma cell lines, derived from independent tumor samples, were analyzed for their capacity to express the S gene after transfection of cloned DNA. Although they no longer expressed the endogenous S gene, they were still able to express it from transfected viral DNA both transiently and stably. The loss of HBsAg expression in tumors and in the cell lines was accompanied by de novo methylation of the S region, which is a way to permanently repress gene expression. Our data confirm in an animal model previous observations of S-gene expression in human hepatocarcinoma and suggest a role for its downregulation in tumor progression.
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Affiliation(s)
- H Farza
- Unité de Recombinaison et Expression Génétique (INSERM U163), Institut Pasteur, Paris, France
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14
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Norman JE, Beebe GW, Hoofnagle JH, Seeff LB. Mortality follow-up of the 1942 epidemic of hepatitis B in the U.S. Army. Hepatology 1993; 18:790-7. [PMID: 8406352 DOI: 10.1002/hep.1840180407] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The hypothesis that adult infection with the hepatitis B virus in the United States leads to a carrier state with a high risk of primary liver cancer was tested in two ways: (a) a cohort mortality study of U.S. Army veterans given yellow fever vaccine contaminated with hepatitis B virus in 1942 and controls and (b) a case-control study comparing veterans with hepatocellular carcinoma in Veterans Affairs hospitals with matched controls with respect to receipt of contaminated vaccine in 1942. Three groups totaling 69,988 men were the subjects of the cohort study: group 1 comprised men hospitalized with hepatitis in 1942, group 2 comprised men subclinically infected in 1942 and group 3 comprised controls who entered service after the contaminated vaccine was discontinued. Hepatocellular carcinoma cases (n = 24) and control subjects (n = 63) derived from Veterans Affairs hospital discharge files were the subjects of the case-control study. Group comparisons of death rates from liver cancer were refined by expert review of records to select hepatocellular carcinoma from among all causes of death so diagnosed in the cohort study. Slightly excess mortality was found for hepatocellular carcinoma in group 2 (subclinical hepatitis B) but not for group 1 (overt hepatitis B) compared with group 3 (controls) (p = 0.08). Mortality from nonalcoholic chronic liver disease was less in group 2 than in group 3. In the case-control study, the relative risk for hepatocellular carcinoma conferred by receipt of contaminated vaccine was estimated as 3.3 (p = 0.06). We conclude from the cohort study that immunocompetent adult males rarely become carriers after hepatitis B virus infection, probably far less often than the frequently assumed rate of 5% to 10%. The small excess liver cancer mortality seen in the cohort study and the results of the case-control study are consistent, nevertheless, with the now well-established etiological role of hepatitis B virus infection in liver cancer.
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Affiliation(s)
- J E Norman
- Medical Follow-Up Agency, National Academy of Sciences, Washington, D.C. 20418
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15
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Abstract
For many years, epidemiological studies have demonstrated a strong link between chronic hepatitis B virus (HBV) infection and the development of primary hepatocellular carcinoma (PHC). Other hepatocarcinogens such as hepatitis C virus and aflatoxin also contribute to hepatocarcinogenesis either in conjunction with HBV infection or alone. Cellular and molecular biological studies are providing explanations for the HBV-PHC relationship, and models are now being formulated to further test the relative importance of various factors such as viral DNA integration, activation of oncogenes, genetic instability, loss of tumor suppressor genes, and trans-activating properties of HBV to the pathogenesis of PHC. Further research will probably define more than a single mechanism whereby chronic HBV infection results in PHC.
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Affiliation(s)
- M Feitelson
- Department of Pathology and Cell Biology, Jefferson Medical School, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
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16
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Nakatsuji Y, Kiyosawa K, Tanaka E, Sodeyama T, Horigome N, Kajikawa S, Naito S, Akahane Y. Expression of hepatitis B surface antigen subtypes in liver of patients with hepatocellular carcinoma; comparison of subtypes in serum and liver. LIVER 1991; 11:176-84. [PMID: 1653386 DOI: 10.1111/j.1600-0676.1991.tb00512.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
To clarify the discrepancy in hepatitis B surface antigen (HBsAg) subtypes present in the serum and liver, as well as among hepatocytes, liver specimens which were resected from 37 HBsAg-positive patients with hepatocellular carcinoma (HCC) were examined. We evaluated HBsAg and the subtypic determinants of HBsAg and hepatitis B core antigen (HBcAg) using the peroxidase-antiperoxidase (PAP) staining method. Hepatitis B antigens were more frequently detected in small tumors (HBsAg in 67%. HBcAg in 40%) than in large ones (HBsAg in 36%, HBcAg in 14%). The prevalence of each subtypic determinant in the HBsAg positive non-tumorous vs. tumorous areas was 100% vs. 67% in a, 100% vs. 57% in d, 100% vs. not tested in y, 100% vs. 53% in r and 25% vs. 0% in w (a, d, y, r and w represent subtypic determinants). There was virtually no difference in a set of subtypic determinants between the serum and liver. However, there were some variations in a set of subtypic determinants among the hepatocytes. On the other hand, liver tissue of compound subtype adyr in serum contained both cells with a,d,r and with a,y,r as well as a few cells with a,d,y,r. These findings suggest that HBV genomes in hepatocytes of type B chronic liver disease may differ genetically among cells even in the same liver tissue.
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Affiliation(s)
- Y Nakatsuji
- Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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Abstract
We studied the frequency of hepatitis B virus replication in Chinese patients with hepatocellular carcinoma. Hepatitis B e antigen and hepatitis B virus DNA could be detected in the sera of 28% and 47% of 116 HBsAg-positive patients, but not in the sera of 15 HBsAg-negative patients. Replicative forms of hepatitis B virus DNA were detected in the neoplastic and nonneoplastic liver tissues from 34% and 62% of 29 HBsAg-positive patients and 0% and 20% of five HBsAg-negative patients by Southern blot hybridization analysis. Of the 10 patients with chronic hepatitis B virus infection in whom hepatocellular carcinoma developed during follow-up, hepatitis B e antigen and hepatitis B virus DNA were detected in the sera of seven and eight patients, respectively, at presentation, 13 to 43 mo before the diagnosis of hepatocellular carcinoma. In nine patients, hepatitis B virus DNA was persistently or intermittently detected in the serum during follow-up. Five patients remained hepatitis B e antigen-positive and seven were detectable for hepatitis B virus DNA in serum when hepatocellular carcinoma was diagnosed. Four patients had one or more episodes of exacerbations before the diagnosis of hepatocellular carcinoma; in three, the exacerbations were associated with changes in level of hepatitis B virus replication. Our study demonstrated that despite the long interval between the onset of hepatitis B virus infection and the development of hepatocellular carcinoma, hepatitis B virus replication persisted in most patients with hepatocellular carcinoma, albeit at a low level.
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Affiliation(s)
- A S Lok
- Department of Medicine, University of Hong Kong, Queen Mary Hospital
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