|
1
|
Bréchot C, Charnay P, de Thé H, Dejean A, Michel ML, Pineau P, Sonigo P, Wain-Hobson S, Wei Y, Weissenbach J. Biographical Feature: In memoriam Pierre Tiollais (1934-2024). J Virol 2025; 99:e0212524. [PMID: 40209070 PMCID: PMC11852772 DOI: 10.1128/jvi.02125-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2025] Open
Affiliation(s)
- Christian Bréchot
- Global Virus Network, University of South Florida, Tampa, Florida, USA
| | - Patrick Charnay
- Ecole Normale Supérieure, PSL Research University, CNRS, INSERM, Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Paris, France
| | - Hugues de Thé
- Collège de France, Inserm, CNRS, PSL Research University, University Paris Cité, AP/HP: St-Louis Hospital, Paris, France
| | - Anne Dejean
- Inserm U933, Paris, France
- Institut Pasteur, Paris, France
| | | | - Pascal Pineau
- Inserm U933, Paris, France
- Institut Pasteur, Paris, France
| | | | | | - Yu Wei
- Institut Pasteur, Paris, France
| | - Jean Weissenbach
- Génomique Métabolique, Genoscope, Institut François Jacob, CEA, CNRS, University of Évry, Université Paris-Saclay, Evry, France
| |
Collapse
|
|
2
|
Guo X, Nie H, Zhang W, Li J, Ge J, Xie B, Hu W, Zhu Y, Zhong N, Zhang X, Zhao X, Wang X, Sun Q, Wei K, Chen X, Ni L, Zhang T, Lu S, Zhang L, Dong C. Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer. Cancer Cell 2025; 43:248-268.e9. [PMID: 39889705 DOI: 10.1016/j.ccell.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 09/04/2024] [Accepted: 01/06/2025] [Indexed: 02/03/2025]
Abstract
Combination of anti-PD-1 with lenvatinib showed clinical efficacy in multiple cancers, yet the underlying immunological mechanisms are unclear. Here, we compared T cells in hepatocellular carcinoma (HCC) patients before and after combination treatment using single-cell transcriptomics and T cell receptor (scTCR) clonotype analyses. We found that tumor-infiltrating GZMK+ CD8+ effector/effector memory T (Teff/Tem) cells, showing a favorable response to combination therapy, comprise progenitor exhausted T (Tpex) cells and also unappreciated circulating Tem (cTem) cells enriched with hepatitis B virus (HBV) specificity. Further integrated analyses revealed that cTem cells are specifically associated with responsiveness to the combination therapy, whereas Tpex cells contribute to responses in both combination therapy and anti-PD-1 monotherapy. Notably, an underexplored KIR+ CD8+ T cell subset in the tumor and FOXP3+ CD4+ regulatory T cells are specifically enriched in non-responders after the combination therapy. Our study thus elucidated T cell subsets associated with clinical benefits and resistance in cancer immunotherapy.
Collapse
Affiliation(s)
- Xinyi Guo
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Hu Nie
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518132, China; State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
| | - Wenwen Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital / Key Laboratory of Digital Hepatobiliary Surgery, PLA / Institute of Hepatobiliary Surgery of Chinese PLA, Beijing 100953, China
| | - Jiesheng Li
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518132, China; State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
| | - Jing Ge
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China
| | - Bowen Xie
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Wenbo Hu
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yicheng Zhu
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China
| | - Na Zhong
- Shenzhen Peacock Biotechnology Co., Ltd, Shenzhen, Guangdong 518112, China
| | - Xinmei Zhang
- Shenzhen Peacock Biotechnology Co., Ltd, Shenzhen, Guangdong 518112, China
| | - Xiaohong Zhao
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiaoshuang Wang
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Qinli Sun
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Kun Wei
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiaoyuan Chen
- Tsinghua Clinical Research Institute, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Ling Ni
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ting Zhang
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China
| | - Shichun Lu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital / Key Laboratory of Digital Hepatobiliary Surgery, PLA / Institute of Hepatobiliary Surgery of Chinese PLA, Beijing 100953, China.
| | - Lei Zhang
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518132, China; State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China; Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, Guangdong 518107, China.
| | - Chen Dong
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Research Unit of Immune Regulation and Immune Diseases (2022RU001), Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Westlake University School of Medicine, Hangzhou, Zhejiang 310030, China.
| |
Collapse
|
|
3
|
Zoulim F, Chen PJ, Dandri M, Kennedy PT, Seeger C. Hepatitis B virus DNA integration: Implications for diagnostics, therapy, and outcome. J Hepatol 2024; 81:1087-1099. [PMID: 38971531 DOI: 10.1016/j.jhep.2024.06.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/26/2024] [Accepted: 06/29/2024] [Indexed: 07/08/2024]
Abstract
Hepatitis B virus (HBV) DNA integration - originally recognised as a non-functional byproduct of the HBV life cycle - has now been accepted as a significant contributor to HBV pathogenesis and hepatitis D virus (HDV) persistence. Integrated HBV DNA is derived from linear genomic DNA present in viral particles or produced from aberrantly processed relaxed circular genomic DNA following an infection, and can drive expression of hepatitis B surface antigen (HBsAg) and HBx. DNA integration events accumulate over the course of viral infection, ranging from a few percent during early phases to nearly 100 percent of infected cells after prolonged chronic infections. HBV DNA integration events have primarily been investigated in the context of hepatocellular carcinoma development as they can activate known oncogenes and other growth promoting genes, cause chromosomal instability and, presumably, induce epigenetic alterations, promoting tumour growth. More recent evidence suggests that HBsAg expression from integrated DNA might contribute to HBV pathogenesis by attenuating the immune response. Integrated DNA provides a source for envelope proteins required for HDV replication and hence represents a means for HDV persistence. Because integrated DNA is responsible for persistence of HBsAg in the absence of viral replication it impacts established criteria for the resolution of HBV infection, which rely on HBsAg as a diagnostic marker. Integrated HBV DNA has been useful in assessing the turnover of infected hepatocytes which occurs during all phases of chronic hepatitis B including the initial phase of infection historically termed immune tolerant. HBV DNA integration has also been shown to impact the development of novel therapies targeting viral RNAs.
Collapse
Affiliation(s)
- Fabien Zoulim
- Université Claude Bernard Lyon 1, Hospices Civils de Lyon, INSERM, Lyon Hepatology Institute, Lyon, France.
| | - Pei-Jer Chen
- Hepatitis Research Center and Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Partner Site, Germany
| | - Patrick T Kennedy
- Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK
| | | |
Collapse
|
|
4
|
Li W, Wang S, Jin Y, Mu X, Guo Z, Qiao S, Jiang S, Liu Q, Cui X. The role of the hepatitis B virus genome and its integration in the hepatocellular carcinoma. Front Microbiol 2024; 15:1469016. [PMID: 39309526 PMCID: PMC11412822 DOI: 10.3389/fmicb.2024.1469016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 08/19/2024] [Indexed: 09/25/2024] Open
Abstract
The integration of Hepatitis B Virus (HBV) is now known to be closely associated with the occurrence of liver cancer and can impact the functionality of liver cells through multiple dimensions. However, despite the detailed understanding of the characteristics of HBV integration and the mechanisms involved, the subsequent effects on cellular function are still poorly understood in current research. This study first systematically discusses the relationship between HBV integration and the occurrence of liver cancer, and then analyzes the status of the viral genome produced by HBV replication, highlighting the close relationship and structure between double-stranded linear (DSL)-HBV DNA and the occurrence of viral integration. The integration of DSL-HBV DNA leads to a certain preference for HBV integration itself. Additionally, exploration of HBV integration hotspots reveals obvious hotspot areas of HBV integration on the human genome. Virus integration in these hotspot areas is often associated with the occurrence and development of liver cancer, and it has been determined that HBV integration can promote the occurrence of cancer by inducing genome instability and other aspects. Furthermore, a comprehensive study of viral integration explored the mechanisms of viral integration and the internal integration mode, discovering that HBV integration may form extrachromosomal DNA (ecDNA), which exists outside the chromosome and can integrate into the chromosome under certain conditions. The prospect of HBV integration as a biomarker was also probed, with the expectation that combining HBV integration research with CRISPR technology will vigorously promote the progress of HBV integration research in the future. In summary, exploring the characteristics and mechanisms in HBV integration holds significant importance for an in-depth comprehension of viral integration.
Collapse
Affiliation(s)
- Weiyang Li
- Jining Medical University, Jining, China
- School of Biological Science, Jining Medical University, Rizhao, China
| | - Suhao Wang
- School of Biological Science, Jining Medical University, Rizhao, China
| | - Yani Jin
- School of Biological Science, Jining Medical University, Rizhao, China
| | - Xiao Mu
- School of Biological Science, Jining Medical University, Rizhao, China
| | - Zhenzhen Guo
- Jining First People's Hospital, Shandong First Medical University, Jining, China
| | - Sen Qiao
- Jining First People's Hospital, Shandong First Medical University, Jining, China
| | - Shulong Jiang
- Jining First People's Hospital, Shandong First Medical University, Jining, China
| | - Qingbin Liu
- Jining First People's Hospital, Shandong First Medical University, Jining, China
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, China
| | - Xiaofang Cui
- Jining Medical University, Jining, China
- School of Biological Science, Jining Medical University, Rizhao, China
| |
Collapse
|
|
5
|
Zhang M, Chen H, Liu H, Tang H. The impact of integrated hepatitis B virus DNA on oncogenesis and antiviral therapy. Biomark Res 2024; 12:84. [PMID: 39148134 PMCID: PMC11328401 DOI: 10.1186/s40364-024-00611-y] [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: 05/22/2024] [Accepted: 06/29/2024] [Indexed: 08/17/2024] Open
Abstract
The global burden of hepatitis B virus (HBV) infection remains high, with chronic hepatitis B (CHB) patients facing a significantly increased risk of developing cirrhosis and hepatocellular carcinoma (HCC). The ultimate objective of antiviral therapy is to achieve a sterilizing cure for HBV. This necessitates the elimination of intrahepatic covalently closed circular DNA (cccDNA) and the complete eradication of integrated HBV DNA. This review aims to summarize the oncogenetic role of HBV integration and the significance of clearing HBV integration in sterilizing cure. It specifically focuses on the molecular mechanisms through which HBV integration leads to HCC, including modulation of the expression of proto-oncogenes and tumor suppressor genes, induction of chromosomal instability, and expression of truncated mutant HBV proteins. The review also highlights the impact of antiviral therapy in reducing HBV integration and preventing HBV-related HCC. Additionally, the review offers insights into future objectives for the treatment of CHB. Current strategies for HBV DNA integration inhibition and elimination include mainly antiviral therapies, RNA interference and gene editing technologies. Overall, HBV integration deserves further investigation and can potentially serve as a biomarker for CHB and HBV-related HCC.
Collapse
Affiliation(s)
- Mingming Zhang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Han Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Huan Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China.
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
|
6
|
Peng L, Dou Z, Yu S, Wu X, Zhang J, Li Z, Zhang L. Hepatitis B virus infection and the risk of gynecologic cancers: a systematic review and meta-analysis. Discov Oncol 2024; 15:340. [PMID: 39120631 PMCID: PMC11315852 DOI: 10.1007/s12672-024-01213-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 08/01/2024] [Indexed: 08/10/2024] Open
Abstract
OBJECTIVES The relationship between hepatitis B virus (HBV) infection and gynecologic cancers is controversial. We aimed to evaluate the risk of gynecologic cancers associated with HBV infection using a meta-analysis. METHODS Two independent reviewers identified publications in the PubMed, Embase and Cochrane Library databases that reported an association between HBV and the risk of gynecologic malignancy from inception to December 31, 2022. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included articles. Pooled odds ratios (ORs) and 95% corresponding confidence intervals (CIs) were calculated using a fixed effects model or random effects model. RESULTS We collected data from 7 studies that met the inclusion criteria, including 2 cohort studies and 5 case-control studies. HBV was significantly associated with the risk of cervical cancer in the general population (OR 1.22, 95% CI 1.09-1.38, P = 0.001), although the same trend was not found in endometrial cancer (OR 1.30, 95% CI 0.95-1.77, P = 0.105) and ovarian cancer (OR 1.03, 95% CI 0.79-1.35, P = 0.813). Subgroup analysis showed that HBV infection was positively associated with the risk of cervical cancer (OR 1.27, 95% CI 1.13-1.44, P = 0.000) in case-control studies. Asian women infected with HBV have a significantly increased risk of cervical cancer (OR 1.24, 95% CI 1.10-1.40, P = 0.001) and endometrial cancer (OR 1.46, 95% CI 1.07-1.99, P = 0.018). Hospital-based studies were found to be associated with an increased risk of cervical cancer (OR 1.30, 95% CI 1.14-1.47, P = 0.000) and endometrial cancer (OR 1.61, 95% CI 1.04-2.49, P = 0.032). The results of Begg's and Egger's tests showed no publication bias. CONCLUSIONS This meta-analysis shows a positive association between HBV infection and cervical cancer. HBV is positively correlated with the risk of cervical cancer and endometrial cancer in Asian women and hospital-based populations. More multicenter prospective studies are required to confirm the findings.
Collapse
Affiliation(s)
- Lan Peng
- Department of Radiation Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), 519 Kunzhou Road, Kunming, 650118, People's Republic of China
| | - Zhongyan Dou
- Department of Radiation Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), 519 Kunzhou Road, Kunming, 650118, People's Republic of China
| | - Shuhui Yu
- Department of Radiation Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), 519 Kunzhou Road, Kunming, 650118, People's Republic of China
| | - Xingrao Wu
- Department of Radiation Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), 519 Kunzhou Road, Kunming, 650118, People's Republic of China
| | - Jinping Zhang
- Department of Medical Administration, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), 519 Kunzhou Road, Kunming, 650118, China
| | - Zheng Li
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), 519 Kunzhou Road, Kunming, 650118, China
| | - Lan Zhang
- Department of Radiation Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), 519 Kunzhou Road, Kunming, 650118, People's Republic of China.
| |
Collapse
|
|
7
|
Negro F. EASL Recognition Award Recipient 2024: Prof. Christian Bréchot. J Hepatol 2024; 81:6-8. [PMID: 38906623 DOI: 10.1016/j.jhep.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 04/22/2024] [Indexed: 06/23/2024]
Affiliation(s)
- Francesco Negro
- Service of Gastroenterology and Hepatology, University Hospitals, 1211 Geneva 14, Switzerland.
| |
Collapse
|
|
8
|
Roggendorf H, Shouval D, Roggendorf M, Gerken G. Longterm Outcome of Therapeutic Vaccination with a Third Generation Pre-S/S HBV Vaccine (PreHevbrio R) of Chronically HBV Infected Patients. J Pers Med 2024; 14:364. [PMID: 38672991 PMCID: PMC11050803 DOI: 10.3390/jpm14040364] [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: 01/31/2024] [Revised: 03/13/2024] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection. Previous studies in non-responders to yeast-derived HBV vaccines, using a third-generation pre-S/S vaccine, have led to up to 95% anti-HBs seroconversion. This report evaluates the long-term outcome after experimental vaccination with a pre-S/S HBV vaccine intended as a therapeutic intervention in chronic HBV carriers. Four low-level HBsAg carriers (<500 IU/mL) were vaccinated three to seven times with 20 μg PreHevbrioR. Three out of four carriers eliminated HBsAg completely and seroconverted to anti-HBs. One patient seroconverted to anti-HBs but remained with a borderline HBsAg titer (10 IU/mL). Serum anti-HBs levels following repeated vaccination varied between 27 and >1000 IU/L, respectively. Long-term observation (>6 years) showed that after discontinuing NUC treatment for at least two years, HBsAg and HBV DNA remained negative with anti-HBs positive titers ranging between 80 and >1000 IU/L. Based on our preliminary observations, there is a rationale to further evaluate the role of this vaccine as a therapeutic agent.
Collapse
Affiliation(s)
- Hedwig Roggendorf
- Institute of Molecular Immunology, University Hospital TUM, 81675 Munich, Germany
| | - Daniel Shouval
- Liver Unit, Hadassah Medical Center, POB 12000, Jerusalem 91120, Israel;
| | - Michael Roggendorf
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum, 81675 Munich, Germany;
| | - Guido Gerken
- Department of Gastroenterology, Helios Klinikum Niedernberg, 42551 Velbert, Germany;
| |
Collapse
|
|
9
|
Varghese N, Majeed A, Nyalakonda S, Boortalary T, Halegoua-DeMarzio D, Hann HW. Review of Related Factors for Persistent Risk of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:777. [PMID: 38398168 PMCID: PMC10887172 DOI: 10.3390/cancers16040777] [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: 12/24/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs has not been fully elucidated. However, it has been discovered that HBV's covalently closed circular DNA (cccDNA) integrates into the critical HCC driver genes in hepatocytes upon initial infection; additionally, these are not targets of current NA therapies. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to behave more aggressively during treatment. Curative novel therapies which target the life cycle of HBV, modulate host immune response, and inhibit HBV RNA translation are being investigated.
Collapse
Affiliation(s)
- Nevin Varghese
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Amry Majeed
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Suraj Nyalakonda
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Tina Boortalary
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Hie-Won Hann
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| |
Collapse
|
|
10
|
Zhang Y, Bourgine M, Wan Y, Song J, Li Z, Yu Y, Jiang W, Zhou M, Guo C, Santucci D, Liang X, Brechot C, Zhang W, Charneau P, Wu H, Qiu C. Therapeutic vaccination with lentiviral vector in HBV-persistent mice and two inactive HBsAg carriers. J Hepatol 2024; 80:31-40. [PMID: 37827470 DOI: 10.1016/j.jhep.2023.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 08/09/2023] [Accepted: 09/06/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND & AIMS Immunotherapy for chronic hepatitis B virus (HBV) infection has not yet demonstrated sufficient efficacy. We developed a non-integrative lentiviral-vectored therapeutic vaccine for chronic hepatitis B and tested its antiviral effects in HBV-persistent mice and two inactive HBsAg carriers. METHODS Lentiviral vectors (LVs) encoding the core, preS1, or large HBsAg (LHBs) proteins of HBV were evaluated for immunogenicity in HBV-naïve mice and therapeutic efficacy in a murine model of chronic HBV infection. In addition, two inactive HBsAg carriers each received two doses of 5×107 transduction units (TU) or 1×108 TU of lentiviral-vectored LHBs (LV-LHBs), respectively. The endpoints were safety, LHBs-specific T-cell responses, and serum HBsAg levels during a 24-week follow-up. RESULTS In the mouse models, LV-LHBs was the most promising in eliciting robust antigen-specific T cells and in reducing the levels of serum HBsAg and viral load. By the end of the 34-week observation period, six out of ten (60%) HBV-persistent mice vaccinated with LV-LHBs achieved serum HBsAg loss and significant depletion of HBV-positive hepatocytes in the liver. In the two inactive HBsAg carriers, vaccination with LV-LHBs induced a considerable increase in the number of peripheral LHBs-specific T cells in one patient, and a weak but detectable response in the other, accompanied by a sustained reduction of HBsAg (-0.31 log10 IU/ml and -0.46 log10 IU/ml, respectively) from baseline to nadir. CONCLUSIONS A lentiviral-vectored therapeutic vaccine for chronic HBV infection demonstrated the potential to improve HBV-specific T-cell responses and deplete HBV-positive hepatocytes, leading to a sustained loss or reduction of serum HBsAg. IMPACT AND IMPLICATIONS Chronic HBV infection is characterized by an extremely low number and profound hypo-responsiveness of HBV-specific T cells. Therapeutic vaccines are designed to improve HBV-specific T-cell responses. We show that immunization with a lentiviral-vectored therapeutic HBV vaccine was able to expand HBV-specific T cells in vivo, leading to reductions of HBV-positive hepatocytes and serum HBsAg.
Collapse
Affiliation(s)
- Yumeng Zhang
- Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, 200052, China
| | - Maryline Bourgine
- Institut Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université Paris Cité, F-75015 Paris, France
| | - Yanmin Wan
- Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, 200052, China
| | - Jieyu Song
- Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China
| | | | - Yiqi Yu
- Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China
| | | | - Mingzhe Zhou
- Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China
| | - Cuiyuan Guo
- Department of Laboratory Medicine, Shanghai Public Health Clinical Center, Shanghai, China; Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Key Laboratory of Laboratory Medicine of Henan Province, Zhengzhou, China
| | | | | | - Christian Brechot
- TheraVectys S.A., Paris, France; University of South Florida, Tampa, USA.
| | - Wenhong Zhang
- Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, 200052, China.
| | - Pierre Charneau
- Institut Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université Paris Cité, F-75015 Paris, France.
| | - Hong Wu
- Changzhi People's Hospital, Changzhi, China.
| | - Chao Qiu
- Department of Infectious Disease, National Medical Center for Infectious Diseases and Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, 200052, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China..
| |
Collapse
|
|
11
|
Bartosh UI, Dome AS, Zhukova NV, Karitskaya PE, Stepanov GA. CRISPR/Cas9 as a New Antiviral Strategy for Treating Hepatitis Viral Infections. Int J Mol Sci 2023; 25:334. [PMID: 38203503 PMCID: PMC10779197 DOI: 10.3390/ijms25010334] [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: 11/15/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatitis is an inflammatory liver disease primarily caused by hepatitis A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV) viruses. The chronic forms of hepatitis resulting from HBV and HCV infections can progress to cirrhosis or hepatocellular carcinoma (HCC), while acute hepatitis can lead to acute liver failure, sometimes resulting in fatality. Viral hepatitis was responsible for over 1 million reported deaths annually. The treatment of hepatitis caused by viral infections currently involves the use of interferon-α (IFN-α), nucleoside inhibitors, and reverse transcriptase inhibitors (for HBV). However, these methods do not always lead to a complete cure for viral infections, and chronic forms of the disease pose significant treatment challenges. These facts underscore the urgent need to explore novel drug developments for the treatment of viral hepatitis. The discovery of the CRISPR/Cas9 system and the subsequent development of various modifications of this system have represented a groundbreaking advance in the quest for innovative strategies in the treatment of viral infections. This technology enables the targeted disruption of specific regions of the genome of infectious agents or the direct manipulation of cellular factors involved in viral replication by introducing a double-strand DNA break, which is targeted by guide RNA (spacer). This review provides a comprehensive summary of our current knowledge regarding the application of the CRISPR/Cas system in the regulation of viral infections caused by HAV, HBV, and HCV. It also highlights new strategies for drug development aimed at addressing both acute and chronic forms of viral hepatitis.
Collapse
Affiliation(s)
| | | | | | | | - Grigory A. Stepanov
- The Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk 630090, Russia; (U.I.B.); (A.S.D.); (N.V.Z.); (P.E.K.)
| |
Collapse
|
|
12
|
Michalak TI. The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular Oncogenesis. Int J Mol Sci 2023; 24:14849. [PMID: 37834296 PMCID: PMC10573506 DOI: 10.3390/ijms241914849] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/30/2023] [Accepted: 09/30/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatitis B virus (HBV) remains a dominant cause of hepatocellular carcinoma (HCC). Recently, it was shown that HBV and woodchuck hepatitis virus (WHV) integrate into the hepatocyte genome minutes after invasion. Retrotransposons and transposable sequences were frequent sites of the initial insertions, suggesting a mechanism for spontaneous HBV DNA dispersal throughout the hepatocyte genome. Several somatic genes were also identified as early insertional targets in infected hepatocytes and woodchuck livers. Head-to-tail joints (HTJs) dominated amongst fusions, indicating their creation by non-homologous end-joining (NHEJ). Their formation coincided with the robust oxidative damage of hepatocyte DNA. This was associated with the activation of poly(ADP-ribose) polymerase 1 (PARP1)-mediated dsDNA repair, as reflected by the augmented transcription of PARP1 and XRCC1; the PARP1 binding partner OGG1, a responder to oxidative DNA damage; and increased activity of NAD+, a marker of PARP1 activation, and HO1, an indicator of cell oxidative stress. The engagement of the PARP1-mediated NHEJ repair pathway explains the HTJ format of the initial merges. The findings show that HBV and WHV are immediate inducers of oxidative DNA damage and hijack dsDNA repair to integrate into the hepatocyte genome, and through this mechanism, they may initiate pro-oncogenic processes. Tracking initial integrations may uncover early markers of HCC and help to explain HBV-associated oncogenesis.
Collapse
Affiliation(s)
- Tomasz I Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Science, Faculty of Medicine, Health Science Center, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada
| |
Collapse
|
|
13
|
Mendoza G, González-Pastor R, Sánchez JM, Arce-Cerezo A, Quintanilla M, Moreno-Bueno G, Pujol A, Belmar-López C, de Martino A, Riu E, Rodriguez TA, Martin-Duque P. The E1a Adenoviral Gene Upregulates the Yamanaka Factors to Induce Partial Cellular Reprogramming. Cells 2023; 12:1338. [PMID: 37174738 PMCID: PMC10177049 DOI: 10.3390/cells12091338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/29/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
The induction of pluripotency by enforced expression of different sets of genes in somatic cells has been achieved with reprogramming technologies first described by Yamanaka's group. Methodologies for generating induced pluripotent stem cells are as varied as the combinations of genes used. It has previously been reported that the adenoviral E1a gene can induce the expression of two of the Yamanaka factors (c-Myc and Oct-4) and epigenetic changes. Here, we demonstrate that the E1a-12S over-expression is sufficient to induce pluripotent-like characteristics closely to epiblast stem cells in mouse embryonic fibroblasts through the activation of the pluripotency gene regulatory network. These findings provide not only empirical evidence that the expression of one single factor is sufficient for partial reprogramming but also a potential mechanistic explanation for how viral infection could lead to neoplasia if they are surrounded by the appropriate environment or the right medium, as happens with the tumorogenic niche.
Collapse
Affiliation(s)
- Gracia Mendoza
- Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain
| | - Rebeca González-Pastor
- Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- Centro de Investigación Biomédica (CENBIO), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador
| | - Juan Miguel Sánchez
- National Heart and Lung Institute, Imperial College London, London W12 ONN, UK
| | - Altamira Arce-Cerezo
- Centro de Biotecnología Animal y de Terapia Génica (CBATEG), Universidad Autónoma de Barcelona, 08193 Bellaterra, Spain
| | - Miguel Quintanilla
- Departamento de Bioquímica, Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Universidad Autónoma de Madrid (UAM), (UAM-CSIC), 28029 Madrid, Spain
| | - Gema Moreno-Bueno
- Departamento de Bioquímica, Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Universidad Autónoma de Madrid (UAM), (UAM-CSIC), 28029 Madrid, Spain
- Fundación MD Anderson Internacional, 28033 Madrid, Spain
- Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Red de Cáncer (CIBERONC) and Red de Nanomedicina y Nanomateriales (CIBER-BBN), 28029 Madrid, Spain
| | - Anna Pujol
- Centro de Biotecnología Animal y de Terapia Génica (CBATEG), Universidad Autónoma de Barcelona, 08193 Bellaterra, Spain
| | - Carolina Belmar-López
- Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- OncoGenomics Lab, Universidad Privada San Juan Bautista, Lima 15038, Peru
| | - Alba de Martino
- Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
| | - Efrén Riu
- Centro de Biotecnología Animal y de Terapia Génica (CBATEG), Universidad Autónoma de Barcelona, 08193 Bellaterra, Spain
| | | | - Pilar Martin-Duque
- Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain
- Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Red de Cáncer (CIBERONC) and Red de Nanomedicina y Nanomateriales (CIBER-BBN), 28029 Madrid, Spain
- Fundación Araid, 50018 Zaragoza, Spain
- Departamento de Cirugía, Facultad de Medicina, Universidad de Zaragoza, 50009 Zaragoza, Spain
| |
Collapse
|
|
14
|
Diakite M, Shaw-Saliba K, Lau CY. Malignancy and viral infections in Sub-Saharan Africa: A review. FRONTIERS IN VIROLOGY (LAUSANNE, SWITZERLAND) 2023; 3:1103737. [PMID: 37476029 PMCID: PMC10358275 DOI: 10.3389/fviro.2023.1103737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/22/2023]
Abstract
The burden of malignancy related to viral infection is increasing in Sub-Saharan Africa (SSA). In 2018, approximately 2 million new cancer cases worldwide were attributable to infection. Prevention or treatment of these infections could reduce cancer cases by 23% in less developed regions and about 7% in developed regions. Contemporaneous increases in longevity and changes in lifestyle have contributed to the cancer burden in SSA. African hospitals are reporting more cases of cancer related to infection (e.g., cervical cancer in women and stomach and liver cancer in men). SSA populations also have elevated underlying prevalence of viral infections compared to other regions. Of 10 infectious agents identified as carcinogenic by the International Agency for Research on Cancer, six are viruses: hepatitis B and C viruses (HBV and HCV, respectively), Epstein-Barr virus (EBV), high-risk types of human papillomavirus (HPV), Human T-cell lymphotropic virus type 1 (HTLV-1), and Kaposi's sarcoma herpesvirus (KSHV, also known as human herpesvirus type 8, HHV-8). Human immunodeficiency virus type 1 (HIV) also facilitates oncogenesis. EBV is associated with lymphomas and nasopharyngeal carcinoma; HBV and HCV are associated with hepatocellular carcinoma; KSHV causes Kaposi's sarcoma; HTLV-1 causes T-cell leukemia and lymphoma; HPV causes carcinoma of the oropharynx and anogenital squamous cell cancer. HIV-1, for which SSA has the greatest global burden, has been linked to increasing risk of malignancy through immunologic dysregulation and clonal hematopoiesis. Public health approaches to prevent infection, such as vaccination, safer injection techniques, screening of blood products, antimicrobial treatments and safer sexual practices could reduce the burden of cancer in Africa. In SSA, inequalities in access to cancer screening and treatment are exacerbated by the perception of cancer as taboo. National level cancer registries, new screening strategies for detection of viral infection and public health messaging should be prioritized in SSA's battle against malignancy. In this review, we discuss the impact of carcinogenic viruses in SSA with a focus on regional epidemiology.
Collapse
Affiliation(s)
- Mahamadou Diakite
- University Clinical Research Center, University of Sciences, Techniques, and Technologies, Bamako, Mali
| | - Kathryn Shaw-Saliba
- Collaborative Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Chuen-Yen Lau
- HIV Dynamics and Replication Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
| |
Collapse
|
|
15
|
Zhao JF, Teng QP, Lv Y, Li XY, Ding Y. Association between hepatitis B or hepatitis C virus infection and risk of pancreatic cancer: a systematic review and meta-analysis of cohort studies. Ther Adv Infect Dis 2023; 10:20499361231212161. [PMID: 37954404 PMCID: PMC10634262 DOI: 10.1177/20499361231212161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 10/18/2023] [Indexed: 11/14/2023] Open
Abstract
Background and aim With conflicting data from previous observational studies on the relationship between hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and pancreatic cancer (PC), we decided to conduct a systematic review and meta-analysis in order to evaluate any potential association. Design This is a systematic review and meta-analysis. Methods We conducted a search of three databases (PubMed, Embase, and Web of Science) from the time of their creation up to June 2023. The summary results, including hazard ratio (HR) with 95% confidence interval (CI), were pooled using a generic inverse variance method and a random-effects model. Furthermore, subgroup and sensitivity analyses were conducted. Results In this meta-analysis, 22 cohort studies with a total of 10,572,865 participants were analyzed. Meta-analysis from 15 cohort studies revealed that HBV infection was correlated with an increased risk of PC (HR = 1.53, 95% CI: 1.40-1.68, p < 0.00001) with no heterogeneity (I2 = 0%, p = 0.49). Meta-analysis from 14 cohort studies showed that HCV infection was associated with an increased risk of PC (HR = 1.82, 95% CI: 1.51-2.21, p < 0.00001). Most of our subgroup analyses yielded similar results. Meta-analysis from four cohort studies indicated that co-infection with HBV and HCV was linked to an increased risk of PC (HR = 2.32, 95% CI: 1.40-3.85, p = 0.001) with no heterogeneity observed (I2 = 0%, p = 0.60). The results of sensitivity analyses were robust. Conclusion Our meta-analysis showed that HBV/HCV infection or co-infection with HBV and HCV was associated with an increased risk of PC. Future prospective cohort studies need to take into account various ethnicities and any confounding factors, as well as investigate the potential mechanisms of PC development in those with HBV/HCV. Trial registration Open Science Framework registries (No: osf.io/n64ua).
Collapse
Affiliation(s)
- Jian-Feng Zhao
- Department of Gastrointestinal Surgery, Jingmen People’s Hospital, Jingchu University of Technology Affiliated Central Hospital, Jingmen, Hubei Province, China
- Central Hospital, Jingmen, Hubei Province, China
| | - Qiu-Ping Teng
- Department of Nephrology, The central Hospital of Jingmen, Jingmen, Hubei Province, China
| | - Yang Lv
- Department of Gastrointestinal Surgery, Jingmen People’s Hospital, Jingchu University of Technology Affiliated Central Hospital, Jingmen, Hubei Province, China
- Central Hospital, Jingmen, Hubei Province, China
| | - Xiao-Yi Li
- Imaging Diagnosis Center, Jingmen People’s Hospital, Jingchu University of Technology Affiliated, Jingmen, Hubei, China
| | - Yi Ding
- Department of Gastrointestinal Surgery, Jingmen People’s Hospital, Jingchu University of Technology Affiliated Central Hospital, No. 39, Xiangshan Avenue, Jingmen City, Hubei Province 448000, China
| |
Collapse
|
|
16
|
Yeh SH, Li CL, Lin YY, Ho MC, Wang YC, Tseng ST, Chen PJ. Hepatitis B Virus DNA Integration Drives Carcinogenesis and Provides a New Biomarker for HBV-related HCC. Cell Mol Gastroenterol Hepatol 2023; 15:921-929. [PMID: 36690297 PMCID: PMC9972564 DOI: 10.1016/j.jcmgh.2023.01.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/24/2022] [Accepted: 01/02/2023] [Indexed: 01/25/2023]
Abstract
Hepatitis B virus (HBV) DNA integration is an incidental event in the virus replication cycle and occurs in less than 1% of infected hepatocytes during viral infection. However, HBV DNA is present in the genome of approximately 90% of HBV-related HCCs and is the most common somatic mutation. Whole genome sequencing of liver tissues from chronic hepatitis B patients showed integration occurring at random positions in human chromosomes; however, in the genomes of HBV-related HCC patients, there are integration hotspots. Both the enrichment of the HBV-integration proportion in HCC and the emergence of integration hotspots suggested a strong positive selection of HBV-integrated hepatocytes to progress to HCC. The activation of HBV integration hotspot genes, such as telomerase (TERT) or histone methyltransferase (MLL4/KMT2B), resembles insertional mutagenesis by oncogenic animal retroviruses. These candidate oncogenic genes might shed new light on HBV-related HCC biology and become targets for new cancer therapies. Finally, the HBV integrations in individual HCC contain unique sequences at the junctions, such as virus-host chimera DNA (vh-DNA) presumably being a signature molecule for individual HCC. HBV integration may thus provide a new cell-free tumor DNA biomarker to monitor residual HCC after curative therapies or to track the development of de novo HCC.
Collapse
Affiliation(s)
- Shiou-Hwei Yeh
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan; National Taiwan University Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan
| | - Chiao-Ling Li
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Yu Lin
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University College of Life Science, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | | | | | - Pei-Jer Chen
- National Taiwan University Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
| |
Collapse
|
|
17
|
Batskikh S, Morozov S, Dorofeev A, Borunova Z, Kostyushev D, Brezgin S, Kostyusheva A, Chulanov V. Previous hepatitis B viral infection-an underestimated cause of pancreatic cancer. World J Gastroenterol 2022; 28:4812-4822. [PMID: 36156926 PMCID: PMC9476854 DOI: 10.3748/wjg.v28.i33.4812] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/15/2022] [Accepted: 08/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The etiology of pancreatic cancer remains unclear. This limits the possibility of prevention and effective treatment. Hepatitis B virus (HBV) is responsible for the development of different types of cancer, but its role in pancreatic cancer is still being discussed. AIM To assess the prevalence of previous HBV infection and to identify viral biomarkers in patients with pancreatic ductal adenocarcinoma (PDAC) to support the role of the virus in etiology of this cancer. METHODS The data of 130 hepatitis B surface antigen-negative subjects were available for the final analysis, including 60 patients with PDAC confirmed by cytology or histology and 70 sex- and age-matched controls. All the participants were tested for HBV biomarkers in blood [antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs) and HBV DNA], and for those with PDAC, biomarkers in resected pancreatic tissues were tested (HBV DNA, HBV pregenomic RNA and covalently closed circular DNA). We performed immunohistochemistry staining of pancreatic tissues for hepatitis B virus X antigen and Ki-67 protein. Non-parametric statistics were used for the analysis. RESULTS Anti-HBc was detected in 18/60 (30%) patients with PDAC and in 9/70 (13%) participants in the control group (P = 0.029). Accordingly, the odds of PDAC in anti-HBc-positive subjects were higher compared to those with no previous HBV infection (odds ratio: 2.905, 95% confidence interval: 1.191-7.084, standard error 0.455). HBV DNA was detected in 8 cases of PDAC and in 6 of them in the pancreatic tumor tissue samples only (all patients were anti-HBc positive). Blood HBV DNA was negative in all subjects of the control group with positive results of the serum anti-HBc test. Among 9 patients with PDAC, 5 revealed signs of replicative competence of the virus (covalently closed circular DNA with or without pregenomic RNA) in the pancreatic tumor tissue samples. Hepatitis B virus X antigen expression and active cell proliferation was revealed by immunohistochemistry in 4 patients with PDAC in the pancreatic tumor tissue samples. CONCLUSION We found significantly higher risks of PDAC in anti-HBc-positive patients. Detection of viral replication and hepatitis B virus X protein expression in the tumor tissue prove involvement of HBV infection in pancreatic cancer development.
Collapse
Affiliation(s)
- Sergey Batskikh
- Department of Hepatology, Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia
| | - Sergey Morozov
- Department of Gastroenterology, Hepatology and Nutrition, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow 115446, Russia
| | - Alexey Dorofeev
- Department of Scientific and Clinical Laboratory Research, Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia
| | - Zanna Borunova
- Department of Scientific and Clinical Laboratory Research, Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia
| | - Dmitry Kostyushev
- Laboratory of Genetic Technologies, Sechenov University, Moscow 119435, Russia
- Division of Biotechnology, Scientific Center for Genetics and Life Sciences, Sirius University of Science and Technology, Sochi 354340, Russia
| | - Sergey Brezgin
- Laboratory of Genetic Technologies, Sechenov University, Moscow 119435, Russia
- Division of Biotechnology, Scientific Center for Genetics and Life Sciences, Sirius University of Science and Technology, Sochi 354340, Russia
| | | | - Vladimir Chulanov
- Laboratory of Genetic Technologies, Sechenov University, Moscow 119435, Russia
- Division of Biotechnology, Scientific Center for Genetics and Life Sciences, Sirius University of Science and Technology, Sochi 354340, Russia
- Laboratory of Genetic Technologies and Translational Research, National Medical Research Center for Tuberculosis and Infectious Diseases of Ministry of Health of Russia, Moscow 127994, Russia
| |
Collapse
|
|
18
|
Batskikh S, Morozov S, Kostyushev D. Hepatitis B virus markers in hepatitis B surface antigen negative patients with pancreatic cancer: Two case reports. World J Hepatol 2022; 14:1512-1519. [PMID: 36158906 PMCID: PMC9376784 DOI: 10.4254/wjh.v14.i7.1512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/25/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is a known carcinogen that may be involved in pancreatic cancer development. Detection of HBV biomarkers [especially expression of HBV regulatory X protein (HBx)] within the tumor tissue may provide direct support for this. However, there is still a lack of such reports, particularly in non-endemic regions for HBV infection. Here we present two cases of patients with pancreatic ductal adenocarcinoma, without a history of viral hepatitis, in whom the markers of HBV infection were detected in blood and in the resected pancreatic tissue. CASE SUMMARY The results of examination of two patients with pancreatic cancer, who gave informed consent for participation and publication, were the source for this study. Besides standards of care, special examination to reveal occult HBV infection was performed. This included blood tests for HBsAg, anti-HBc, anti-HBs, HBV DNA, and pancreatic tissue examinations with polymerase chain reaction for HBV DNA, pregenomic HBV RNA (pgRNA HBV), and covalently closed circular DNA HBV (cccDNA) and immunohistochemistry staining for HBxAg and Ki-67. Both subjects were operated on due to pancreatic ductal adenocarcinoma and serum HBsAg was not detected. However, in both of them anti-HBc antibodies were detected in blood, although HBV DNA was not found. Examination of the resected pancreatic tissue gave positive results for HBV DNA, expression of HBx, and active cellular proliferation by Ki-67 index in both cases. However, HBV pgRNA and cccDNA were detected only in case 1. CONCLUSION These cases may reflect potential involvement of HBV infection in the development of pancreatic cancer.
Collapse
Affiliation(s)
- Sergey Batskikh
- Department of Hepatology, Moscow Clinical Research Center named after A.S. Loginov, Moscow 111123, Russia
| | - Sergey Morozov
- Department of Gastroenterology, Hepatology and Nutrition, Federal Research Center of Nutrition and Biotechnology, Moscow 115446, Russia.
| | - Dmitry Kostyushev
- Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
- Division of Biotechnology, Sirius University of Science and Technology, Sochi 354340, Russia
| |
Collapse
|
|
19
|
Olakowski M, Bułdak Ł. Modifiable and Non-Modifiable Risk Factors for the Development of Non-Hereditary Pancreatic Cancer. Medicina (B Aires) 2022; 58:medicina58080978. [PMID: 35893093 PMCID: PMC9394367 DOI: 10.3390/medicina58080978] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic cancer is becoming an increasing healthcare concern. Though it is a 14th most common cancer worldwide, its incidence is steadily rising. Results of currently available therapies are still not satisfactory. Therefore, great attention should be put on the identification and reduction of risk factors for pancreatic cancer. A thorough up-to-date review of available data on the impact of well-established and novel risk factors of pancreatic cancer development have been performed. Several risk factors associated with lifestyle have significant impact on the risk of pancreatic cancer (i.e., smoking, obesity, alcohol consumption). Physicians should also be aware of the novel findings suggesting increasing role of microbiome, including viral and bacterial infections, in the development of pancreatic cancer. A growing body of evidence suggest also an increased risk during certain occupational exposures. In general, lifestyle seems to be a major contributor in the development of pancreatic cancer. Special attention should be given to individuals with a vicious cluster consisting of metabolic syndrome, tobacco smoking and alcohol consumption. Physicians should urge patients to comply to healthy diet, cessation of smoking and moderation of alcohol consumption, which may halve pancreatic cancer incidence. Further studies are warranted to explore the potential use of therapeutic approach on novel risk factors (e.g., microbiome).
Collapse
Affiliation(s)
- Marek Olakowski
- Department of Gastrointestinal Surgery, Medical University of Silesia, Medyków 14, 40-752 Katowice, Poland;
| | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
- Correspondence:
| |
Collapse
|
|
20
|
Design, synthesis and biological evaluation of 3-arylisoquinoline derivatives as topoisomerase I and II dual inhibitors for the therapy of liver cancer. Eur J Med Chem 2022; 237:114376. [DOI: 10.1016/j.ejmech.2022.114376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/01/2022] [Accepted: 04/08/2022] [Indexed: 11/21/2022]
|
|
21
|
Fusion HBx from HBV Integrant Affects Hepatocarcinogenesis through Deregulation of ER Stress Response. Virus Res 2022; 315:198787. [DOI: 10.1016/j.virusres.2022.198787] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 03/31/2022] [Accepted: 04/12/2022] [Indexed: 01/04/2023]
|
|
22
|
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus and an important human pathogen. There are an estimated 296 million people in the world that are chronically infected by this virus, and many of them will develop severe liver diseases including hepatitis, cirrhosis and hepatocellular carcinoma (HCC). HBV is a small DNA virus that replicates via the reverse transcription pathway. In this review, we summarize the molecular pathways that govern the replication of HBV and its interactions with host cells. We also discuss viral and non-viral factors that are associated with HBV-induced carcinogenesis and pathogenesis, as well as the role of host immune responses in HBV persistence and liver pathogenesis.
Collapse
Affiliation(s)
- Yu-Chen Chuang
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| |
Collapse
|
|
23
|
Bousali M, Karamitros T. Hepatitis B Virus Integration into Transcriptionally Active Loci and HBV-Associated Hepatocellular Carcinoma. Microorganisms 2022; 10:microorganisms10020253. [PMID: 35208708 PMCID: PMC8879149 DOI: 10.3390/microorganisms10020253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/10/2022] [Accepted: 01/20/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatitis B Virus (HBV) DNA integrations into the human genome are considered major causative factors to HBV-associated hepatocellular carcinoma development. In the present study, we investigated whether HBV preferentially integrates parts of its genome in specific genes and evaluated the contribution of the integrations in HCC development per gene. We applied dedicated in-house developed pipelines on all of the available HBV DNA integration data and performed a statistical analysis to identify genes that could be characterized as hotspots of integrations, along with the evaluation of their association with HBV-HCC. Our results suggest that 15 genes are recurrently affected by HBV integrations and they are significantly associated with HBV-HCC. Further studies that focus on HBV integrations disrupting these genes are mandatory in order to understand the role of HBV integrations in clonal advantage gain and oncogenesis promotion, as well as to determine whether inhibition of the HBV-disrupted genes can provide a therapy strategy for HBV-HCC.
Collapse
Affiliation(s)
- Maria Bousali
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
- Correspondence: ; Tel.: +30-210-6478871
| |
Collapse
|
|
24
|
Gheorghe G, Diaconu CC, Ionescu V, Constantinescu G, Bacalbasa N, Bungau S, Gaman MA, Stan-Ilie M. Risk Factors for Pancreatic Cancer: Emerging Role of Viral Hepatitis. J Pers Med 2022; 12:83. [PMID: 35055398 PMCID: PMC8780367 DOI: 10.3390/jpm12010083] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/09/2021] [Accepted: 12/29/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive malignant neoplastic diseases. The incidence and mortality rates of this disease vary depending on geographical area, which might be explained by the different exposure to risk factors. To improve the prognosis of patients with pancreatic cancer, different approaches are needed for an earlier diagnosis. Identification of risk factors and implementation of screening strategies are essential for a better prognosis. Currently, the risk factors for pancreatic cancer fall into two broad categories, namely extrinsic and intrinsic factors. Extrinsic factors include alcohol consumption, smoking, a diet rich in saturated fats, and viral infections such as chronic infection with hepatitis B and C viruses. The pathophysiological mechanisms explaining how these hepatotropic viruses contribute to the development of pancreatic cancer are not fully elucidated. The common origin of hepatocytes and pancreatic cells in the multipotent endodermal cells, the common origin of the blood vessels and biliary ducts of the pancreas and the liver, or chronic inflammatory changes may be involved in this interaction. A careful monitoring of patients with viral liver infections may contribute to the early diagnosis of pancreatic cancer and improve the prognosis of these patients.
Collapse
Affiliation(s)
- Gina Gheorghe
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (G.C.); (M.-A.G.); (M.S.-I.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania;
| | - Camelia Cristina Diaconu
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (G.C.); (M.-A.G.); (M.S.-I.)
- Department of Internal Medicine, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Vlad Ionescu
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania;
| | - Gabriel Constantinescu
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (G.C.); (M.-A.G.); (M.S.-I.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania;
| | - Nicolae Bacalbasa
- Department of Visceral Surgery, “Carol Davila” University of Medicine and Pharmacy, Center of Excellence in Translational Medicine “Fundeni” Clinical Institute, 022328 Bucharest, Romania;
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania;
| | - Mihnea-Alexandru Gaman
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (G.C.); (M.-A.G.); (M.S.-I.)
- Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Madalina Stan-Ilie
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (G.C.); (M.-A.G.); (M.S.-I.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania;
| |
Collapse
|
|
25
|
Salpini R, D’Anna S, Benedetti L, Piermatteo L, Gill U, Svicher V, Kennedy PTF. Hepatitis B virus DNA integration as a novel biomarker of hepatitis B virus-mediated pathogenetic properties and a barrier to the current strategies for hepatitis B virus cure. Front Microbiol 2022; 13:972687. [PMID: 36118192 PMCID: PMC9478028 DOI: 10.3389/fmicb.2022.972687] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic infection with Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality worldwide. HBV-DNA integration into the human genome is recognized as a frequent event occurring during the early phases of HBV infection and characterizing the entire course of HBV natural history. The development of refined molecular biology technologies sheds new light on the functional implications of HBV-DNA integration into the human genome, including its role in the progression of HBV-related pathogenesis and in triggering the establishment of pro-oncogenic mechanisms, promoting the development of hepatocellular carcinoma. The present review provides an updated and comprehensive overview of the current body of knowledge on HBV-DNA integration, focusing on the molecular mechanisms underlying HBV-DNA integration and its occurrence throughout the different phases characterizing the natural history of HBV infection. Furthermore, here we discuss the main clinical implications of HBV integration as a biomarker of HBV-related pathogenesis, particularly in reference to hepatocarcinogenesis, and how integration may act as a barrier to the achievement of HBV cure with current and novel antiviral therapies. Overall, a more refined insight into the mechanisms and functionality of HBV integration is paramount, since it can potentially inform the design of ad hoc diagnostic tools with the ability to reveal HBV integration events perturbating relevant intracellular pathways and for identifying novel therapeutic strategies targeting alterations directly related to HBV integration.
Collapse
Affiliation(s)
- Romina Salpini
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Stefano D’Anna
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Livia Benedetti
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Lorenzo Piermatteo
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Upkar Gill
- Barts Liver Centre, Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Valentina Svicher
- Department of Biology, University of Rome Tor Vergata, Roma, Italy
- *Correspondence: Valentina Svicher,
| | - Patrick T. F. Kennedy
- Barts Liver Centre, Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
- Patrick T. F. Kennedy,
| |
Collapse
|
|
26
|
Lang-Meli J, Neumann-Haefelin C, Thimme R. Immunotherapy and therapeutic vaccines for chronic HBV infection. Curr Opin Virol 2021; 51:149-157. [PMID: 34710645 DOI: 10.1016/j.coviro.2021.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 09/08/2021] [Accepted: 10/07/2021] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a major global health burden causing severe complications like liver cirrhosis or hepatocellular carcinoma. Curative treatment options are lacking. Therefore, there is an urgent need for new therapeutic options. Immunotherapy with the goal to restore dysfunctional HBV-specific T cell immunity is an interesting new therapeutic strategy. Based on current evidence on dysfunction of the HBV-specific CD8+ T cell response in chronic HBV infection, we will review the growing field of immunotherapeutic approaches for treatment of chronic HBV infection. The review will focus on therapies targeting T cells and will cover checkpoint inhibitors, T cell engineering, Toll-like receptor agonists and therapeutic vaccination.
Collapse
Affiliation(s)
- Julia Lang-Meli
- Dept. of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany; IMM-PACT Programm, Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Christoph Neumann-Haefelin
- Dept. of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Robert Thimme
- Dept. of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany.
| |
Collapse
|
|
27
|
Lv W, Li T, Wang S, Wang H, Li X, Zhang S, Wang L, Xu Y, Wei W. The Application of the CRISPR/Cas9 System in the Treatment of Hepatitis B Liver Cancer. Technol Cancer Res Treat 2021; 20:15330338211045206. [PMID: 34605326 PMCID: PMC8493308 DOI: 10.1177/15330338211045206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system was originally discovered in prokaryotes and functions as part of the adaptive immune system. The experimental research of many scholars, as well as scientific and technological advancements, has allowed prokaryote-derived CRISPR/Cas genome-editing systems to transform our ability to manipulate, detect, image, and annotate specific DNA and RNA sequences in the living cells of diverse species. Through modern genetic engineering editing technology and high-throughput gene sequencing, we can edit and splice covalently closed circular DNA to silence it, and correct the mutation and deletion of liver cancer genes to achieve precise in situ repair of defective genes and prohibit viral infection or replication. Such manipulations do not destroy the structure of the entire genome and facilitate the cure of diseases. In this review, we discussed the possibility that CRISPR/Cas could be used as a treatment for patients with liver cancer caused by hepatitis B virus infection, and reviewed the challenges incurred by this effective gene-editing technology.
Collapse
Affiliation(s)
- Wei Lv
- 36639The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Tao Li
- 36639The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shanshan Wang
- 36639The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Huihui Wang
- 36639The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xuemei Li
- 36639The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shubing Zhang
- 36639The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lianzi Wang
- 36639The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuanhong Xu
- 36639The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Wei
- 36639The First Affiliated Hospital of Anhui Medical University, Hefei, China
| |
Collapse
|
|
28
|
Meier MA, Calabrese D, Suslov A, Terracciano LM, Heim MH, Wieland S. Ubiquitous expression of HBsAg from integrated HBV DNA in patients with low viral load. J Hepatol 2021; 75:840-847. [PMID: 34004216 DOI: 10.1016/j.jhep.2021.04.051] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/21/2021] [Accepted: 04/27/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Loss of serum HBsAg is a hallmark of spontaneous and therapy induced resolution of HBV infection, since it generally reflects a profound decrease in viral replication. However, integrated HBV DNA can contribute to HBsAg expression independent of viral replication. The relative contributions of these sources of HBsAg are not well understood. Specifically, it is not known whether actively transcribed HBV integration could spread throughout the entire liver. METHODS The relative distribution of HBsAg and HBV RNA in liver biopsy tissue from HBeAg-negative (HBe-) patients was analyzed by immunohistochemistry and in situ hybridization (ISH), respectively. Frozen biopsy tissue was used for molecular analysis of intrahepatic viral RNA, virus-host chimeric transcripts and viral DNA. RESULTS Immunohistochemistry and ISH analysis revealed HBsAg and HBV RNA positivity in virtually all hepatocytes in the liver of some HBe- patients despite very low viremia. Reverse transcription quantitative PCR and RNA-sequencing analysis confirmed high expression levels of HBV envelope-encoding RNAs. However, the amount of viral transcriptional template (covalently closed circular (ccc)DNA) was too low to support this ubiquitous HBV RNA expression. In contrast, levels of total cellular HBV DNA were consistent with ubiquitous HBV integration. Finally, RNA-sequencing revealed the presence of many HBV-host chimeric transcripts with the potential for HBsAg expression. CONCLUSIONS Transcriptionally active HBV integration can extend to the entire liver in some HBe- patients. This can lead to ubiquitous HBsAg expression independent of HBV replication. In such patients, HBsAg is probably not a clinically useful surrogate marker for viral resolution or functional cure. LAY SUMMARY Loss of serum hepatitis B surface antigen (HBsAg) indicates resolution of HBV infection. However, integrated HBV DNA can contribute to HBsAg production independently of viral replication. We investigated the extent of HBsAg-producing viral integration in the livers of patients with low serum viral loads. Our findings suggest that transcriptionally active HBV integration can extend to the entire liver in some patients, questioning the clinical utility of HBsAg as a surrogate marker for viral replication.
Collapse
Affiliation(s)
- Marie-Anne Meier
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland; Institute of Pathology, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland
| | - Diego Calabrese
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland
| | - Aleksei Suslov
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland
| | - Luigi M Terracciano
- Division of Gastroenterology and Hepatology, University Hospital Basel, Basel CH-4031, Switzerland
| | - Markus H Heim
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland; Institute of Pathology, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland.
| | - Stefan Wieland
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland.
| |
Collapse
|
|
29
|
Higuera-de-la-Tijera F, Castro-Narro GE, Velarde-Ruiz Velasco JA, Cerda-Reyes E, Moreno-Alcántar R, Aiza-Haddad I, Castillo-Barradas M, Cisneros-Garza LE, Dehesa-Violante M, Flores-Calderón J, González-Huezo MS, Márquez-Guillén E, Muñóz-Espinosa LE, Pérez-Hernández JL, Ramos-Gómez MV, Sierra-Madero J, Sánchez-Ávila JF, Torre-Delgadillo A, Torres R, Marín-López ER, Kershenobich D, Wolpert-Barraza E. Asociación Mexicana de Hepatología A.C. Clinical guideline on hepatitis B. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:403-432. [PMID: 34483073 DOI: 10.1016/j.rgmxen.2021.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/14/2021] [Indexed: 12/24/2022]
Abstract
Hepatitis B virus (HBV) infection continues to be a worldwide public health problem. In Mexico, at least three million adults are estimated to have acquired hepatitis B (total hepatitis B core antibody [anti-HBc]-positive), and of those, 300,000 active carriers (hepatitis B surface antigen [HBsAg]-positive) could require treatment. Because HBV is preventable through vaccination, its universal application should be emphasized. HBV infection is a major risk factor for developing hepatocellular carcinoma. Semi-annual liver ultrasound and serum alpha-fetoprotein testing favor early detection of that cancer and should be carried out in all patients with chronic HBV infection, regardless of the presence of advanced fibrosis or cirrhosis. Currently, nucleoside/nucleotide analogues that have a high barrier to resistance are the first-line therapies.
Collapse
Affiliation(s)
- F Higuera-de-la-Tijera
- Departamento de Gastroenterología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - G E Castro-Narro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico.
| | - J A Velarde-Ruiz Velasco
- Departamento de Gastroenterología, Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
| | - E Cerda-Reyes
- Departamento de Gastroenterología, Hospital Central Militar, Mexico City, Mexico
| | - R Moreno-Alcántar
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - I Aiza-Haddad
- Clínica de Enfermedades Hepáticas, Hospital Ángeles Lomas, Mexico City, Mexico
| | - M Castillo-Barradas
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional "La Raza", IMSS, Mexico City, Mexico
| | - L E Cisneros-Garza
- Centro de Enfermedades Hepáticas, Hospital San José, Nuevo León, Monterrey, Mexico
| | - M Dehesa-Violante
- Fundación Mexicana para la Salud Hepática A.C. (FUNDHEPA), Mexico City, Mexico
| | - J Flores-Calderón
- Departamento de Gastroenterología, Hospital de Pediatría del Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - M S González-Huezo
- Servicio de Gastroenterología y Endoscopia Gastrointestinal, ISSSEMYM, Metepec, Estado de México, Mexico
| | - E Márquez-Guillén
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - L E Muñóz-Espinosa
- Clínica de Hígado, Departamento de Medicina Interna, Hospital Universitario "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
| | - J L Pérez-Hernández
- Departamento de Gastroenterología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - M V Ramos-Gómez
- Departamento de Gastroenterología, Centro Médico Nacional "20 de Noviembre", ISSSTE, Mexico City, Mexico
| | - J Sierra-Madero
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - J F Sánchez-Ávila
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - A Torre-Delgadillo
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - R Torres
- Hospital de Infectología del Centro Médico Nacional "La Raza", IMSS, Mexico City, Mexico
| | | | - D Kershenobich
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | | |
Collapse
|
|
30
|
Tsuge M. Are Humanized Mouse Models Useful for Basic Research of Hepatocarcinogenesis through Chronic Hepatitis B Virus Infection? Viruses 2021; 13:v13101920. [PMID: 34696350 PMCID: PMC8541657 DOI: 10.3390/v13101920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/14/2021] [Accepted: 09/20/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a global health problem that can lead to liver dysfunction, including liver cirrhosis and hepatocellular carcinoma (HCC). Current antiviral therapies can control viral replication in patients with chronic HBV infection; however, there is a risk of HCC development. HBV-related proteins may be produced in hepatocytes regardless of antiviral therapies and influence intracellular metabolism and signaling pathways, resulting in liver carcinogenesis. To understand the mechanisms of liver carcinogenesis, the effect of HBV infection in human hepatocytes should be analyzed. HBV infects human hepatocytes through transfer to the sodium taurocholate co-transporting polypeptide (NTCP). Although the NTCP is expressed on the hepatocyte surface in several animals, including mice, HBV infection is limited to human primates. Due to this species-specific liver tropism, suitable animal models for analyzing HBV replication and developing antivirals have been lacking since the discovery of the virus. Recently, a humanized mouse model carrying human hepatocytes in the liver was developed based on several immunodeficient mice; this is useful for analyzing the HBV life cycle, antiviral effects of existing/novel antivirals, and intracellular signaling pathways under HBV infection. Herein, the usefulness of human hepatocyte chimeric mouse models in the analysis of HBV-associated hepatocarcinogenesis is discussed.
Collapse
Affiliation(s)
- Masataka Tsuge
- Natural Science Center for Basic Research and Development, Department of Biomedical Science, Research and Development Division, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; ; Tel.: +81-82-257-1510
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| |
Collapse
|
|
31
|
Liu Q, Tian Y, Li Y, Zhang W, Cai W, Liu Y, Ren Y, Liang Z, Zhou P, Zhang Y, Bao Y, Li Y. In vivo therapeutic effects of affinity-improved-TCR engineered T-cells on HBV-related hepatocellular carcinoma. J Immunother Cancer 2021; 8:jitc-2020-001748. [PMID: 33323464 PMCID: PMC7745518 DOI: 10.1136/jitc-2020-001748] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2020] [Indexed: 12/24/2022] Open
Abstract
Background In patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), virus-specific cytotoxic T lymphocytes (CTLs) fail to eliminate HCC cells expressing HBV antigens. As the expression of viral antigen in HBV-associated HCC may decrease to allow tumor to escape immune attacks, we hypothesized that an HBV surface antigen (HBsAg)-specific affinity-improved-T-cell receptor (TCR) will enable T cells to target HCC more effectively than corresponding wild-type-TCR. We also postulated that TCR promiscuity can be exploited to efficiently capture HBV variants that can hinder CTL-based therapeutics. Methods We applied flexi-panning to isolate affinity-improved TCRs binding to a variant antigen, the human leukocyte antigen (HLA)-A*02:01-restricted nonapeptide HBs371-379-ILSPFLPLL, from libraries constructed with a TCR cloned using the decapeptide HBs370-379-SIVSPFIPLL. The potency and safety of the affinity-improved-TCR engineered T-cells (Ai-TCR-T) were verified with potentially cross-reactive human and HBV-variant peptides, tumor and normal cells, and xenograft mouse models. Results Ai-TCR-T cells retained cognate HBV antigen specificity and recognized a wide range of HBV genotypic variants with improved sensitivity and cytotoxicity. Cell infusions produced complete elimination of HCC without recurrence in the xenograft mouse models. Elevated accumulation of CD8+ Ai-TCR-T cells in tumors correlated with tumor shrinkage. Conclusion The in vitro and in vivo studies demonstrated that HBsAg-specific Ai-TCR-T cells had safety profiles similar to those of their wild-type counterparts and significantly enhanced potency. This study presents an approach to develop new therapeutic strategies for HBV-related HCC.
Collapse
Affiliation(s)
- Qi Liu
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,University of the Chinese Academy of Sciences, Beijing, China
| | - Ye Tian
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yanyan Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Wei Zhang
- Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Hefei, Anhui, China
| | - Wenxuan Cai
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yaju Liu
- Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Hefei, Anhui, China
| | - Yuefei Ren
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhaoduan Liang
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Peipei Zhou
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China
| | - Yajing Zhang
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,University of the Chinese Academy of Sciences, Beijing, China
| | - Yifeng Bao
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yi Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China .,University of the Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
32
|
Zhang D, Guo S, Schrodi SJ. Mechanisms of DNA Methylation in Virus-Host Interaction in Hepatitis B Infection: Pathogenesis and Oncogenetic Properties. Int J Mol Sci 2021; 22:9858. [PMID: 34576022 PMCID: PMC8466338 DOI: 10.3390/ijms22189858] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV), the well-studied oncovirus that contributes to the majority of hepatocellular carcinomas (HCC) worldwide, can cause a severe inflammatory microenvironment leading to genetic and epigenetic changes in hepatocyte clones. HBV replication contributes to the regulation of DNA methyltransferase gene expression, particularly by X protein (HBx), and subsequent methylation changes may lead to abnormal transcription activation of adjacent genes and genomic instability. Undoubtedly, the altered expression of these genes has been known to cause diverse aspects of infected hepatocytes, including apoptosis, proliferation, reactive oxygen species (ROS) accumulation, and immune responses. Additionally, pollutant-induced DNA methylation changes and aberrant methylation of imprinted genes in hepatocytes also complicate the process of tumorigenesis. Meanwhile, hepatocytes also contribute to epigenetic modification of the viral genome to affect HBV replication or viral protein production. Meanwhile, methylation levels of HBV integrants and surrounding host regions also play crucial roles in their ability to produce viral proteins in affected hepatocytes. Both host and viral changes can provide novel insights into tumorigenesis, individualized responses to therapeutic intervention, disease progress, and early diagnosis. As such, DNA methylation-mediated epigenetic silencing of cancer-related genes and viral replication is a compelling therapeutic goal to reduce morbidity and mortality from liver cancer caused by chronic HBV infection. In this review, we summarize the most recent research on aberrant DNA methylation associated with HBV infection, which is involved in HCC development, and provide an outlook on the future direction of the research.
Collapse
Affiliation(s)
- Dake Zhang
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Shicheng Guo
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA;
| | - Steven J. Schrodi
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA;
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
| |
Collapse
|
|
33
|
Rim CH. Differences in radiotherapy application according to regional disease characteristics of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2021; 21:113-123. [PMID: 37383087 PMCID: PMC10035685 DOI: 10.17998/jlc.2021.05.26] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/25/2021] [Accepted: 06/01/2021] [Indexed: 06/30/2023]
Abstract
There are differences in opinion regarding the application of external beam radiotherapy in the treatment of hepatocellular carcinoma. Some major guidelines state that external beam radiotherapy is yet to attain a sufficient level of evidence. However, caution should be exercised when attempting to understand the clinical need for external beam radiotherapy solely based on the level of evidence. Previously, external beam radiotherapy had low applicability in the treatment of hepatocellular carcinoma before computed tomography-based planning was popularized. Modern external beam radiotherapy can selectively target tumor cells while sparing normal liver tissues. Recent technologies such as stereotactic body radiotherapy have enabled more precise treatment. The characteristics of hepatocellular carcinoma differ significantly according to the regional etiology. The main cause of hepatocellular carcinoma is the hepatitis B virus. It is commonly diagnosed as a locally advanced tumor but with relatively preserved hepatic function. The majority of these hepatocellular carcinoma cases are found in the East Asian population. Hepatocellular carcinoma caused by hepatitis C virus or other benign hepatitis tends to be diagnosed as a less locally aggressive tumor but with deteriorated liver function. The western world and Japan tend to have patients with such causes. External beam radiotherapy has been more commonly performed for the former, although the use of external beam radiotherapy in the latter might have more concerns with regard to hepatic toxicity. This review discusses the above subjects along with perspectives regarding external beam radiotherapy in recent guidelines.
Collapse
Affiliation(s)
- Chai Hong Rim
- Department of Radiation Oncology, Korea University Ansan Hospital, Ansan, Korea
- Korea University Medical College, Seoul, Korea
| |
Collapse
|
|
34
|
Bousali M, Papatheodoridis G, Paraskevis D, Karamitros T. Hepatitis B Virus DNA Integration, Chronic Infections and Hepatocellular Carcinoma. Microorganisms 2021; 9:1787. [PMID: 34442866 PMCID: PMC8398950 DOI: 10.3390/microorganisms9081787] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B Virus (HBV) is an Old World virus with a high mutation rate, which puts its origins in Africa alongside the origins of Homo sapiens, and is a member of the Hepadnaviridae family that is characterized by a unique viral replication cycle. It targets human hepatocytes and can lead to chronic HBV infection either after acute infection via horizontal transmission usually during infancy or childhood or via maternal-fetal transmission. HBV has been found in ~85% of HBV-related Hepatocellular Carcinomas (HCC), and it can integrate the whole or part of its genome into the host genomic DNA. The molecular mechanisms involved in the HBV DNA integration is not yet clear; thus, multiple models have been described with respect to either the relaxed-circular DNA (rcDNA) or the double-stranded linear DNA (dslDNA) of HBV. Various genes have been found to be affected by HBV DNA integration, including cell-proliferation-related genes, oncogenes and long non-coding RNA genes (lincRNAs). The present review summarizes the advances in the research of HBV DNA integration, focusing on the evolutionary and molecular side of the integration events along with the arising clinical aspects in the light of WHO's commitment to eliminate HBV and viral hepatitis by 2030.
Collapse
Affiliation(s)
- Maria Bousali
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - George Papatheodoridis
- Department of Gastroenterology, “Laiko” General Hospital of Athens, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Paraskevis
- Department of Hygiene Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
| |
Collapse
|
|
35
|
Menati Rashno M, Mehraban H, Naji B, Radmehr M. Microbiome in human cancers. Access Microbiol 2021; 3:000247. [PMID: 34888478 PMCID: PMC8650843 DOI: 10.1099/acmi.0.000247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 06/17/2021] [Indexed: 12/19/2022] Open
Abstract
A microbiome is defined as the aggregate of all microbiota that reside in human digestive system and other tissues. This microbiota includes viruses, bacteria, fungi that live in various human organs and tissues like stomach, guts, oesophagus, mouth cavity, urinary tract, vagina, lungs, and skin. Almost 20 % of malignant cancers worldwide are related to microbial infections including bacteria, parasites, and viruses. The human body is constantly being attacked by microbes during its lifetime and microbial pathogens that have tumorigenic effects in 15-20 % of reported cancer cases. Recent scientific advances and the discovery of the effect of microbes on cancer as a pathogen or as a drug have significantly contributed to our understanding of the complex relationship between microbiome and cancer. The aim of this study is to overview some microbiomes that reside in the human body and their roles in cancer.
Collapse
Affiliation(s)
| | - Hamed Mehraban
- Department of Biology, Payame Noor University (PNU), Tehran, Iran
| | - Behnaz Naji
- Department of Microbiology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Mohadeseh Radmehr
- Department of Microbiology, Damghan Branch, Islamic Azad University, Damghan, Iran
| |
Collapse
|
|
36
|
Higuera-de-la-Tijera F, Castro-Narro GE, Velarde-Ruiz Velasco JA, Cerda-Reyes E, Moreno-Alcántar R, Aiza-Haddad I, Castillo-Barradas M, Cisneros-Garza LE, Dehesa-Violante M, Flores-Calderón J, González-Huezo MS, Márquez-Guillén E, Muñóz-Espinosa LE, Pérez-Hernández JL, Ramos-Gómez MV, Sierra-Madero J, Sánchez-Ávila JF, Torre-Delgadillo A, Torres R, Marín-López ER, Kershenobich D, Wolpert-Barraza E. Asociación Mexicana de Hepatología A.C. Clinical guideline on hepatitis B. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:S0375-0906(21)00061-6. [PMID: 34384668 DOI: 10.1016/j.rgmx.2021.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 04/11/2021] [Accepted: 04/14/2021] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infection continues to be a worldwide public health problem. In Mexico, at least three million adults are estimated to have acquired hepatitis B (total hepatitis B core antibody [anti-HBc]-positive), and of those, 300,000 active carriers (hepatitis B surface antigen [HBsAg]-positive) could require treatment. Because HBV is preventable through vaccination, its universal application should be emphasized. HBV infection is a major risk factor for developing hepatocellular carcinoma. Semi-annual liver ultrasound and serum alpha-fetoprotein testing favor early detection of that cancer and should be carried out in all patients with chronic HBV infection, regardless of the presence of advanced fibrosis or cirrhosis. Currently, nucleoside/nucleotide analogues that have a high barrier to resistance are the first-line therapies.
Collapse
Affiliation(s)
- F Higuera-de-la-Tijera
- Departamento de Gastroenterología, Hospital General de México «Dr. Eduardo Liceaga», Ciudad de México, México
| | - G E Castro-Narro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México.
| | - J A Velarde-Ruiz Velasco
- Departamento de Gastroenterología, Hospital Civil de Guadalajara «Fray Antonio Alcalde», Guadalajara, Jalisco, México
| | - E Cerda-Reyes
- Departamento de Gastroenterología, Hospital Central Militar, Ciudad de México, México
| | - R Moreno-Alcántar
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, México
| | - I Aiza-Haddad
- Clínica de Enfermedades Hepáticas, Hospital Ángeles Lomas, Ciudad de México, México
| | - M Castillo-Barradas
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional «La Raza», IMSS, Ciudad de México, México
| | - L E Cisneros-Garza
- Centro de Enfermedades Hepáticas, Hospital San José, Nuevo León, Monterrey, México
| | - M Dehesa-Violante
- Fundación Mexicana para la Salud Hepática A.C. (FUNDHEPA), Ciudad de México, México
| | - J Flores-Calderón
- Departamento de Gastroenterología, Hospital de Pediatría del Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, México
| | - M S González-Huezo
- Servicio de Gastroenterología y Endoscopia Gastrointestinal, ISSSEMYM, Metepec, Estado de México, México
| | - E Márquez-Guillén
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | - L E Muñóz-Espinosa
- Clínica de Hígado, Departamento de Medicina Interna, Hospital Universitario «Dr. José E. González», Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México
| | - J L Pérez-Hernández
- Departamento de Gastroenterología, Hospital General de México «Dr. Eduardo Liceaga», Ciudad de México, México
| | - M V Ramos-Gómez
- Departamento de Gastroenterología, Centro Médico Nacional «20 de Noviembre», ISSSTE, Ciudad de México, México
| | - J Sierra-Madero
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | - J F Sánchez-Ávila
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ciudad de México, México
| | - A Torre-Delgadillo
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | - R Torres
- Hospital de Infectología del Centro Médico Nacional «La Raza», IMSS, Ciudad de México, México
| | | | - D Kershenobich
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | | |
Collapse
|
|
37
|
Zhang D, Zhang K, Protzer U, Zeng C. HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site. J Clin Transl Hepatol 2021; 9:399-408. [PMID: 34221926 PMCID: PMC8237140 DOI: 10.14218/jcth.2021.00062] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV), one of the well-known DNA oncogenic viruses, is the leading cause of hepatocellular carcinoma (HCC). In infected hepatocytes, HBV DNA can be integrated into the host genome through an insertional mutagenesis process inducing tumorigenesis. Dissection of the genomic features surrounding integration sites will deepen our understanding of mechanisms underlying integration. Moreover, the quantity and biological activity of integration sites may reflect the DNA damage within affected cells or the potential survival benefits they may confer. The well-known human genomic features include repeat elements, particular regions (such as telomeres), and frequently interrupted genes (e.g., telomerase reverse transcriptase [i.e. TERT], lysine methyltransferase 2B [i.e. KMT2B], cyclin E1 [CCNE1], and cyclin A2 [CCNA2]). Consequently, distinct genomic features within diverse integrations differentiate their biological functions. Meanwhile, accumulating evidence has shown that viral proteins produced by integrants may cause cell damage even after the suppression of HBV replication. The integration-derived gene products can also serve as tumor markers, promoting the development of novel therapeutic strategies for HCC. Viral integrants can be single copy or multiple copies of different fragments with complicated rearrangement, which warrants elucidation of the whole viral integrant arrangement in future studies. All of these considerations underlie an urgent need to develop novel methodology and technology for sequence characterization and function evaluation of integration events in chronic hepatitis B-associated disease progression by monitoring both host genomic features and viral integrants. This endeavor may also serve as a promising solution for evaluating the risk of tumorigenesis and as a companion diagnostic for designing therapeutic strategies targeting integration-related disease complications.
Collapse
Affiliation(s)
- Dake Zhang
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Ke Zhang
- SCG Cell Therapy Pte. Ltd, Singapore
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Urlike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Changqing Zeng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
38
|
Péneau C, Zucman-Rossi J, Nault JC. Genomics of Viral Hepatitis-Associated Liver Tumors. J Clin Med 2021; 10:1827. [PMID: 33922394 PMCID: PMC8122827 DOI: 10.3390/jcm10091827] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/15/2021] [Accepted: 04/18/2021] [Indexed: 12/25/2022] Open
Abstract
Virus-related liver carcinogenesis is one of the main contributors of cancer-related death worldwide mainly due to the impact of chronic hepatitis B and C infections. Three mechanisms have been proposed to explain the oncogenic properties of hepatitis B virus (HBV) infection: induction of chronic inflammation and cirrhosis, expression of HBV oncogenic proteins, and insertional mutagenesis into the genome of infected hepatocytes. Hepatitis B insertional mutagenesis modifies the function of cancer driver genes and could promote chromosomal instability. In contrast, hepatitis C virus promotes hepatocellular carcinoma (HCC) occurrence mainly through cirrhosis development whereas the direct oncogenic role of the virus in human remains debated. Finally, adeno associated virus type 2 (AAV2), a defective DNA virus, has been associated with occurrence of HCC harboring insertional mutagenesis of the virus. Since these tumors developed in a non-cirrhotic context and in the absence of a known etiological factor, AAV2 appears to be the direct cause of tumor development in these patients via a mechanism of insertional mutagenesis altering similar oncogenes and tumor suppressor genes targeted by HBV. A better understanding of virus-related oncogenesis will be helpful to develop new preventive strategies and therapies directed against specific alterations observed in virus-related HCC.
Collapse
Affiliation(s)
- Camille Péneau
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
- Hôpital Européen Georges Pompidou, APHP, F-75015 Paris, France
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
- Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, F-93000 Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, F-93000 Bobigny, France
| |
Collapse
|
|
39
|
Baudoin NC, Bloomfield M. Karyotype Aberrations in Action: The Evolution of Cancer Genomes and the Tumor Microenvironment. Genes (Basel) 2021; 12:558. [PMID: 33921421 PMCID: PMC8068843 DOI: 10.3390/genes12040558] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/27/2021] [Accepted: 04/06/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is a disease of cellular evolution. For this cellular evolution to take place, a population of cells must contain functional heterogeneity and an assessment of this heterogeneity in the form of natural selection. Cancer cells from advanced malignancies are genomically and functionally very different compared to the healthy cells from which they evolved. Genomic alterations include aneuploidy (numerical and structural changes in chromosome content) and polyploidy (e.g., whole genome doubling), which can have considerable effects on cell physiology and phenotype. Likewise, conditions in the tumor microenvironment are spatially heterogeneous and vastly different than in healthy tissues, resulting in a number of environmental niches that play important roles in driving the evolution of tumor cells. While a number of studies have documented abnormal conditions of the tumor microenvironment and the cellular consequences of aneuploidy and polyploidy, a thorough overview of the interplay between karyotypically abnormal cells and the tissue and tumor microenvironments is not available. Here, we examine the evidence for how this interaction may unfold during tumor evolution. We describe a bidirectional interplay in which aneuploid and polyploid cells alter and shape the microenvironment in which they and their progeny reside; in turn, this microenvironment modulates the rate of genesis for new karyotype aberrations and selects for cells that are most fit under a given condition. We conclude by discussing the importance of this interaction for tumor evolution and the possibility of leveraging our understanding of this interplay for cancer therapy.
Collapse
Affiliation(s)
- Nicolaas C. Baudoin
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Biological Sciences and Fralin Life Sciences Institute, Virginia Tech, Blacksburg, VA 24061, USA
| | - Mathew Bloomfield
- Department of Biological Sciences and Fralin Life Sciences Institute, Virginia Tech, Blacksburg, VA 24061, USA
| |
Collapse
|
|
40
|
Li W, Qi Y, Xu H, Wei W, Cui X. Profile of different Hepatitis B virus integration frequency in hepatocellular carcinoma patients. Biochem Biophys Res Commun 2021; 553:160-164. [PMID: 33773138 DOI: 10.1016/j.bbrc.2021.03.056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 02/19/2021] [Accepted: 03/11/2021] [Indexed: 11/26/2022]
Abstract
Hepatitis B virus (HBV) DNA integration is closely related to the occurrence of liver cancer. However, current studies mostly focus on the detection of the viral integration sites, ignoring the relationship between the frequency of viral integration and liver cancer. Thus, this study uses previous data to distinguish the breakpoints according to the integration frequency and analyzes the characteristics of different groups. This analysis revealed that three sets of breakpoints were characterized by its own integrated sample frequency, breakpoint distribution, and affected gene pathways. This result indicated an evolution in the virus integration sites in the process of tumor formation and development. Therefore, our research clarified the characteristics and differences in the sites of viral integration in tumors and adjacent tissues, and clarified the key signaling pathways affected by viral integration. Hence, these findings might be of great significance in the understanding of the role of viral integration frequency in hepatocellular carcinoma.
Collapse
Affiliation(s)
- Weiyang Li
- Jining Medical University, Jining, Shandong, 272067, China; Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, Shandong, 272067, China.
| | - Yanwei Qi
- Jining Medical University, Jining, Shandong, 272067, China.
| | - Hanshi Xu
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China.
| | - Wei Wei
- Jining Medical University, Jining, Shandong, 272067, China.
| | - Xiaofang Cui
- Jining Medical University, Jining, Shandong, 272067, China; Shandong Key Laboratory of Behavioral Medicine, School of Mental Health, Jining Medical University, Jining, Shandong, 272067, China.
| |
Collapse
|
|
41
|
Liu X, Zhang ZH, Jiang F. Hepatitis B virus infection increases the risk of pancreatic cancer: a meta-analysis. Scand J Gastroenterol 2021; 56:252-258. [PMID: 33399501 DOI: 10.1080/00365521.2020.1868568] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The relationship between hepatitis B virus (HBV) and pancreatic cancer has been controversial for years, but more recently new information on this relationship has been updated Therefore, we performed a meta-analysis to provide summary estimates of the risk of pancreatic cancer associated with HBV infection. METHODS A systematic literature search on HBV and pancreatic cancer in English was performed in Pubmed, Cochrane library and Embase up to July 2020. Pooled rate ratios (RRs) and 95% confidence intervals (CIs) were calculated by the random-effects model. Stata software version 15.1 was used to perform this meta-analysis of the 17 studies considered to be eligible. RESULTS 17 studies including 7 case-control and 10 cohort studies met the selection criteria. Begg's and Egger's test results indicated that there was no publication bias. Individuals with Hepatitis B surface antigen (HBsAg) or HBV DNA seropositivity had a significantly increased risk of pancreatic cancer showing an RR (95% CI) of 1.39 (1.19, 1.63). Similar conclusions were drawn from the results of the subgroup analysis (subgroup by study design, population, sex ratio) except when subgrouped by patient's region: the RR and 95% CI in Europe and Oceania were 1.44 (0.88, 2.34) and 1.47(0.38, 5.71) respectively. CONCLUSIONS The findings of this meta-analysis suggest that HBV infections may increase the risk of pancreatic cancer under most conditions, while there remains some doubt when comparison is made between European and Oceania patients.
Collapse
Affiliation(s)
- Xue Liu
- Department of Ultrasonic Diagnosis, Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhi-Hua Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Fan Jiang
- Department of Ultrasonic Diagnosis, Second Affiliated Hospital of Anhui Medical University, Hefei, China
| |
Collapse
|
|
42
|
Tu T, Zhang H, Urban S. Hepatitis B Virus DNA Integration: In Vitro Models for Investigating Viral Pathogenesis and Persistence. Viruses 2021; 13:v13020180. [PMID: 33530322 PMCID: PMC7911709 DOI: 10.3390/v13020180] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/12/2021] [Accepted: 01/21/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) is a globally-distributed pathogen and is a major cause of liver disease. HBV (or closely-related animal hepadnaviruses) can integrate into the host genome, but (unlike retroviruses) this integrated form is replication-defective. The specific role(s) of the integrated HBV DNA has been a long-standing topic of debate. Novel in vitro models of HBV infection combined with sensitive molecular assays now enable researchers to investigate this under-characterised phenomenon with greater ease and precision. This review covers the contributions these systems have made to understanding how HBV DNA integration induces liver cancer and facilitates viral persistence. We summarise the current findings into a working model of chronic HBV infection and discuss the clinical implications of this hypothetical framework on the upcoming therapeutic strategies used to curb HBV-associated pathogenesis.
Collapse
Affiliation(s)
- Thomas Tu
- Storr Liver Centre, Faculty of Medicine and Health, Westmead Clinical School and Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia;
- Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia
- Correspondence:
| | - Henrik Zhang
- Storr Liver Centre, Faculty of Medicine and Health, Westmead Clinical School and Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia;
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany;
- German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany
| |
Collapse
|
|
43
|
Abstract
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in nearly 1 million deaths every year. Many of these patients die from severe liver diseases, including HCC. HBV may induce HCC through the induction of chronic liver inflammation, which can cause oxidative stress and DNA damage. However, many studies also indicated that HBV could induce HCC via the alteration of hepatocellular physiology that may involve genetic and epigenetic changes of the host DNA, the alteration of cellular signaling pathways, and the inhibition of DNA repair mechanisms. This alteration of cellular physiology can lead to the accumulation of DNA damages and the promotion of cell cycles and predispose hepatocytes to oncogenic transformation.
Collapse
Affiliation(s)
- Jiyoung Lee
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA.
| |
Collapse
|
|
44
|
Ely A, Singh P, Smith TS, Arbuthnot P. In vitro transcribed mRNA for expression of designer nucleases: Advantages as a novel therapeutic for the management of chronic HBV infection. Adv Drug Deliv Rev 2021; 168:134-146. [PMID: 32485207 DOI: 10.1016/j.addr.2020.05.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 05/14/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023]
Abstract
Chronic infection with the hepatitis B virus (HBV) remains a significant worldwide medical problem. While diseases caused by HIV infection, tuberculosis and malaria are on the decline, new cases of chronic hepatitis B are on the rise. Because often fatal complications of cirrhosis and hepatocellular carcinoma are associated with chronic hepatitis B, the need for a cure is as urgent as ever. Currently licensed therapeutics fail to eradicate the virus and this is attributable to persistence of the viral replication intermediate comprising covalently closed circular DNA (cccDNA). Elimination or inactivation of the viral cccDNA is thus a goal of research aimed at hepatitis B cure. The ability to engineer nucleases that are capable of specific cleavage of a DNA sequence now provides the means to disable cccDNA permanently. The scientific literature is replete with many examples of using designer zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and RNA-guided endonucleases (RGENs) to inactivate HBV. However, important concerns about safety, dose control and efficient delivery need to be addressed before the technology is employed in a clinical setting. Use of in vitro transcribed mRNA to express therapeutic gene editors goes some way to overcoming these concerns. The labile nature of RNA limits off-target effects and enables dose control. Compatibility with hepatotropic non-viral vectors is convenient for the large scale preparation that will be required for advancing gene editing as a mode of curing chronic hepatitis B.
Collapse
|
|
45
|
Preece R, Pavesi A, Gkazi SA, Stegmann KA, Georgiadis C, Tan ZM, Aw JYJ, Maini MK, Bertoletti A, Qasim W. CRISPR-Mediated Base Conversion Allows Discriminatory Depletion of Endogenous T Cell Receptors for Enhanced Synthetic Immunity. Mol Ther Methods Clin Dev 2020; 19:149-161. [PMID: 33102612 PMCID: PMC7549055 DOI: 10.1016/j.omtm.2020.09.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/04/2020] [Indexed: 12/26/2022]
Abstract
Emerging base editing technology exploits CRISPR RNA-guided DNA modification effects for highly specific C > T conversion, which has been used to efficiently disrupt gene expression. These tools can enhance synthetic T cell immunity by restricting specificity, addressing histocompatibility leukocyte antigen (HLA) barriers, and promoting persistence. We report lentiviral delivery of a hepatitis B-virus (HBV)-specific recombinant T cell receptor (rTCR) and a linked CRISPR single-guide RNA for simultaneous disruption of endogenous TCRs (eTCRs) when combined with transient cytosine deamination. Discriminatory depletion of eTCR and coupled expression of rTCR resulted in enrichment of HBV-specific populations from 55% (SEM, ±2.4%) to 95% (SEM, ±0.5%). Intensity of rTCR expression increased 1.8- to 2.9-fold compared to that in cells retaining their competing eTCR, and increased cytokine production and killing of HBV antigen-expressing hepatoma cells in a 3D microfluidic model were exhibited. Molecular signatures confirmed that seamless conversion of C > T (G > A) had created a premature stop codon in TCR beta constant 1/2 loci, with no notable activity at predicted off-target sites. Thus, targeted disruption of eTCR by cytosine deamination and discriminatory enrichment of antigen-specific T cells offers the prospect of enhanced, more specific T cell therapies against HBV-associated hepatocellular carcinoma (HCC) as well as other viral and tumor antigens.
Collapse
Affiliation(s)
- Roland Preece
- Molecular and Cellular Immunology Unit, UCL Great Ormond Street Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre, 30 Guilford Street, London WC1N 1EH, UK
| | - Andrea Pavesi
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR) 61 Biopolis Drive, Singapore 138673, Singapore
| | - Soragia Athina Gkazi
- Molecular and Cellular Immunology Unit, UCL Great Ormond Street Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre, 30 Guilford Street, London WC1N 1EH, UK
| | - Kerstin A. Stegmann
- UCL Division of Infection and Immunity, The Rayne Building, 5 University Street, London WC1E 6EJ, UK
| | - Christos Georgiadis
- Molecular and Cellular Immunology Unit, UCL Great Ormond Street Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre, 30 Guilford Street, London WC1N 1EH, UK
| | - Zhi Ming Tan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR) 61 Biopolis Drive, Singapore 138673, Singapore
| | - Jia Ying Joey Aw
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR) 61 Biopolis Drive, Singapore 138673, Singapore
| | - Mala K. Maini
- UCL Division of Infection and Immunity, The Rayne Building, 5 University Street, London WC1E 6EJ, UK
| | - Antonio Bertoletti
- Program Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
- Singapore Immunology Network (SigN), Agency of Science Technology and Research (A∗STAR), Singapore, Singapore
| | - Waseem Qasim
- Molecular and Cellular Immunology Unit, UCL Great Ormond Street Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre, 30 Guilford Street, London WC1N 1EH, UK
| |
Collapse
|
|
46
|
Nakayama J, Gong Z. Transgenic zebrafish for modeling hepatocellular carcinoma. MedComm (Beijing) 2020; 1:140-156. [PMID: 34766114 PMCID: PMC8491243 DOI: 10.1002/mco2.29] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/05/2020] [Accepted: 08/05/2020] [Indexed: 12/14/2022] Open
Abstract
Liver cancer is the third leading cause of cancer‐related deaths throughout the world, and more than 0.6 million people die from liver cancer annually. Therefore, novel therapeutic strategies to eliminate malignant cells from liver cancer patients are urgently needed. Recent advances in high‐throughput genomic technologies have identified de novo candidates for oncogenes and pharmacological targets. However, testing and understanding the mechanism of oncogenic transformation as well as probing the kinetics and therapeutic responses of spontaneous tumors in an intact microenvironment require in vivo examination using genetically modified animal models. The zebrafish (Danio rerio) has attracted increasing attention as a new model for studying cancer biology since the organs in the model are strikingly similar to human organs and the model can be genetically modified in a short time and at a low cost. This review summarizes the current knowledge of epidemiological data and genetic alterations in hepatocellular carcinoma (HCC), zebrafish models of HCC, and potential therapeutic strategies for targeting HCC based on knowledge from the models.
Collapse
Affiliation(s)
- Joji Nakayama
- Department of Biological Sciences National University of Singapore Singapore
| | - Zhiyuan Gong
- Department of Biological Sciences National University of Singapore Singapore
| |
Collapse
|
|
47
|
Abstract
Hepatitis B virus (HBV), which was discovered in 1965, is a threat to global public health. HBV infects human hepatocytes and leads to acute and chronic liver diseases, and there is no cure. In cells infected by HBV, viral DNA can be integrated into the cellular genome. HBV DNA integration is a complicated process during the HBV life cycle. Although HBV integration normally results in replication-incompetent transcripts, it can still act as a template for viral protein expression. Of note, it is a primary driver of hepatocellular carcinoma (HCC). Recently, with the development of detection methods and research models, the molecular biology and the pathogenicity of HBV DNA integration have been better revealed. Here, we review the advances in the research of HBV DNA integration, including molecular mechanisms, detection methods, research models, the effects on host and viral gene expression, the role of HBV integrations in the pathogenesis of HCC, and potential treatment strategies. Finally, we discuss possible future research prospects of HBV DNA integration.
Collapse
Affiliation(s)
- Kaitao Zhao
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Andrew Liu
- Laboratory of Molecular Cardiology, National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA
| | - Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| |
Collapse
|
|
48
|
Ishii T, Tamura A, Shibata T, Kuroda K, Kanda T, Sugiyama M, Mizokami M, Moriyama M. Analysis of HBV Genomes Integrated into the Genomes of Human Hepatoma PLC/PRF/5 Cells by HBV Sequence Capture-Based Next-Generation Sequencing. Genes (Basel) 2020; 11:genes11060661. [PMID: 32570699 PMCID: PMC7348787 DOI: 10.3390/genes11060661] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/11/2020] [Accepted: 06/16/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC) worldwide. The integration of HBV genomic DNA into the host genome occurs randomly, early after infection, and is associated with hepatocarcinogenesis in HBV-infected patients. Therefore, it is important to analyze HBV genome integration. We analyzed HBV genome integration in human hepatoma PLC/PRF/5 cells by HBV sequence capture-based next-generation sequencing (NGS) methods. We confirmed the results by using Sanger sequencing methods. We observed that HBV genotype A is integrated into the genome of PLC/PRF/5 cells. HBV sequence capture-based NGS is useful for the analysis of HBV genome integrants and their locations in the human genome. Among the HBV genome integrants, we performed functional analysis and demonstrated the automatic expression of some HBV proteins encoded by HBV integrants from chromosomes 3 and 11 in Huh7 cells transfected with these DNA sequences. HBV sequence capture-based NGS may be a useful tool for the assessment of HBV genome integration into the human genome in clinical samples and suggests new strategies for hepatocarcinogenesis in HBV infection.
Collapse
Affiliation(s)
- Tomotaka Ishii
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan; (T.I.); (A.T.); (T.S.); (K.K.); (M.M.)
| | - Akinori Tamura
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan; (T.I.); (A.T.); (T.S.); (K.K.); (M.M.)
| | - Toshikatsu Shibata
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan; (T.I.); (A.T.); (T.S.); (K.K.); (M.M.)
| | - Kazumichi Kuroda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan; (T.I.); (A.T.); (T.S.); (K.K.); (M.M.)
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan; (T.I.); (A.T.); (T.S.); (K.K.); (M.M.)
- Correspondence: ; Tel.: +81-3-3972-8111; Fax: +81-3-3956-8496
| | - Masaya Sugiyama
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan; (M.S.); (M.M.)
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan; (M.S.); (M.M.)
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan; (T.I.); (A.T.); (T.S.); (K.K.); (M.M.)
| |
Collapse
|
|
49
|
The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. J Hepatol 2020; 72:990-1002. [PMID: 32044402 DOI: 10.1016/j.jhep.2020.01.019] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/16/2020] [Accepted: 01/21/2020] [Indexed: 12/13/2022]
Abstract
Chronic liver disease and primary liver cancer are a massive global problem, with a future increase in incidences predicted. The most prevalent form of primary liver cancer, hepatocellular carcinoma, occurs after years of chronic liver disease. Mutations in the genome are a causative and defining feature of all cancers. Chronic liver disease, mostly at the cirrhotic stage, causes the accumulation of progressive mutations which can drive cancer development. Within the liver, a Darwinian process selects out dominant clones with selected driver mutations but also leaves a trail of passenger mutations which can be used to track the evolution of a tumour. Understanding what causes specific mutations and how they combine with one another to form cancer is a question at the heart of understanding, preventing and tackling liver cancer. Herein, we review the landscape of gene mutations in cirrhosis, especially those paving the way toward hepatocellular carcinoma development, that have been characterised by recent studies capitalising on technological advances in genomic sequencing. With these insights, we are beginning to understand how cancers form in the liver, particularly on the background of chronic liver disease. This knowledge may soon lead to breakthroughs in the way we detect, diagnose and treat this devastating disease.
Collapse
|
|
50
|
Cheng CW, Tse E. Targeting PIN1 as a Therapeutic Approach for Hepatocellular Carcinoma. Front Cell Dev Biol 2020; 7:369. [PMID: 32010690 PMCID: PMC6974617 DOI: 10.3389/fcell.2019.00369] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 12/16/2019] [Indexed: 12/12/2022] Open
Abstract
PIN1 is a peptidyl-prolyl cis/trans isomerase that specifically binds and catalyzes the cis/trans isomerization of the phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif of its interacting proteins. Through this phosphorylation-dependent prolyl isomerization, PIN1 is involved in the regulation of various important cellular processes including cell cycle progression, cell proliferation, apoptosis and microRNAs biogenesis; hence its dysregulation contributes to malignant transformation. PIN1 is highly expressed in hepatocellular carcinoma (HCC). By fine-tuning the functions of its interacting proteins such as cyclin D1, x-protein of hepatitis B virus and exportin 5, PIN1 plays an important role in hepatocarcinogenesis. Growing evidence supports that targeting PIN1 is a potential therapeutic approach for HCC by inhibiting cell proliferation, inducing cellular apoptosis, and restoring microRNAs biogenesis. Novel formulation of PIN1 inhibitors that increases in vivo bioavailability of PIN1 inhibitors represents a promising future direction for the therapeutic strategy of HCC treatment. In this review, the mechanisms underlying PIN1 over-expression in HCC are explored. Furthermore, we also discuss the roles of PIN1 in HCC tumorigenesis and metastasis through its interaction with various phosphoproteins. Finally, recent progress in the therapeutic options targeting PIN1 for HCC treatment is examined and summarized.
Collapse
Affiliation(s)
- Chi-Wai Cheng
- Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Eric Tse
- Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| |
Collapse
|