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Liu Q, Zhang X, Qi J, Tian X, Dovjak E, Zhang J, Du H, Zhang N, Zhao J, Zhang Y, Wang L, Wei Y, Liu C, Qian R, Xiang L, Li W, Xiu P, Ma C, Yu Y, Jiang S. Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for HCC. Hepatology 2025; 81:1164-1180. [PMID: 38899975 PMCID: PMC11902616 DOI: 10.1097/hep.0000000000000962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 05/11/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND AND AIMS Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature. APPROACH AND RESULTS Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 ( LPCAT1 ) and ceramide synthase 5 ( CERS5 ) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy. CONCLUSIONS In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.
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Affiliation(s)
- Qingbin Liu
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
- Post-Doctoral Research Center, Cisen Pharmaceutical Co. Ltd, Jining, Shandong, China
- School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Xiangyu Zhang
- Pathology Department, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Jingjing Qi
- Medical Faculty, Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | - Xinchen Tian
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Eva Dovjak
- Medical Faculty, Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | - Jiaqi Zhang
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Honghuan Du
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Ni Zhang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jing Zhao
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Yiming Zhang
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Lijuan Wang
- Department of Ultrasonic Medicine, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Yangang Wei
- Post-Doctoral Research Center, Cisen Pharmaceutical Co. Ltd, Jining, Shandong, China
| | - Chenqiao Liu
- Hepatobiliary Surgery Department, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Ruikun Qian
- Hepatobiliary Surgery Department, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Longquan Xiang
- Pathology Department, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Weiyang Li
- School of Biological Sciences, Jining Medical University, Rizhao, Shandong, China
| | - Peng Xiu
- Department of General Surgery, Shandong Province Qianfoshan Hospital, The First Hospital Affiliated With Shandong First Medical University, Jinan, Shandong, China
| | - Changlin Ma
- Hepatobiliary Surgery Department, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Yong Yu
- Medical Faculty, Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | - Shulong Jiang
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
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Zdziarski P, Gamian A. Role of B Cells beyond Antibodies in HBV-Induced Oncogenesis: Fulminant Cancer in Common Variable Immunodeficiency-Clinical and Immunotransplant Implications with a Review of the Literature. Diseases 2024; 12:80. [PMID: 38785735 PMCID: PMC11119213 DOI: 10.3390/diseases12050080] [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: 12/07/2023] [Revised: 01/17/2024] [Accepted: 04/17/2024] [Indexed: 05/25/2024] Open
Abstract
Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially affected by oncogenic viruses, are not considered. Furthermore, in vitro genetic studies and cell cultures are not adequate for immune system and HBV interaction. We adopted a previously introduced clinical model of host-virus interaction (i.e., infectious process in immunodeficiency) for analysis of B cells and the specific IgG role (an observational study of a CVID patient who received intravenous immunoglobulin (IVIG). Suddenly, the patient deteriorated and a positive results of for HBs and HBV-DNA (369 × 106 copies) were detected. Despite lamivudine therapy and IVIG escalation (from 0.3 to 0.4 g/kg), CT showed an 11 cm intrahepatic tumor (hepatocellular carcinoma). Anti-HBs were positive in time-lapse analysis (range 111-220 IU/mL). Replacement therapy intensification was complicated by an immune complex disease with renal failure. Fulminant HCC in CVID and the development of a tumor as the first sign is of interest. Unfortunately, treatment with hepatitis B immune globulins (HBIG) plays a major role in posttransplant maintenance therapy. Anti-HB substitution has not been proven to be effective, oncoprotective, nor safe. Therefore, immunosuppression in HBV-infected recipients should be carefully minimized, and patient selection more precise with the exclusion of HBV-positive donors. Our clinical model showed an HCC pathway with important humoral host factors, contrary to epidemiological/cohort studies highlighting risk factors only (e.g., chronic hepatitis). The lack of cell cooperation as well as B cell deficiency observed in CVID play a crucial role in high HBV replication, especially in carcinogenesis.
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Affiliation(s)
- Przemyslaw Zdziarski
- Lower Silesian Center for Cellular Transplantation, 53-439 Wroclaw, Poland
- Clinical Research Center PRION, 50-385 Wroclaw, Poland
| | - Andrzej Gamian
- Hirszfeld Institute of Immunology and Experimental Therapy, 53-114 Wroclaw, Poland;
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Abu Baker F, Kopelman Y, Taher R, Abu Much S, Green I, Mari A, Davidov Y, Ben-Ari Z, Israel A. Hepatitis B virus infection and risk of colorectal cancer: a large, population-based cohort study from Israel. Minerva Med 2024; 115:185-190. [PMID: 38197570 DOI: 10.23736/s0026-4806.23.08964-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
BACKGROUND Recent population-based studies have suggested a possible link between hepatitis B (HBV) infection and extra-hepatic malignancies. We aimed to evaluate the association between HBV and colorectal cancer (CRC) using a large, population-based cohort study utilizing data from a large health maintenance organization (HMO). METHODS The study included patients with non-cirrhotic HBV based on relevant ICD-9-CM codes and supportive serology identified from the HMO's database. Age-, sex-, ethnicity-, and BMI-matched non-HBV patients in a 1:10 ratio were included in the control group. We assessed the overall diagnosis rate of CRC and hepatocellular carcinoma (HCC) during the study period and calculated the diagnosis rate of CRC in each age category (≤50, 51-70, and ≥70) in both groups. RESULTS A total of 3430 HBV patients and 34,300 controls were included in the study. The mean age, sex, BMI, and ethnic composition were similar, and the rates of family history of CRC did not differ between both groups. The overall follow-up period was 134±16 months. The diagnosis rate of HCC (1.6% vs. 0.1%; P<0.0001) was significantly higher in the HBV patients. However, the proportion of CRC was comparable for both groups (0.6% vs. 0.8%, P=0.404), which was evident in all age subgroups. CONCLUSIONS Our findings suggest that HBV infection is associated with an increased risk of HCC diagnosis but is not linked to an elevated risk of CRC. These findings may inform future clinical practice and research regarding the relationship between HBV and extrahepatic malignancies.
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Affiliation(s)
- Fadi Abu Baker
- Department of Gastroenterology and Hepatology, Hillel Yaffe Medical Center, Hadera, Israel
| | - Yael Kopelman
- Department of Gastroenterology and Hepatology, Hillel Yaffe Medical Center, Hadera, Israel
| | - Randa Taher
- Department of Gastroenterology and Hepatology, Hillel Yaffe Medical Center, Hadera, Israel -
- Department of Internal Medicine, Hillel Yaffe Medical Center, Hadera, Israel
| | - Saif Abu Much
- Department of Internal Medicine, Hillel Yaffe Medical Center, Hadera, Israel
| | - Ilan Green
- Leumit Healthcare Service, Tel Aviv, Israel
| | - Amir Mari
- Department of Gastroenterology and Hepatology, EMMS Hospital, Nazareth, Israel
| | - Yana Davidov
- Center for Liver Diseases, Tel HaShomer Hospital, Ramat Gan, Israel
| | - Ziv Ben-Ari
- Center for Liver Diseases, Tel HaShomer Hospital, Ramat Gan, Israel
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Mak LY, Chung MSH, Li X, Lai FTT, Wan EYF, Chui CSL, Cheng FWT, Chan EWY, Cheung CL, Au ICH, Xiong X, Seto WK, Yuen MF, Wong CKH, Wong ICK. Effects of SARS-CoV-2 infection on incidence and treatment strategies of hepatocellular carcinoma in people with chronic liver disease. World J Hepatol 2024; 16:211-228. [PMID: 38495273 PMCID: PMC10941734 DOI: 10.4254/wjh.v16.i2.211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/31/2023] [Accepted: 01/30/2024] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Chronic liver disease (CLD) was associated with adverse clinical outcomes among people with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. AIM To determine the effects of SARS-CoV-2 infection on the incidence and treatment strategy of hepatocellular carcinoma (HCC) among patients with CLD. METHODS A retrospective, territory-wide cohort of CLD patients was identified from an electronic health database in Hong Kong. Patients with confirmed SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)+CLD] between January 1, 2020 and October 25, 2022 were identified and matched 1:1 by propensity-score with those without (COVID-19-CLD). Each patient was followed up until death, outcome event, or November 15, 2022. Primary outcome was incidence of HCC. Secondary outcomes included all-cause mortality, adverse hepatic outcomes, and different treatment strategies to HCC (curative, non-curative treatment, and palliative care). Analyses were further stratified by acute (within 20 d) and post-acute (21 d or beyond) phases of SARS-CoV-2 infection. Incidence rate ratios (IRRs) were estimated by Poisson regression models. RESULTS Of 193589 CLD patients (> 95% non-cirrhotic) in the cohort, 55163 patients with COVID-19+CLD and 55163 patients with COVID-19-CLD were included after 1:1 propensity-score matching. Upon 249-d median follow-up, COVID-19+CLD was not associated with increased risk of incident HCC (IRR: 1.19, 95%CI: 0.99-1.42, P = 0.06), but higher risks of receiving palliative care for HCC (IRR: 1.60, 95%CI: 1.46-1.75, P < 0.001), compared to COVID-19-CLD. In both acute and post-acute phases of infection, COVID-19+CLD were associated with increased risks of all-cause mortality (acute: IRR: 7.06, 95%CI: 5.78-8.63, P < 0.001; post-acute: IRR: 1.24, 95%CI: 1.14-1.36, P < 0.001) and adverse hepatic outcomes (acute: IRR: 1.98, 95%CI: 1.79-2.18, P < 0.001; post-acute: IRR: 1.24, 95%CI: 1.13-1.35, P < 0.001), compared to COVID-19-CLD. CONCLUSION Although CLD patients with SARS-CoV-2 infection were not associated with increased risk of HCC, they were more likely to receive palliative treatment than those without. The detrimental effects of SARS-CoV-2 infection persisted in post-acute phase.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Matthew Shing Hin Chung
- Department of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Xue Li
- Department of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong, China
| | - Francisco Tsz Tsun Lai
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong, China
| | - Eric Yuk Fai Wan
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong, China
- Department of Family Medicine and Primary Care, The University of Hong Kong, Hong Kong, China
| | - Celine Sze Ling Chui
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong, China
- School of Nursing, The University of Hong Kong, Hong Kong, China
- School of Public Health, The University of Hong Kong, Hong Kong, China
| | - Franco Wing Tak Cheng
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Esther Wai Yin Chan
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong, China
| | - Ching Lung Cheung
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong, China
| | - Ivan Chi Ho Au
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
- School of Public Health, The University of Hong Kong, Hong Kong, China
| | - Xi Xiong
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Carlos King Ho Wong
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong, China
- Department of Family Medicine and Primary Care, The University of Hong Kong, Hong Kong, China.
| | - Ian Chi Kei Wong
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong, China
- Research Department of Practice and Policy, University College London, London WC1E 6BT, United Kingdom
- Aston School of Pharmacy, Aston University, Birmingham B4 7ET, United Kingdom
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Tavakolian S, Tabaeian SP, Namazi A, Faghihloo E, Akbari A. Role of the VEGF in virus-associated cancers. Rev Med Virol 2024; 34:e2493. [PMID: 38078693 DOI: 10.1002/rmv.2493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 11/14/2023] [Indexed: 01/30/2024]
Abstract
The role of numerous risk factors, including consumption of alcohol, smoking, having diet high in fat and sugar and many other items, on caner progression cannot be denied. Viral diseases are one these factors, and they can initiate some signalling pathways causing cancer. For example, they can be effective on providing oxygen and nutrients by inducing VEGF expression. In this review article, we summarised the mechanisms of angiogenesis and VEGF expression in cancerous tissues which are infected with oncoviruses (Epstein-Barr virus, Human papillomavirus infection, Human T-lymphotropic virus, Kaposi's sarcoma-associated herpesvirus, Hepatitis B and hepatitis C virus).
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Affiliation(s)
- Shaian Tavakolian
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Seidamir Pasha Tabaeian
- Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Namazi
- Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
- Occupational Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
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Rabaan AA, Bello KE, Irekeola AA, Kaabi NAA, Halwani MA, Yousuf AA, Alshengeti A, Alfaraj AH, Khamis F, Al-Subaie MF, AlShehail BM, Almuthree SA, Ibraheem NY, Khalifa MH, Alfaresi M, Fares MAA, Garout M, Alsayyah A, Alshehri AA, Alqahtani AS, Alissa M. Prevalence of Hepatocellular Carcinoma in Hepatitis B Population within Southeast Asia: A Systematic Review and Meta-Analysis of 39,050 Participants. Pathogens 2023; 12:1220. [PMID: 37887736 PMCID: PMC10609743 DOI: 10.3390/pathogens12101220] [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: 08/17/2023] [Revised: 09/09/2023] [Accepted: 10/02/2023] [Indexed: 10/28/2023] Open
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is a significant complication of hepatitis B and still poses a global public health concern. This systematic review and meta-analysis provide adequate details on the prevalence of HCC in the HBV population within Southeast Asian countries. METHOD Following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria, a thorough search for literature discussing the prevalence of HCC in the HBV population within southeast Asia was performed. Eligible studies were subjected to a meta-analysis utilising a DerSimonian and Laird approach and a random effect model. A protocol was registered with PROSPERO (CRD42023423953). RESULT Our study meticulously recovered 41 articles from seven countries in Southeast Asia, namely Cambodia, Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam. A total of 39,050 HBV patients and 7479 HCC cases in southeast Asia were analysed. The pooled prevalence of HCC in HBV cases within southeast Asia was 45.8% (95% CI, 34.3-57.8%, I2 = 99.51%, p < 0.001). Singapore (62.5%, CI: 42.4-79.1) had the highest pooled prevalence of HCC in the HBV population compared to Vietnam, with the lowest estimate (22.4%, CI: 9.9-44.9). There was a drop in the pooled prevalence of HCC in HBV from 2016 until now (37.6%, CI: 19.2-60.5). CONCLUSION The findings of this review reveal a high pooled prevalence of HCC in the HBV population and therefore stir the need for routine screening, management, and surveillance.
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Affiliation(s)
- Ali A. Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran 31311, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Public Health and Nutrition, The University of Haripur, Haripur 22610, Pakistan
| | - Kizito Eneye Bello
- Department of Microbiology, Faculty of Natural Science, Kogi State University (Prince Abubakar Audu University) Anyigba, Anyigba PMB 1008, Nigeria
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Ahmad Adebayo Irekeola
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
- Microbiology Unit, Department of Biological Sciences, College of Natural and Applied Sciences, Summit University Offa, Offa PMB 4412, Nigeria
| | - Nawal A. Al Kaabi
- College of Medicine and Health Science, Khalifa University, Abu Dhabi 127788, United Arab Emirates
- Sheikh Khalifa Medical City, Abu Dhabi Health Services Company (SEHA), Abu Dhabi 51900, United Arab Emirates
| | - Muhammad A. Halwani
- Department of Medical Microbiology, Faculty of Medicine, Al Baha University, Al Baha 4781, Saudi Arabia
| | - Amjad A. Yousuf
- Department of Medical Laboratories Technology, College of Applied Medical Sciences, Taibah University, Madinah 41411, Saudi Arabia
| | - Amer Alshengeti
- Department of Pediatrics, College of Medicine, Taibah University, Al-Madinah 41491, Saudi Arabia
- Department of Infection Prevention and Control, Prince Mohammad Bin Abdulaziz Hospital, National Guard Health Affairs, Al-Madinah 41491, Saudi Arabia
| | - Amal H. Alfaraj
- Pediatric Department, Abqaiq General Hospital, First Eastern Health Cluster, Abqaiq 33261, Saudi Arabia
| | - Faryal Khamis
- Infection Diseases Unit, Department of Internal Medicine, Royal Hospital, Muscat 1331, Oman
| | - Maha F. Al-Subaie
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Research Center, Dr. Sulaiman Alhabib Medical Group, Riyadh 13328, Saudi Arabia
- Department of Infectious Diseases, Dr. Sulaiman Alhabib Medical Group, Riyadh 13328, Saudi Arabia
| | - Bashayer M. AlShehail
- Pharmacy Practice Department, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Souad A. Almuthree
- Department of Infectious Disease, King Abdullah Medical City, Makkah 43442, Saudi Arabia
| | - Noha Y. Ibraheem
- Department of Infectious Disease, King Abdullah Medical City, Makkah 43442, Saudi Arabia
| | - Mahassen H. Khalifa
- Department of Infectious Disease, King Abdullah Medical City, Makkah 43442, Saudi Arabia
| | - Mubarak Alfaresi
- Department of Pathology and Laboratory Medicine, Zayed Military Hospital, Abu Dhabi 3740, United Arab Emirates
- Department of Pathology, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai 505055, United Arab Emirates
| | - Mona A. Al Fares
- Department of Internal Medicine, King Abdulaziz University Hospital, Jeddah 21589, Saudi Arabia
| | - Mohammed Garout
- Department of Community Medicine and Health Care for Pilgrims, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Ahmed Alsayyah
- Department of Pathology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Ahmad A. Alshehri
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia
| | - Ali S. Alqahtani
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Khalid University, Abha 61481, Saudi Arabia
| | - Mohammed Alissa
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
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Wu CS, Chien YC, Yen CJ, Wu JY, Bai LY, Yu YL. EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasis. Cancer Cell Int 2023; 23:199. [PMID: 37689710 PMCID: PMC10493019 DOI: 10.1186/s12935-023-03002-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 07/25/2023] [Indexed: 09/11/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV)-encoded X antigen, HBx, assists in the development of hepatocellular carcinoma (HCC) through complex mechanisms. Our results provide new insights into the EZH2 epigenetic repression of let-7c that promotes HCC migration induced by HBx. Thus, let-7c and HMGA2 represent key diagnostic markers and potential therapeutic targets for the treatment of HBV-related HCC. RESULTS We investigated the epigenetic regulation of let-7c, an important representative miRNA in liver tumor metastasis, in human HCC cells to verify the effect of HBx. Based on quantitative PCR (qPCR) of mRNA isolated from tumor and adjacent non-tumor liver tissues of 24 patients with HBV-related HCC, EZH2 expression was significantly overexpressed in most HCC tissues (87.5%). We executed a miRNA microarray analysis in paired HBV-related HCC tumor and adjacent non-tumorous liver tissue from six of these patients and identified let-7c, miR-199a-3p, and miR-99a as being downregulated in the tumor tissue. Real-time PCR analysis verified significant downregulation of let-7c and miR-99a in both HepG2X and Hep3BX cells, which stably overexpress HBx, relative to parental cells. HBX enhanced EZH2 expression and attenuated let-7c expression to induce HMGA2 expression in the HCC cells. Knockdown of HMGA2 significantly downregulated the metastatic potential of HCC cells induced by HBx. CONCLUSIONS The deregulation of let-7c expression by HBx may indicate a potential novel pathway through deregulating cell metastasis and imply that HMGA2 might be used as a new prognostic marker and/or as an effective therapeutic target for HCC.
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Affiliation(s)
- Chen-Shiou Wu
- Institute of Translational Medicine and New Drug Development, Taichung, 40402, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, 40402, Taiwan
| | - Yi-Chung Chien
- Institute of Translational Medicine and New Drug Development, Taichung, 40402, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, 40402, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan
| | - Chia-Jui Yen
- Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, 70403, Taiwan
| | - Jia-Yan Wu
- Institute of Translational Medicine and New Drug Development, Taichung, 40402, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, 40402, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan
| | - Li-Yuan Bai
- Division of Hematology and Oncology, China Medical University Hospital, Taichung, 40402, Taiwan.
| | - Yung-Luen Yu
- Institute of Translational Medicine and New Drug Development, Taichung, 40402, Taiwan.
- Center for Molecular Medicine, China Medical University Hospital, Taichung, 40402, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, 41354, Taiwan.
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8
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Ghufran SM, Sharma P, Roy B, Jaiswal S, Aftab M, Sengupta S, Ghose S, Biswas S. Transcriptome wide functional analysis of HBx expressing human hepatocytes stimulated with endothelial cell cross-talk. Genomics 2023; 115:110642. [PMID: 37209778 PMCID: PMC7615065 DOI: 10.1016/j.ygeno.2023.110642] [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: 01/26/2023] [Revised: 05/11/2023] [Accepted: 05/17/2023] [Indexed: 05/22/2023]
Abstract
Identification of genes dysregulated during the hepatitis B virus (HBV)-host cell interaction adds to the understanding of underlying molecular mechanisms and aids in discovering effective therapies to improve prognosis in hepatitis B virus (HBV)-infected individuals. Through bioinformatics analyses of transcriptomics data, this study aimed to identify potential genes involved in the cross-talk of human hepatocytes expressing the HBV viral protein HBx with endothelial cells. Transient transfection of HBV viral gene X (HBx) was performed in THLE2 cells using pcDNA3 constructs. Through mRNA Sequencing (RNA Seq) analysis, differentially expressed genes (DEGs) were identified. THLE2 cells transfected with HBx (THLE2x) were further treated with conditioned medium from cultured human umbilical vein derived endothelial cells (HUVEC-CM). Gene Ontology (GO) enrichment analysis revealed that interferon and cytokine signaling pathways were primarily enriched for the downregulated DEGs in THLE2x cells treated with HUVEC-CM. One significant module was selected following protein-protein interaction (PPI) network generation, and thirteen hub genes were identified from the module. The prognostic values of the hub genes were evaluated using Kaplan-Meier (KM) plotter, and three genes (IRF7, IFIT1, and IFITM1) correlated with poor disease specific survival (DSS) in HCC patients with chronic hepatitis. A comparison of the DEGs identified in HUVEC-stimulated THLE2x cells with four publicly available HBV-related HCC microarray datasets revealed that PLAC8 was consistently downregulated in all four HCC datasets as well as in HUVEC-CM treated THLE2x cells. KM plots revealed that PLAC8 correlated with worse relapse free survival and progression free survival in HCC patients with hepatitis B virus infection. This study provided molecular insights which may help develop a deeper understanding of HBV-host stromal cell interaction and open avenues for future research.
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Affiliation(s)
| | - Prachi Sharma
- Amity Institute of Molecular Medicine & Stem Cell Research, AUUP, Noida, India
| | - Bornika Roy
- Amity Institute of Molecular Medicine & Stem Cell Research, AUUP, Noida, India
| | - Shivani Jaiswal
- Amity Institute of Molecular Medicine & Stem Cell Research, AUUP, Noida, India
| | - Mehreen Aftab
- Division of Cellular and Molecular Oncology, National Institute of Cancer Prevention and Research, Noida, India
| | - Shinjinee Sengupta
- Amity Institute of Molecular Medicine & Stem Cell Research, AUUP, Noida, India
| | - Sampa Ghose
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.
| | - Subhrajit Biswas
- Amity Institute of Molecular Medicine & Stem Cell Research, AUUP, Noida, India.
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9
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Wang P, Wang X, Liu X, Yan F, Yan H, Zhou D, Yu L, Wang X, Yang Z. Primary non-response to antiviral therapy affects the prognosis of hepatitis B virus-related hepatocellular carcinoma. BMC Cancer 2023; 23:564. [PMID: 37340357 PMCID: PMC10280839 DOI: 10.1186/s12885-023-11059-y] [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: 12/02/2022] [Accepted: 06/12/2023] [Indexed: 06/22/2023] Open
Abstract
BACKGROUND AND AIM Although antiviral treatments have been shown to affect the recurrence and long-term survival of patients with hepatocellular carcinoma (HCC) who have high viral loads, the effect of different responses to antiviral therapy on the clinical outcomes remains unclear. This study aimed to assess the effect of primary non-response (no-PR) to antiviral therapy on the survival or prognosis of patients with HCC with a high load of hepatitis B virus (HBV) DNA. METHODS A total of 493 HBV-HCC patients hospitalized at Beijing Ditan Hospital of Capital Medical University were admitted to this retrospective study. Patients were divided into two groups based on viral response (no-PR and primary response). Kaplan-Meier (KM) curves were used to compare the overall survival of the two cohorts. Serum viral load comparison and subgroup analysis were performed. Additionally, risk factors were screened and the risk score chart was created. RESULTS This study consisted of 101 patients with no-PR and 392 patients with primary response. In the different categories based on hepatitis B e antigen and HBV DNA, no-PR group had a poor 1-year overall survival (OS). In addition, in the alanine aminotransferase < 50 IU/L and cirrhosis groups, primary nonresponse was related to poor overall survival and progression-free survival. Based on multivariate risk analysis, primary non-response (hazard ratio (HR) = 1.883, 95% CI 1.289-2.751, P = 0.001), tumor multiplicity (HR = 1.488, 95% CI 1.036-2.136, P = 0.031), portal vein tumor thrombus (HR = 2.732, 95% CI 1.859-4.015, P < 0.001), hemoglobin < 120 g/L (HR = 2.211, 95% CI 1.548-3.158, P < 0.001) and tumor size ≥ 5 cm (HR = 2.202, 95% CI 1.533-3.163, P < 0.001) were independent risk factors for 1-year OS. According to the scoring chart, patients were divided into three risk groups (high-, medium-, and low-risk groups) with mortality rates of 61.7%, 30.5%, and 14.1%, respectively. CONCLUSIONS The level of viral decline at 3 months post-antiviral treatment may predict the OS of patients with HBV-related HCC, and primary non-response may shorten the median survival time of patients with high HBV-DNA levels.
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Affiliation(s)
- Peng Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Fengna Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Huiwen Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Dongdong Zhou
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Zhiyun Yang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China.
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10
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Soliman M, Guys N, Liu P, Moshiri M, Menias CO, Mellnick VM, Savas H, Badawy M, Elsayes KM, Gaballah AH. Multimodality imaging findings of infection-induced tumors. ABDOMINAL RADIOLOGY (NEW YORK) 2022; 47:3930-3953. [PMID: 36069914 DOI: 10.1007/s00261-022-03651-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/06/2022] [Accepted: 08/09/2022] [Indexed: 01/18/2023]
Abstract
Several infections can predispose to certain malignancies in different body parts. These infections include viral, bacterial, and fungal pathogens. Imaging plays a vital role in the diagnosis, staging, and management of these neoplastic conditions. Furthermore, it can help in differentiating infection-related non-neoplastic processes that can mimic malignancies. Both radiologists and clinicians should be familiar with these conditions. This review discusses the epidemiology, pathogenesis, and imaging features of infection-related tumors.
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Affiliation(s)
- Moataz Soliman
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Nicholas Guys
- Department of Diagnostic Radiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Peter Liu
- Department of Radiology, Cleveland Clinic, Cleveland, OH, USA
| | - Mariam Moshiri
- Department of Diagnostic Radiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Vincent M Mellnick
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Hatice Savas
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | | | - Ayman H Gaballah
- Department of Diagnostic Radiology, University of Missouri, Columbia, MO, USA.
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11
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Dieterich D, Graham C, Wang S, Kwo P, Lim YS, Liu CJ, Agarwal K, Sulkowski M. It Is Time for a Simplified Approach to Hepatitis B Elimination. GASTRO HEP ADVANCES 2022; 2:209-218. [PMID: 39132618 PMCID: PMC11307636 DOI: 10.1016/j.gastha.2022.10.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 10/04/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Hepatitis B virus (HBV) infection continues to threaten millions of lives across the globe, despite universal vaccination efforts. Current guidelines for screening, vaccination, and treatment are complex and have left too many people undiagnosed or improperly managed. Antiviral therapy has been shown to significantly reduce the incidence of liver-related complications, including liver cancer. However, the complexity of existing guidelines can make it difficult to identify which patients to target for treatment, and recommendations that are difficult to implement in real-world settings pose a barrier to eligible patients to receive therapy and contribute to health disparities in HBV care. The goal of this global expert panel was to gain consensus on a streamlined approach to HBV care to facilitate implementation of HBV intervention and treatment, especially in the primary care setting. Methods A group of 8 liver and infectious disease specialists attended a meeting in January 2021 with the objective of gaining consensus on a streamlined algorithm for HBV care that would encourage implementation of HBV intervention and treatment. Results We have created a comprehensive perspective highlighting screening optimization, diagnostic workup, treatment, and monitoring. This treatment algorithm is designed to provide a streamlined visual pathway for risk stratification and management of patients with HBV that can be adapted in various care settings. Conclusion Simplification of guidelines will be critical to achieving health equity to address this public health threat and achieve HBV elimination.
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Affiliation(s)
- Douglas Dieterich
- Division of Liver Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Camilla Graham
- Division of Infectious Disease, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Su Wang
- Center for Asian Health, Saint Barnabas Medical Center, RWJ Barnabas Health, Florham Park, New Jersey
| | - Paul Kwo
- Department of Gastroenterology and Hepatology, Stanford Medical Center, Pleasanton, California
| | - Young-Suk Lim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chun-Jen Liu
- Department of Internal Medicine and Hepatitis Research Center at the National Taiwan University Hospital, Taipei, Taiwan
| | - Kosh Agarwal
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, England
| | - Mark Sulkowski
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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12
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Xia S, Ding J, Zhang Z, Li X, Gan J, He X. Cluster of Differentiation 24 Polymorphism Has No Significant Association with Chronic Hepatitis B Virus Infection in the Chinese Han Population: A Family-Based Association Study. Infect Drug Resist 2022; 15:4837-4843. [PMID: 36043159 PMCID: PMC9420416 DOI: 10.2147/idr.s368392] [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: 03/30/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
Objective Studies have shown that cluster of differentiation (CD) 24 gene polymorphism is associated with several diseases. Among these, chronic hepatitis B (CHB) infection has not been investigated. This study aimed to assess the function of CD24 in CHB. Methods The study included 478 cases of CHB and 318 cases without CHB from 230 families that underwent genotyping. Polymerase chain reaction-restriction fragment length polymorphism was performed to assess the single nucleotide polymorphism (SNP) P170 of the CD24 gene. The detected genotypes were TT, CT, and CC. Then, family based-association analysis was carried out to investigate the association between CD24 gene polymorphism and susceptibility to CHB. Results In the 478 patients with CHB, the frequencies of CD24 P170 T and C alleles were 35.5% and 64.5%, respectively, and the frequencies of CD24 P170 CC, CT, and TT genotypes were 39.3%, 50.4% and 10.3%, respectively. In a CD24 single-locus analysis by a family-based association test of P170 polymorphisms, T and C were not significantly associated with CHB in the additive (Z = 0.169, P = 0.866; Z = −0.169, P = 0.866, respectively), dominant (Z = 0.522, P = 0.602; Z = 0.428, P = 0.669, respectively), or recessive (Z = −0.428, P = 0.669; Z = −0.522, P = 0.602, respectively) models. Transmission-disequilibrium (TD) and sib-transmission disequilibrium (STD) tests revealed no excess of T or C alleles from heterozygous parents to their children with the disease or higher frequencies of these alleles in patients compared with their normal siblings (χ2 = 0.06, P = 0.897). Conclusion The study findings suggest that the SNP P170 of CD24 has no significant association with susceptibility to the HB virus and related phenotypes in Chinese patients.
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Affiliation(s)
- Shulin Xia
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.,Department of Infectious Disease, Affiliated Taixing People's Hospital of Yangzhou University, Taixing, People's Republic of China
| | - Jiachen Ding
- Department of Infectious Disease, Affiliated Taixing People's Hospital of Yangzhou University, Taixing, People's Republic of China
| | - Zhenhua Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei, 230000, People's Republic of China
| | - Xu Li
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei, 230000, People's Republic of China
| | - Jianhe Gan
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China
| | - Xiaomin He
- Department of Infectious Disease, Affiliated Taixing People's Hospital of Yangzhou University, Taixing, People's Republic of China
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13
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Wei F, Cheng XX, Xue JZ, Xue SA. Emerging Strategies in TCR-Engineered T Cells. Front Immunol 2022; 13:850358. [PMID: 35432319 PMCID: PMC9006933 DOI: 10.3389/fimmu.2022.850358] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/03/2022] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy of cancer has made tremendous progress in recent years, as demonstrated by the remarkable clinical responses obtained from adoptive cell transfer (ACT) of patient-derived tumor infiltrating lymphocytes, chimeric antigen receptor (CAR)-modified T cells (CAR-T) and T cell receptor (TCR)-engineered T cells (TCR-T). TCR-T uses specific TCRS optimized for tumor engagement and can recognize epitopes derived from both cell-surface and intracellular targets, including tumor-associated antigens, cancer germline antigens, viral oncoproteins, and tumor-specific neoantigens (neoAgs) that are largely sequestered in the cytoplasm and nucleus of tumor cells. Moreover, as TCRS are naturally developed for sensitive antigen detection, they are able to recognize epitopes at far lower concentrations than required for CAR-T activation. Therefore, TCR-T holds great promise for the treatment of human cancers. In this focused review, we summarize basic, translational, and clinical insights into the challenges and opportunities of TCR-T. We review emerging strategies used in current ACT, point out limitations, and propose possible solutions. We highlight the importance of targeting tumor-specific neoAgs and outline a strategy of combining neoAg vaccines, checkpoint blockade therapy, and adoptive transfer of neoAg-specific TCR-T to produce a truly tumor-specific therapy, which is able to penetrate into solid tumors and resist the immunosuppressive tumor microenvironment. We believe such a combination approach should lead to a significant improvement in cancer immunotherapies, especially for solid tumors, and may provide a general strategy for the eradication of multiple cancers.
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Affiliation(s)
- Fang Wei
- Genetic Engineering Laboratory, School of Biological & Environmental Engineering, Xi'An University, Xi'An, China
| | - Xiao-Xia Cheng
- Genetic Engineering Laboratory, School of Biological & Environmental Engineering, Xi'An University, Xi'An, China
| | - John Zhao Xue
- Genetic Engineering Laboratory, School of Biological & Environmental Engineering, Xi'An University, Xi'An, China
| | - Shao-An Xue
- Genetic Engineering Laboratory, School of Biological & Environmental Engineering, Xi'An University, Xi'An, China
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14
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OUP accepted manuscript. J Antimicrob Chemother 2022; 77:2120-2124. [DOI: 10.1093/jac/dkac148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 04/12/2022] [Indexed: 11/15/2022] Open
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15
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Hepatitis B virus small envelope protein promotes HCC angiogenesis via ER stress signaling to upregulate VEGFA expression. J Virol 2021; 96:e0197521. [PMID: 34910612 DOI: 10.1128/jvi.01975-21] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular tumor and accumulating evidence has indicated that stimulation of angiogenesis by HBV may contribute to HCC malignancy. The small protein of hepatitis B virus surface antigen (HBsAg), SHBs, is the most abundant HBV viral protein and has a close clinical association with HCC, however, whether SHBs contributes to HCC angiogenesis remains unknown. This study reports that forced expression of SHBs in HCC cells promoted xenograft tumor growth and increased the microvessel density (MVD) within the tumors. Consistently, HBsAg was also positively correlated with MVD count in HCC patients' specimens. The conditioned media from the SHBs-transfected HCC cells increased the capillary tube formation and migration of human umbilical vein endothelial cells (HUVECs). Intriguingly, overexpression of SHBs increased VEGFA expression at both mRNA and protein levels. A higher VEGFA expression level was also observed in the xenograft tumors transplanted with SHBs-expressing HCC cells and in HBsAg-positive HCC tumor tissues as compared to their negative controls. As expected, in the culture supernatants, the secretion of VEGFA was also significantly enhanced from HCC cells expressing SHBs, which promoted HUVECs migration and vessel formation. Furthermore, all the three unfolded protein response (UPR) sensors IRE1α, PERK and ATF6 associated with endoplasmic reticulum (ER) stress were found activated in the SHBs-expressing cells and correlated with VEGFA protein expression and secretion. Taken together, these results suggest an important role of SHBs in HCC angiogenesis and may highlight a potential target for preventive and therapeutic intervention of HBV-related HCC and its malignant progression. IMPORTANCE Chronic hepatitis B virus infection is one of the important risk factors for the development and progression of hepatocellular carcinoma (HCC). HCC is characteristic of hypervascularization even at early phases of the disease due to overexpression of angiogenic factors like vascular endothelial growth factor-A (VEGFA). However, a detailed mechanism in the HBV-induced angiogenesis remains to be established. In this study, we demonstrate for the first time that the most abundant HBV viral protein, i.e. small surface antigens (SHBs) can enhance the angiogenic capacity of HCC cells by upregulation of VEGFA expression both in vitro and in vivo. Mechanistically, SHBs induced endoplasmic reticulum (ER) stress which consequently activated unfolded protein response (UPR) signaling to increase VEGFA expression and secretion. This study suggests that SHBs plays an important pro-angiogenic role in HBV-associated HCC and may represent a potential target for anti-angiogenic therapy in the HCC.
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16
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More DNA and RNA of HBV SP1 splice variants are detected in genotypes B and C at low viral replication. Sci Rep 2021; 11:23838. [PMID: 34903774 PMCID: PMC8668879 DOI: 10.1038/s41598-021-03304-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 11/29/2021] [Indexed: 12/13/2022] Open
Abstract
HBV produces unspliced and spliced RNAs during replication. Encapsidated spliced RNA is converted into DNA generating defective virions that are detected in plasma and associated with HCC development. Herein we describe a quantitative real-time PCR detection of splice variant SP1 DNA/RNA in HBV plasma. Three PCR primers/probe sets were designed detecting the SP1 variants, unspliced core, or X gene. Plasmids carrying the three regions were constructed for the nine HBV genotypes to evaluate the three sets, which were also tested on DNA/RNA extracted from 193 HBV plasma with unknown HCC status. The assay had an LOD of 80 copies/ml and was equally efficient for detecting all nine genotypes and three targets. In testing 84 specimens for both SP1 DNA (77.4%) and RNA (82.1%), higher viral loads resulted in increased SP1 levels. Most samples yielded < 1% of SP1 DNA, while the average SP1 RNA was 3.29%. At viral load of ≤ 5 log copies/ml, the detectable SP1 DNA varied by genotype, with 70% for B, 33.3% for C, 10.5% for E, 4% for D and 0% for A, suggesting higher levels of splicing in B and C during low replication. At > 5 log, all samples regardless of genotype had detectable SP1 DNA.
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Roberts SK, Majeed A, Kemp W. Controversies in the Management of Hepatitis B: Hepatocellular Carcinoma. Clin Liver Dis 2021; 25:785-803. [PMID: 34593153 DOI: 10.1016/j.cld.2021.06.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis B is the leading cause of hepatocellular cancer (HCC) worldwide. Untreated, annual HCC incidence rates in chronic hepatitis B subjects are 0.4% in noncirrhotics and 2% to 3% in cirrhotics. Surveillance with ultrasound with/without α-fetoprotein at 6-month intervals is recommended in at-risk persons including children. Antiviral therapy in chronic hepatitis B with entecavir or tenofovir significantly lowers the risk of HCC across all stages of liver disease, and lowers the risk of HCC recurrence following curative therapy. There are insufficient data to recommend use of tenofovir over entecavir in the prevention of de novo or recurrent HCC postcurative therapy.
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Affiliation(s)
- Stuart K Roberts
- The Alfred, 55 Commercial Road, Melbourne 3004, Australia; Monash University, Melbourne, Australia.
| | - Ammar Majeed
- The Alfred, 55 Commercial Road, Melbourne 3004, Australia; Monash University, Melbourne, Australia
| | - William Kemp
- The Alfred, 55 Commercial Road, Melbourne 3004, Australia; Monash University, Melbourne, Australia
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18
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Ghaderi-Zefrehi H, Rezaei M, Sadeghi F, Heiat M. Genetic polymorphisms in DNA repair genes and hepatocellular carcinoma risk. DNA Repair (Amst) 2021; 107:103196. [PMID: 34416543 DOI: 10.1016/j.dnarep.2021.103196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 05/23/2021] [Accepted: 07/26/2021] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent types of tumors worldwide. Its occurrence and development have been related to various risk factors, such as chronic infection with hepatitis B or C viruses and alcohol addiction. DNA repair systems play a critical role in maintaining the integrity of the genome. Defects in these systems have been related to increased susceptibility to various types of cancer. Multiple genetic polymorphisms in genes of DNA repair systems have been reported that may affect DNA repair capacity (DRC) and modulate risk to cancer. Several studies have been conducted to assess the role of polymorphisms of DNA repair genes on the HCC risk. Identifying these polymorphisms and their association with HCC risk may help to improve prevention and treatment strategies. In this study, we review investigations that evaluated the association between genetic polymorphisms of DNA repair genes and risk of HCC.
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Affiliation(s)
- Hossein Ghaderi-Zefrehi
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Maryam Rezaei
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Farzin Sadeghi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Qi W, Shen J, Dai J, Wu Y, Zhang Y, Leng S, Gao F, Ran S, Peng W, Zhang X, Wen T, Li C. Comparison of nucleoside and nucleotide analogs in the recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection: A multicenter study. Cancer Med 2021; 10:8421-8431. [PMID: 34643050 PMCID: PMC8633233 DOI: 10.1002/cam4.4348] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/31/2021] [Accepted: 09/07/2021] [Indexed: 02/05/2023] Open
Abstract
Background Antiviral therapy should reduce the recurrence of hepatitis B virus‐related hepatocellular carcinoma (HBV‐related HCC) after surgical resection. However, there is little research on whether various antiviral drugs have different prognostic effects in patients with HBV‐related HCC after curative liver resection. The present study compared the effects of nucleotide analog (NtA) and nucleoside analog (NsA) antiviral therapies after surgical resection on the prognosis of HBV‐related HCC. Methods A total of 1303 patients with HBV‐related HCC who received curative hepatectomy at five institutes between April 2014 and April 2019 were retrospectively enrolled and analyzed. Propensity matching analysis was used to compare the outcomes of HCC patients given NsA versus NtA therapy. Subgroup analysis of patients treated with entecavir (ETV) and tenofovir disoproxil fumarate (TDF) was also performed. Results Among 1303 patients, 759 (58.2%) patients developed recurrence, and 460 (35.3%) patients died. Multivariable analyses revealed that NtA therapy significantly decreased the risk of HCC recurrence (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.51–0.80; p < 0.001) and HCC‐related death (HR, 0.52; 95% CI, 0.36–0.76; p = 0.001) compared to that with NsA therapy. Subgroup analysis showed that TDF treatment was associated with significantly lower rates of HCC recurrence (HR, 0.64; 95% CI, 0.49–0.83; p = 0.001) and death (HR, 0.32; 95% CI, 0.20–0.50; p < 0.001) than ETV treatment. Conclusions Nucleotide analog treatment, but not NsA treatment, significantly reduced the risk of HCC recurrence in patients with HBV‐related HCC and improved overall survival after curative hepatic resection.
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Affiliation(s)
- Weili Qi
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Junyi Shen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Junlong Dai
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Youwei Wu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yu Zhang
- Organ Transplantation Center, Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Shusheng Leng
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Fengwei Gao
- HBPS Diseases Center for Diagnosis and Treatment of Leshan City, People's Hospital of Leshan, Leshan, Sichuan, China
| | - Shun Ran
- Department of Hepatopancreatobiliary Surgery, Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Wei Peng
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xiaoyun Zhang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Tianfu Wen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Chuan Li
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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20
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Different Risk Factors for Early and Late Recurrence After Curative Resection of Hepatocellular Carcinoma. World J Surg 2021; 46:197-206. [PMID: 34533588 DOI: 10.1007/s00268-021-06308-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Factors of early and late recurrence after curative resection of hepatocellular carcinoma (HCC) may be different. The aim of this study was to identify clinical factors, including liver stiffness measurement (LSM), which are associated with HCC recurrence after curative resection. METHODS Patients who underwent preoperative LSM and primary curative resection for HCC between October 2015 and May 2018 were retrospectively reviewed, with 1 year as the cut-off between early and late recurrence. RESULTS Recurrence was observed in 42/149 (28.2%) patients over a median follow-up of 38.3 months (early recurrence: 10 [6.7%] patients; late recurrence: 32 [21.5%] patients). Multivariate analysis identified LSM (P = 0.026) and tumor size (P = 0.010) as the only factors that were significantly associated with recurrence-free survival. Compared with patients without recurrence, those with early recurrence had larger tumor size (P = 0.035) and those with late recurrence had higher LSM (P = 0.024). Receiver-operating characteristic analysis indicated that the optimal LSM cut-off value for predicting HCC recurrence was 7.4 kPa. CONCLUSION Tumor size was associated with early HCC recurrence after curative resection and LSM was associated with late recurrence. LSM cut-off of 7.4 kPa is recommended in predicting recurrence.
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21
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He G, Ding J, Zhang Y, Cai M, Yang J, Cho WC, Zheng Y. microRNA-21: a key modulator in oncogenic viral infections. RNA Biol 2021; 18:809-817. [PMID: 33499700 DOI: 10.1080/15476286.2021.1880756] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Oncogenic viruses are associated with approximately 15% of human cancers. In viral infections, microRNAs play an important role in host-pathogen interactions. miR-21 is a highly conserved non-coding RNA that not only regulates the development of oncogenic viral diseases, but also responds to the regulation of intracellular signal pathways. Oncogenic viruses, including HBV, HCV, HPV, and EBV, co-evolve with their hosts and cause persistent infections. The upregulation of host miR-21 manipulates key cellular pathways to evade host immune responses and then promote viral replication. Thus, a better understanding of the role of miR-21 in viral infections may help us to develop effective genetically-engineered oncolytic virus-based therapies against cancer.
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Affiliation(s)
- Guitian He
- State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China
| | - Juntao Ding
- College of Life Science and Technology, College of Life Science and Technology, Xinjiang University, Urumqi, China
| | - Yong'e Zhang
- State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China
| | - Mengting Cai
- State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China
| | - Jing Yang
- State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
| | - Yadong Zheng
- State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou China
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22
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Cancer Vaccines: Antigen Selection Strategy. Vaccines (Basel) 2021; 9:vaccines9020085. [PMID: 33503926 PMCID: PMC7911511 DOI: 10.3390/vaccines9020085] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 02/06/2023] Open
Abstract
Unlike traditional cancer therapies, cancer vaccines (CVs) harness a high specificity of the host’s immunity to kill tumor cells. CVs can train and bolster the patient’s immune system to recognize and eliminate malignant cells by enhancing immune cells’ identification of antigens expressed on cancer cells. Various features of antigens like immunogenicity and avidity influence the efficacy of CVs. Therefore, the choice and application of antigens play a critical role in establishing and developing CVs. Tumor-associated antigens (TAAs), a group of proteins expressed at elevated levels in tumor cells but lower levels in healthy normal cells, have been well-studied and developed in CVs. However, immunological tolerance, HLA restriction, and adverse events are major obstacles that threaten TAA-based CVs’ efficacy due to the “self-protein” characteristic of TAAs. As “abnormal proteins” that are completely absent from normal cells, tumor-specific antigens (TSAs) can trigger a robust immune response against tumor cells with high specificity and without going through central tolerance, contributing to cancer vaccine development feasibility. In this review, we focus on the unique features of TAAs and TSAs and their application in vaccines, summarizing their performance in preclinical and clinical trials.
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23
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Risk Factors and Biomarkers for Chronic Hepatitis B Associated Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22020479. [PMID: 33418899 PMCID: PMC7825109 DOI: 10.3390/ijms22020479] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/21/2020] [Accepted: 12/28/2020] [Indexed: 02/08/2023] Open
Abstract
Globally, hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality. This is, in part, due to delayed diagnosis and limited therapeutic options with more advanced stages of the disease. Given the prognostic importance of early diagnosis, novel methods for early detection are in need. Unlike most other cancer types, tissue is not required to diagnose HCC and is frequently avoided given the inherent risks of liver biopsy, so less invasive methods of obtaining tumor material are currently under investigation. Material shed from tumors into the periphery are being investigated for their potential to both surveil and diagnose patients for HCC. These materials include circulating tumor cells, DNA, RNA, and exosomes, and are collectively termed a “liquid biopsy”. In this review article, we discuss the evolving literature regarding the different risk factors for HCC and the types of emerging novel biomarkers that show promise in the prevention and early diagnosis of HCC within the context of HBV infection.
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24
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Liu Y, Zhao ZH, Lv XQ, Tang YW, Cao M, Xiang Q, Wu Y, Zhang HT, Lai GQ. Precise analysis of the effect of basal core promoter/precore mutations on the main phenotype of chronic hepatitis B in mouse models. J Med Virol 2020; 92:3412-3419. [PMID: 32427358 DOI: 10.1002/jmv.26025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/27/2020] [Accepted: 05/14/2020] [Indexed: 12/14/2022]
Abstract
High replication and mutation rates of hepatitis B virus (HBV) often lead to reduced or suppressed hepatitis B e antigen expression. The most common mutations are genomic variations in the basal core promoter (BCP) and pre-core (PC) regions. However, the effect of BCP/PC mutations on HBV phenotype in vivo remains unclear. We compared and analyzed BCP/PC mutations and BCP/PC reverse mutations in mouse models. In addition to terminating the expression of HBeAg, BCP/PC mutations also resulted in a significant decrease in HBsAg, HBV DNA, and cccDNA in the early stage, and an obvious increase in serum alanine aminotransferase throughout the transfection period. In both groups, serum HBV DNA was positively correlated with intracellular HBV DNA and cccDNA. Further, we found that interleukin-4 (IL-4) and L-10 levels were significantly lower in the BCP/PC(M) group than in the BCP/PC(R) group at 4 weeks post-injection. However, IL-1β was significantly lower in the BCP/PC(M) group than in the BCP/PC(R) group at 26 weeks post-injection. In summary, we precisely analyzed the effect of BCP/PC mutations on the phenotype in vivo, which is important to evaluating disease progression and treatment responses of variable chronic hepatitis B patients.
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Affiliation(s)
- Yang Liu
- Laboratory Animal Center, Chongqing Medical University, Chongqing, China
| | - Zhong Hua Zhao
- Center for Biomedical and Device Research, Chongqing Academy of Science and Technology, Chongqing, China
| | - Xiao Qin Lv
- Laboratory Animal Center, Chongqing Medical University, Chongqing, China
| | - Yu Wei Tang
- Center for Biomedical and Device Research, Chongqing Academy of Science and Technology, Chongqing, China
| | - Min Cao
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Qin Xiang
- Laboratory Animal Center, Chongqing Medical University, Chongqing, China
| | - Yue Wu
- Hepatological Surgery Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hua Tang Zhang
- Center for Biomedical and Device Research, Chongqing Academy of Science and Technology, Chongqing, China
| | - Guo Qi Lai
- Laboratory Animal Center, Chongqing Medical University, Chongqing, China
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25
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Cancer Patients Have a Higher Risk Regarding COVID-19 - and Vice Versa? Pharmaceuticals (Basel) 2020; 13:ph13070143. [PMID: 32640723 PMCID: PMC7408191 DOI: 10.3390/ph13070143] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/24/2020] [Accepted: 07/03/2020] [Indexed: 02/06/2023] Open
Abstract
The world is currently suffering from a pandemic which has claimed the lives of over 230,000 people to date. The responsible virus is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and causes the coronavirus disease 2019 (COVID-19), which is mainly characterized by fever, cough and shortness of breath. In severe cases, the disease can lead to respiratory distress syndrome and septic shock, which are mostly fatal for the patient. The severity of disease progression was hypothesized to be related to an overshooting immune response and was correlated with age and comorbidities, including cancer. A lot of research has lately been focused on the pathogenesis and acute consequences of COVID-19. However, the possibility of long-term consequences caused by viral infections which has been shown for other viruses are not to be neglected. In this regard, this opinion discusses the interplay of SARS-CoV-2 infection and cancer with special focus on the inflammatory immune response and tissue damage caused by infection. We summarize the available literature on COVID-19 suggesting an increased risk for severe disease progression in cancer patients, and we discuss the possibility that SARS-CoV-2 could contribute to cancer development. We offer lines of thought to provide ideas for urgently needed studies on the potential long-term effects of SARS-CoV-2 infection.
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26
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Niedźwiedzka-Rystwej P, Grywalska E, Hrynkiewicz R, Wołącewicz M, Becht R, Roliński J. The Double-Edged Sword Role of Viruses in Gastric Cancer. Cancers (Basel) 2020; 12:cancers12061680. [PMID: 32599870 PMCID: PMC7352989 DOI: 10.3390/cancers12061680] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 06/14/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
Due to its high morbidity and mortality, gastric cancer is a topic of a great concern throughout the world. Major ways of treatment are gastrectomy and chemotherapy, unfortunately they are not always successful. In a search for more efficient therapy strategies, viruses and their potential seem to be an important issue. On one hand, several oncogenic viruses have been noticed in the case of gastric cancer, making the positive treatment even more advantageous, but on the other, viruses exist with a potential therapeutic role in this malignancy.
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Affiliation(s)
- Paulina Niedźwiedzka-Rystwej
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
- Correspondence:
| | - Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (E.G.); (J.R.)
| | - Rafał Hrynkiewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
| | - Mikołaj Wołącewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
| | - Rafał Becht
- Clinical Department of Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University of Szczecin, 70-204 Szczecin, Poland;
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (E.G.); (J.R.)
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27
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He Z, Zhu J, Mo J, Zhao H, Chen Q. HBV DNA integrates into upregulated ZBTB20 in patients with hepatocellular carcinoma. Mol Med Rep 2020; 22:380-386. [PMID: 32319639 PMCID: PMC7248478 DOI: 10.3892/mmr.2020.11074] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 03/18/2020] [Indexed: 12/27/2022] Open
Abstract
Hepatitis B virus (HBV) affects the malignant phenotype of hepatocellular carcinoma (HCC). The aim of the present study was to investigate the integration sites of HBV DNA and the expression of the zinc finger protein, zinc finger and BTB domain containing 20 (ZBTB20) in patients with hepatocellular carcinoma. Integration of the HBV gene was detected using a high-throughput sequencing technique based on the HBV-Alu-PCR method. The expression of ZBTB20 was detected by western blotting. HBVX integration sites were detected in ~70% of the HCC tissue samples. HBV-integrated subgene X detection suggested that 67% of the integrated specimens were inserted into the host X gene in a forward direction, 57% in a reverse direction, 24% in both forward and reverse directions, and 38% had two HBV integration sites. A total of 3,320 HBV integration sites were identified, including 1,397 in HCC tissues, 1,205 in paracancerous tissues and 718 in normal liver tissues. HBV integration fragments displayed enrichment in the 200–800 bp region. Additionally, the results suggested that HBV was highly integrated into transmembrane phosphatase with tensin homology, long intergenic non-protein coding RNA (LINC)00618, LOC101929241, ACTR3 pseudogene 5, LINC00999, LOC101928775, deleted in oesophageal cancer 1, LINC00824, EBF transcription factor 2 and ZBTB20 in tumour tissues. Furthermore, the expression of ZBTB20 was upregulated in HCC tissues compared with normal control liver tissues, and was associated with HBV integration frequency. The present study suggested that HBV DNA integrated into upregulated ZBTB20 in patients with hepatocellular carcinoma, which might promote the occurrence and development of HCC. Furthermore, the results of the present study may provide a theoretical basis for the diagnosis and treatment of HCC.
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Affiliation(s)
- Zebao He
- Department of Neurology, Taizhou Enze Medical Center Enze Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Jiansheng Zhu
- Department of Neurology, Taizhou Enze Medical Center Enze Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Jinggang Mo
- Department of Neurology, Taizhou Central Hospital, Taizhou University Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Haihong Zhao
- Department of Neurology, Taizhou Enze Medical Center Enze Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Qiuyue Chen
- Department of Neurology, Taizhou Central Hospital, Taizhou University Hospital, Taizhou, Zhejiang 318000, P.R. China
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28
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Dandri M. Epigenetic modulation in chronic hepatitis B virus infection. Semin Immunopathol 2020; 42:173-185. [PMID: 32185454 PMCID: PMC7174266 DOI: 10.1007/s00281-020-00780-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 01/08/2020] [Indexed: 02/06/2023]
Abstract
The human hepatitis B virus (HBV) is a small-enveloped DNA virus causing acute and chronic hepatitis. Despite the existence of an effective prophylactic vaccine and the strong capacity of approved antiviral drugs to suppress viral replication, chronic HBV infection (CHB) continues to be a major health burden worldwide. Both the inability of the immune system to resolve CHB and the unique replication strategy employed by HBV, which forms a stable viral covalently closed circular DNA (cccDNA) minichromosome in the hepatocyte nucleus, enable infection persistence. Knowledge of the complex network of interactions that HBV engages with its host is still limited but accumulating evidence indicates that epigenetic modifications occurring both on the cccDNA and on the host genome in the course of infection are essential to modulate viral activity and likely contribute to pathogenesis and cancer development. Thus, a deeper understanding of epigenetic regulatory processes may open new venues to control and eventually cure CHB. This review summarizes major findings in HBV epigenetic research, focusing on the epigenetic mechanisms regulating cccDNA activity and the modifications determined in infected host cells and tumor liver tissues.
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Affiliation(s)
- Maura Dandri
- I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, Hamburg, Germany.
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29
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Sinha M, Sundar K, Premalata CS, Asati V, Murali A, Bajpai AK, Davuluri S, Acharya KK, Lakshmaiah KC, Babu K G, Jacob LA, Nandan D, Velayutham D, Datta S, Jayshree RS. Pro-oncogenic, intra host viral quasispecies in Diffuse large B cell lymphoma patients with occult Hepatitis B Virus infection. Sci Rep 2019; 9:14516. [PMID: 31601912 PMCID: PMC6787061 DOI: 10.1038/s41598-019-51157-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 09/26/2019] [Indexed: 02/08/2023] Open
Abstract
Non Hodgkin lymphoma, predominantly Diffuse Large B-cell Lymphoma (DLBCL) has been reported to have a significant association with Hepatitis B virus (HBV). We investigated the presence of different gene segments of HBV in plasma, B-cells and tumor tissues from DLBCL patients and explored the genetic variability of HBV within and across different compartments in a host using Next Generation Sequencing. Despite all 40 patients being HBV seronegative, 68% showed evidence of occult HBV. Sequencing of these gene segments revealed inter-compartment viral variants in 26% of them, each with at least one non-synonymous mutation. Between compartments, core gene variants revealed Arg94Leu, Glu86Arg and Ser41Thr while X gene variants revealed Phe73Val, Ala44Val, Ser146Ala and Ser147Pro. In tumor compartments per se, several mis-sense mutations were detected, notably the classic T1762A/A1764G mutation in the basal core promoter. In addition, a virus surface antigen mis-sense mutation resulting in M125T was detected in all the samples and could account for surface antigen negativity and occult HBV status. It would be interesting to further explore if a temporal accumulation of viral variants within a favored niche, like patients’ lymphocytes, could bestow survival advantage to the virus, and if certain pro-oncogenic HBV variants could drive lymphomagenesis in DLBCL.
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Affiliation(s)
- Mahua Sinha
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India.
| | - Keerthana Sundar
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India
| | - C S Premalata
- Department of Pathology, Kidwai Cancer Institute, Bengaluru, India
| | - Vikas Asati
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | - Alka Murali
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India.,Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru, India
| | | | | | - Kshitish K Acharya
- Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru, India.,Shodhaka Life Sciences Pvt. Ltd., Bengaluru, India
| | - K C Lakshmaiah
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | - Govind Babu K
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | - Linu A Jacob
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | | | | | - Sibnarayan Datta
- Molecular Virology Laboratory, Defence Research Laboratory, Tezpur, Assam, India
| | - R S Jayshree
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India
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30
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Bender D, Hildt E. Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis. Int J Mol Sci 2019; 20:ijms20184659. [PMID: 31546975 PMCID: PMC6769940 DOI: 10.3390/ijms20184659] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open
Abstract
With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). For both viruses chronic infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) play a central role in a variety of chronic inflammatory diseases. In light of this, this review summarizes the impact of both viruses on ROS-generating and ROS-inactivating mechanisms. The focus is on the effect of both viruses on the transcription factor Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2). By binding to its target sequence, the antioxidant response element (ARE), Nrf2 triggers the expression of a variety of cytoprotective genes including ROS-detoxifying enzymes. The review summarizes the literature about the pathways for the modulation of Nrf2 that are deregulated by HBV and HCV and describes the impact of Nrf2 deregulation on the viral life cycle of the respective viruses and the virus-associated pathogenesis.
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Affiliation(s)
- Daniela Bender
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straβe 51-59, D-63225 Langen, Germany.
| | - Eberhard Hildt
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straβe 51-59, D-63225 Langen, Germany.
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31
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Jin XL, Hong SK, Kim H, Lee SK, Yi NJ, Lee KW, Suh KS. Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis. Oncol Lett 2019; 18:4984-4991. [PMID: 31612010 DOI: 10.3892/ol.2019.10833] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 07/18/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC). Covalently closed circular DNA (cccDNA) is an intermediate in the life cycle of HBV. HBV-encoded X protein (HBx), a key viral oncoprotein, can be specifically ubiquitylated by male specific lethal 2 (MSL2), which causes upregulation of HBx activity and promotes transcription, cell proliferation and tumor growth. The present study compared the levels of cccDNA, MSL2 mRNA and HBx mRNA in tumor and peri-tumor tissues, and clarified the effect of antiviral therapy on these indicators. Levels of intrahepatic cccDNA, MSL2 mRNA and HBx mRNA were determined using quantitative PCR in patients with HBV-associated HCC who had undergone liver surgery. A total of 50 patients were included in the present study. Prior to surgery, 31 patients had undergone antiviral treatment. Intrahepatic cccDNA levels were significantly higher in the tumor tissues compared with the peri-tumor tissues (P=0.001), particularly in the hepatitis B e antigen-positive (P=0.008), tumor recurrence (P=0.002) and <3 cm tumor size (P=0.003) groups. Furthermore, in patients with preoperative cirrhosis, levels of cccDNA and MSL2 mRNA were significantly higher in tumor tissues compared with that in peri-tumor tissues (P<0.001 and P=0.023, respectively). The expression levels of HBx mRNA in antiviral-treated tumors and peri-tumor tissues were significantly lower compared with those in untreated tissues (P=0.026 and P=0.035). The levels of cccDNA and MSL2 mRNA in the HBx-positive group were significantly higher in tumor tissues compared with those in peri-tumor tissues (P=0.026 and P=0.013). In conclusion, cccDNA participated in the tumorigenesis of HBV-associated HCC, and antiviral therapy was found to modulate hepatocarcinogenesis by decreasing the levels of HBx to inhibit the tumorigenic effect of MSL2 and cccDNA.
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Affiliation(s)
- Xue-Li Jin
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Suk Kyun Hong
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Hwajung Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Sun-Kyung Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
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32
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Abdoli A, Nakhaie M, Feizi N, Salimi Jeda A, Ramezani A. Harmonized Autophagy Versus Full-Fledged Hepatitis B Virus: Victorious or Defeated. Viral Immunol 2019; 32:322-334. [PMID: 31483214 DOI: 10.1089/vim.2019.0042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Autophagy is a finely tuned process in the regulation of innate immunity to avoid excessive inflammatory responses and inflammasome signaling. In contrast, the results of recent studies have shown that autophagy may disease-dependently contribute to the pathogenesis of liver diseases, such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) during hepatitis B virus (HBV) infection. HBV has learned to subvert the cell's autophagic machinery to promote its replication. Given the great impact of the autophagy mechanism on the HBV infection and HCC, recognizing these factors may be offered new hope for human intervention and treatment of chronic HBV. This review focuses on recent findings viewing the dual role of autophagy plays in the pathogenesis of HBV infected hepatocytes.
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Affiliation(s)
- Asghar Abdoli
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
| | - Mohsen Nakhaie
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Neda Feizi
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - Ali Salimi Jeda
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amitis Ramezani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
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33
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Jin Y, Lee WY, Toh ST, Tennakoon C, Toh HC, Chow PKH, Chung AYF, Chong SS, Ooi LLPJ, Sung WK, Lee CGL. Comprehensive analysis of transcriptome profiles in hepatocellular carcinoma. J Transl Med 2019; 17:273. [PMID: 31429776 PMCID: PMC6701074 DOI: 10.1186/s12967-019-2025-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Accepted: 08/14/2019] [Indexed: 12/31/2022] Open
Abstract
Background Hepatocellular carcinoma is the second most deadly cancer with late presentation and limited treatment options, highlighting an urgent need to better understand HCC to facilitate the identification of early-stage biomarkers and uncover therapeutic targets for the development of novel therapies for HCC. Methods Deep transcriptome sequencing of tumor and paired non-tumor liver tissues was performed to comprehensively evaluate the profiles of both the host and HBV transcripts in HCC patients. Differential gene expression patterns and the dys-regulated genes associated with clinical outcomes were analyzed. Somatic mutations were identified from the sequencing data and the deleterious mutations were predicted. Lastly, human-HBV chimeric transcripts were identified, and their distribution, potential function and expression association were analyzed. Results Expression profiling identified the significantly upregulated TP73 as a nodal molecule modulating expression of apoptotic genes. Approximately 2.5% of dysregulated genes significantly correlated with HCC clinical characteristics. Of the 110 identified genes, those involved in post-translational modification, cell division and/or transcriptional regulation were upregulated, while those involved in redox reactions were downregulated in tumors of patients with poor prognosis. Mutation signature analysis identified that somatic mutations in HCC tumors were mainly non-synonymous, frequently affecting genes in the micro-environment and cancer pathways. Recurrent mutations occur mainly in ribosomal genes. The most frequently mutated genes were generally associated with a poorer clinical prognosis. Lastly, transcriptome sequencing suggest that HBV replication in the tumors of HCC patients is rare. HBV-human fusion transcripts are a common observation, with favored HBV and host insertion sites being the HBx C-terminus and gene introns (in tumors) and introns/intergenic-regions (in non-tumors), respectively. HBV-fused genes in tumors were mainly involved in RNA binding while those in non-tumors tissues varied widely. These observations suggest that while HBV may integrate randomly during chronic infection, selective expression of functional chimeric transcripts may occur during tumorigenesis. Conclusions Transcriptome sequencing of HCC patients reveals key cancer molecules and clinically relevant pathways deregulated/mutated in HCC patients and suggests that while HBV may integrate randomly during chronic infection, selective expression of functional chimeric transcripts likely occur during the process of tumorigenesis.
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Affiliation(s)
- Yu Jin
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - Wai Yeow Lee
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - Soo Ting Toh
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | | | - Han Chong Toh
- Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Level 6, Lab 5, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Pierce Kah-Hoe Chow
- Duke-NUS Medical School, Singapore, 169547, Singapore.,Department of Surgery, Singapore General Hospital, Singapore, 169608, Singapore
| | - Alexander Y-F Chung
- Department of Surgery, Singapore General Hospital, Singapore, 169608, Singapore
| | - Samuel S Chong
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.,Department of Laboratory Medicine, National University Hospital, Singapore, 119074, Singapore
| | - London L-P-J Ooi
- Department of Surgery, Singapore General Hospital, Singapore, 169608, Singapore.,Department of Surgical Oncology, National Cancer Centre Singapore, Singapore, 169610, Singapore
| | - Wing-Kin Sung
- Genome Institute of Singapore, Singapore, Singapore.,School of Computing, National University of Singapore, Singapore, Singapore
| | - Caroline G-L Lee
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore. .,Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Level 6, Lab 5, 11 Hospital Drive, Singapore, 169610, Singapore. .,Duke-NUS Medical School, Singapore, 169547, Singapore.
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Lim LJ, Wong SYS, Huang F, Lim S, Chong SS, Ooi LL, Kon OL, Lee CG. Roles and Regulation of Long Noncoding RNAs in Hepatocellular Carcinoma. Cancer Res 2019; 79:5131-5139. [PMID: 31337653 DOI: 10.1158/0008-5472.can-19-0255] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/06/2019] [Accepted: 07/19/2019] [Indexed: 01/21/2023]
Abstract
Next-generation sequencing has uncovered thousands of long noncoding RNAs (lncRNA). Many are reported to be aberrantly expressed in various cancers, including hepatocellular carcinoma (HCC), and play key roles in tumorigenesis. This review provides an in-depth discussion of the oncogenic mechanisms reported to be associated with deregulated HCC-associated lncRNAs. Transcriptional expression of lncRNAs in HCC is modulated through transcription factors, or epigenetically by aberrant histone acetylation or DNA methylation, and posttranscriptionally by lncRNA transcript stability modulated by miRNAs and RNA-binding proteins. Seventy-four deregulated lncRNAs have been identified in HCC, of which, 52 are upregulated. This review maps the oncogenic roles of these deregulated lncRNAs by integrating diverse datasets including clinicopathologic features, affected cancer phenotypes, associated miRNA and/or protein-interacting partners as well as modulated gene/protein expression. Notably, 63 deregulated lncRNAs are significantly associated with clinicopathologic features of HCC. Twenty-three deregulated lncRNAs associated with both tumor and metastatic clinical features were also tumorigenic and prometastatic in experimental models of HCC, and eight of these mapped to known cancer pathways. Fifty-two upregulated lncRNAs exhibit oncogenic properties and are associated with prominent hallmarks of cancer, whereas 22 downregulated lncRNAs have tumor-suppressive properties. Aberrantly expressed lncRNAs in HCC exert pleiotropic effects on miRNAs, mRNAs, and proteins. They affect multiple cancer phenotypes by altering miRNA and mRNA expression and stability, as well as through effects on protein expression, degradation, structure, or interactions with transcriptional regulators. Hence, these insights reveal novel lncRNAs as potential biomarkers and may enable the design of precision therapy for HCC.
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Affiliation(s)
- Lee Jin Lim
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Samuel Y S Wong
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Feiyang Huang
- NUS High School of Math and Science, Singapore, Singapore
| | - Sheng Lim
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.,Raffles Institution, Singapore, Singapore
| | - Samuel S Chong
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - London Lucien Ooi
- Duke-NUS Graduate Medical School, Singapore, Singapore.,Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Oi Lian Kon
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Caroline G Lee
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.,Duke-NUS Graduate Medical School, Singapore, Singapore.,NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
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35
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Chiu AP, Tschida BR, Sham TT, Lo LH, Moriarity BS, Li XX, Lo RC, Hinton DE, Rowlands DK, Chan CO, Mok DKW, Largaespada DA, Warner N, Keng VW. HBx-K130M/V131I Promotes Liver Cancer in Transgenic Mice via AKT/FOXO1 Signaling Pathway and Arachidonic Acid Metabolism. Mol Cancer Res 2019; 17:1582-1593. [PMID: 30975706 DOI: 10.1158/1541-7786.mcr-18-1127] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 02/18/2019] [Accepted: 04/08/2019] [Indexed: 12/20/2022]
Abstract
Chronic hepatitis B viral (HBV) infection remains a high underlying cause for hepatocellular carcinoma (HCC) worldwide, while the genetic mechanisms behind this remain unclear. This study elucidated the mechanisms contributing to tumor development induced by the HBV X (HBx) gene of predominantly Asian genotype B HBV and its common HBx variants. To compare the potential tumorigenic effects of K130M/V131I (Mut) and wild-type (WT) HBx on HCC, the Sleeping Beauty (SB) transposon system was used to deliver HBx Mut and WT into the livers of fumarylacetoacetate hydrolase (Fah)-deficient mice and in the context of transformation related protein 53 (Trp53) deficiency. From our results, HBx Mut had a stronger tumorigenic effect than its WT variant. Also, inflammation, necrosis, and fibrosis were evident in HBx experimental animals. Reduction of forkhead box O1 (FOXO1) with increased phosphorylation of upstream serine/threonine kinase (AKT) was detected under HBx Mut overexpression. Thus, it is proposed that HBx Mut enhances disease progression by reducing FOXO1 via phosphorylation of AKT. At the metabolomic level, HBx altered the expression of genes that participated in arachidonic acid (AA) metabolism, as a result of inflammation via accumulation of proinflammatory factors such as prostaglandins and leukotriene in liver. Taken together, the increased rate of HCC observed in chronic hepatitis B patients with K130M/V131I-mutated X protein, may be due to changes in AA metabolism and AKT/FOXO1 signaling. IMPLICATIONS: Our findings suggested that HBx-K130M/V131I-mutant variant promoted HCC progression by activating AKT/FOXO1 pathway and inducing stronger inflammation in liver via AA metabolism.
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Affiliation(s)
- Amy P Chiu
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.,Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Barbara R Tschida
- Center for Genome Engineering, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Tung-Ting Sham
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.,Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Lilian H Lo
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.,Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Branden S Moriarity
- Center for Genome Engineering, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Xiao-Xiao Li
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.,Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Regina C Lo
- Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - David E Hinton
- Nicholas School of the Environment, Duke University, Durham, North Carolina
| | - Dewi K Rowlands
- Laboratory Animal Services Centre, The Chinese University of Hong Kong, Sha Tin, New Territories, Hong Kong, China
| | - Chi-On Chan
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.,Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Daniel K W Mok
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.,Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - David A Largaespada
- Center for Genome Engineering, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Nadia Warner
- Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, Victoria, Australia
| | - Vincent W Keng
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China. .,Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
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37
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Meier-Stephenson V, Bremner WTR, Dalton CS, van Marle G, Coffin CS, Patel TR. Comprehensive Analysis of Hepatitis B Virus Promoter Region Mutations. Viruses 2018; 10:E603. [PMID: 30388827 PMCID: PMC6265984 DOI: 10.3390/v10110603] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 10/27/2018] [Accepted: 10/31/2018] [Indexed: 02/06/2023] Open
Abstract
Over 250 million people are infected chronically with hepatitis B virus (HBV), the leading cause of liver cancer worldwide. HBV persists, due, in part, to its compact, stable minichromosome, the covalently-closed, circular DNA (cccDNA), which resides in the hepatocytes' nuclei. Current therapies target downstream replication products, however, a true virological cure will require targeting the cccDNA. Finding targets on such a small, compact genome is challenging. For HBV, to remain replication-competent, it needs to maintain nucleotide fidelity in key regions, such as the promoter regions, to ensure that it can continue to utilize the necessary host proteins. HBVdb (HBV database) is a repository of HBV sequences spanning all genotypes (A⁻H) amplified from clinical samples, and hence implying an extensive collection of replication-competent viruses. Here, we analyzed the HBV sequences from HBVdb using bioinformatics tools to comprehensively assess the HBV core and X promoter regions amongst the nearly 70,000 HBV sequences for highly-conserved nucleotides and variant frequencies. Notably, there is a high degree of nucleotide conservation within specific segments of these promoter regions highlighting their importance in potential host protein-viral interactions and thus the virus' viability. Such findings may have key implications for designing antivirals to target these areas.
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Affiliation(s)
- Vanessa Meier-Stephenson
- Department of Microbiology, Immunology and Infectious Diseases, Cumming, School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
- Alberta RNA Research & Training Institute, Department of Chemistry & Biochemistry, University of Lethbridge, Lethbridge, Alberta, T1K 3M4, Canada.
| | - William T R Bremner
- Department of Ecosystem & Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
| | - Chimone S Dalton
- Department of Ecosystem & Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
| | - Guido van Marle
- Department of Microbiology, Immunology and Infectious Diseases, Cumming, School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
| | - Carla S Coffin
- Department of Microbiology, Immunology and Infectious Diseases, Cumming, School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Calgary, AB T2N 4Z6, Canada.
| | - Trushar R Patel
- Department of Microbiology, Immunology and Infectious Diseases, Cumming, School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
- Alberta RNA Research & Training Institute, Department of Chemistry & Biochemistry, University of Lethbridge, Lethbridge, Alberta, T1K 3M4, Canada.
- DiscoveryLab, Faculty of Medicine & Dentistry, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2H7, Canada.
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38
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Therapeutic Modulation of Virus-Induced Oxidative Stress via the Nrf2-Dependent Antioxidative Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:6208067. [PMID: 30515256 PMCID: PMC6234444 DOI: 10.1155/2018/6208067] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 09/24/2018] [Indexed: 12/17/2022]
Abstract
Virus-induced oxidative stress plays a critical role in the viral life cycle as well as the pathogenesis of viral diseases. In response to reactive oxygen species (ROS) generation by a virus, a host cell activates an antioxidative defense system for its own protection. Particularly, a nuclear factor erythroid 2p45-related factor 2 (Nrf2) pathway works in a front-line for cytoprotection and detoxification. Recently, a series of studies suggested that a group of clinically relevant viruses have the capacity for positive and negative regulations of the Nrf2 pathway. This virus-induced modulation of the host antioxidative response turned out to be a crucial determinant for the progression of several viral diseases. In this review, virus-specific examples of positive and negative modulations of the Nrf2 pathway will be summarized first. Then a number of successful genetic and pharmacological manipulations of the Nrf2 pathway for suppression of the viral replication and the pathogenesis-associated oxidative damage will be discussed later. Understanding of the interplay between virus-induced oxidative stress and antioxidative host response will aid in the discovery of potential antiviral supplements for better management of viral diseases.
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von Olshausen G, Quasdorff M, Bester R, Arzberger S, Ko C, van de Klundert M, Zhang K, Odenthal M, Ringelhan M, Niessen CM, Protzer U. Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion. Oncotarget 2018; 9:33947-33960. [PMID: 30338037 PMCID: PMC6188061 DOI: 10.18632/oncotarget.26103] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 08/27/2018] [Indexed: 12/31/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a prominent cause of hepatocellular carcinoma (HCC) but the underlying molecular mechanisms are complex and multiple pathways have been proposed such as the activation of the Wnt-/β-catenin-signalling and dysregulation of E-cadherin/β-catenin adherens junctions. This study aimed to identify mechanisms of how HBV infection and replication as well as HBV X protein (HBx) gene expression in the context of an HBV genome influence Wnt-/β-catenin-signalling and formation of adherens junctions and to which extent HBx contributes to this. Regulation of E-cadherin/β-catenin junctions and β-catenin-signalling as well as the role of HBx were investigated using constructs transiently or stably inducing replication of HBV+/-HBx in hepatoma cell lines. In addition, HCC and adjacent non-tumorous tissue samples from HBV-infected HCC patients and drug interference in HBV-infected cells were studied. Although HBV did not alter overall expression levels of E-cadherin or β-catenin, it diminished their cell surface localization resulting in nuclear translocation of β-catenin and activation of its target genes. In addition, HBV gene expression increased the amount of phosphorylated c-Src kinase. Treatment with Src kinase inhibitor Dasatinib reduced HBV replication, prevented adherens junction disassembly and reduced β-catenin-signalling, while Sorafenib only did so in cells with mutated β-catenin. Interestingly, none of the HBV induced alterations required HBx. Thus, HBV stimulated β-catenin-signalling and induced disassembly of adherens junctions independently of HBx through Src kinase activation. These pathways may contribute to hepatocellular carcinogenesis and seem to be more efficiently inhibited by Dasatinib than by Sorafenib.
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Affiliation(s)
- Gesa von Olshausen
- Department of Internal Medicine I, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany
| | - Maria Quasdorff
- Molecular Infectiology, Institute for Medical Micro biology, Immunology and Hygiene, University Hospital Cologne, Cologne, Germany.,Department of Gastroenterology and Hepatology, University Hospital Cologne, Cologne, Germany
| | - Romina Bester
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Silke Arzberger
- Molecular Infectiology, Institute for Medical Micro biology, Immunology and Hygiene, University Hospital Cologne, Cologne, Germany.,Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Chunkyu Ko
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Maarten van de Klundert
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Ke Zhang
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Margarete Odenthal
- Institute of Pathology, University Hospital Cologne, Cologne, Germany.,Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Marc Ringelhan
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany.,Department of Internal Medicine II, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany
| | - Carien M Niessen
- Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.,Department of Dermatology, University Hospital of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany.,German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
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40
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Yang L, Ye S, Zhao X, Ji L, Zhang Y, Zhou P, Sun J, Guan Y, Han Y, Ni C, Hu X, Liu W, Wang H, Zhou B, Huang J. Molecular Characterization of HBV DNA Integration in Patients with Hepatitis and Hepatocellular Carcinoma. J Cancer 2018; 9:3225-3235. [PMID: 30271481 PMCID: PMC6160693 DOI: 10.7150/jca.26052] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 07/06/2018] [Indexed: 01/02/2023] Open
Abstract
Infection by chronic hepatitis B virus (HBV) is one of the major causes of liver cirrhosis and primary hepatocellular carcinoma (HCC). Viral DNA integration into the host cell genome is a key mechanism of hepatocarcinogenesis. However, the molecular characterization and the potential clinical implications of HBV DNA integration into patients suffering from different hepatitis and HCC remain unclear. In this study, we analyzed HBV integrations in patients with hepatitis B and HCC using HBV probe-based capturing and next-generation sequencing. The results revealed that the sizes of the HBV integrations ranged from 28 bp to 3215 bp, including the full-length HBV DNA sequence. The integration breakpoints were preferentially distributed in the viral enhancer, X protein, and core protein regions of the HBV genome. The number of HBV integrations followed an increasing trend from hepatitis to HCC, which was positively correlated with the HBV virus load in patients with hepatitis. The number of HBV integrations in the HBeAg positive chronic hepatitis B group was significantly greater than that in the other hepatitis B groups (P < 0.05). However, the relative abundance of HBV integrations was significantly higher in HCC tissues than in the adjacent liver tissues. Interestingly, 61.6% (8/13) of HBV-human DNA integration fragments could be detected at the RNA level. Our results also showed that HBV integration-targeted genes (ITGs) were significantly enriched in many cancer-related pathways, such as MAPK, extracellular matrix (ECM)-receptor interaction, and the hedgehog signaling pathway. Individuals with HBV integrations exhibited shorter disease-free survival (DFS) and overall survival (OS) than those without HBV integrations in some ITGs including LINC00293 (long intergenic non-protein coding RNA 293; DFS P = 0.008, OS P = 0.009), FSHB (follicle stimulating hormone beta subunit; DFS P = 0.05, OS P = 0.186), and LPHN3 (latrophilin-3; DFS P = 0.493, OS P = 0.033). This study determined the underlying mechanism of HBV DNA integration in liver diseases and laid the foundation for future studies on the pathogenesis of liver cancer.
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Affiliation(s)
- Liu Yang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province and Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical Colleg, Shang Tang Road 158, Hangzhou 310014, Zhejiang, P. R China
| | - Song Ye
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Qing Chun Road 79, Hangzhou 310003, Zhejiang, P. R. China
| | - Xinyi Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, P. R. China
| | - Liyan Ji
- Binhai Genomics Institute, BGI-Tianjin, Tianjin, 300308, China
| | - Yinxin Zhang
- Binhai Genomics Institute, BGI-Tianjin, Tianjin, 300308, China
| | - Pingyu Zhou
- STD Institute, Shanghai Skin Disease Hospital, Tong Ji University, Shanghai, China
| | - Jun Sun
- STD Institute, Shanghai Skin Disease Hospital, Tong Ji University, Shanghai, China
| | - Yanfang Guan
- Binhai Genomics Institute, BGI-Tianjin, Tianjin, 300308, China
| | - Yingxin Han
- Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Chinese National Human Genome Center at Shanghai. Shanghai Jiao Tong University, Shanghai, 200240, China.,Binhai Genomics Institute, BGI-Tianjin, Tianjin, 300308, China
| | - Chao Ni
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province and Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical Colleg, Shang Tang Road 158, Hangzhou 310014, Zhejiang, P. R China
| | - Xiaoge Hu
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province and Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical Colleg, Shang Tang Road 158, Hangzhou 310014, Zhejiang, P. R China
| | - Weilong Liu
- Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, 518112, China
| | - Haiyan Wang
- Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, 518112, China
| | - Boping Zhou
- Shenzhen People's Hospital, Second Clinical Medical College of Jinan University. Shenzhen, 518109, China
| | - Jian Huang
- Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Chinese National Human Genome Center at Shanghai. Shanghai Jiao Tong University, Shanghai, 200240, China.,Shenzhen People's Hospital, Second Clinical Medical College of Jinan University. Shenzhen, 518109, China.,Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, 518112, China
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Freitas N, Lukash T, Gunewardena S, Chappell B, Slagle BL, Gudima SO. Relative Abundance of Integrant-Derived Viral RNAs in Infected Tissues Harvested from Chronic Hepatitis B Virus Carriers. J Virol 2018; 92:e02221-17. [PMID: 29491161 PMCID: PMC5923063 DOI: 10.1128/jvi.02221-17] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 02/17/2018] [Indexed: 02/07/2023] Open
Abstract
Five matching sets of nonmalignant liver tissues and hepatocellular carcinoma (HCC) samples from individuals chronically infected with hepatitis B virus (HBV) were examined. The HBV genomic sequences were determined by using overlapping PCR amplicons covering the entire viral genome. Four pairs of tissues were infected with HBV genotype C, while one pair was infected with HBV genotype B. HBV replication markers were found in all tissues. In the majority of HCC samples, the levels of pregenomic/precore RNA (pgRNA) and covalently closed circular DNA (cccDNA) were lower than those in liver tissue counterparts. Regardless of the presence of HBV replication markers, (i) integrant-derived HBV RNAs (id-RNAs) were found in all tissues by reverse transcription-PCR (RT-PCR) analysis and were considerably abundant or predominant in 6/10 tissue samples (2 liver and 4 HCC samples), (ii) RNAs that were polyadenylated using the cryptic HBV polyadenylation signal and therefore could be produced by HBV replication or derived from integrated HBV DNA were found in 5/10 samples (3 liver and 2 HCC samples) and were considerably abundant species in 3/10 tissues (2 livers and 1 HCC), and (iii) cccDNA-transcribed RNAs polyadenylated near position 1931 were not abundant in 7/10 tissues (2 liver and 5 HCC samples) and were predominant in only two liver samples. Subsequent RNA sequencing analysis of selected liver/HCC samples also showed relative abundance of id-RNAs in most of the examined tissues. Our findings suggesting that id-RNAs could represent a significant source of HBV envelope proteins, which is independent of viral replication, are discussed in the context of the possible contribution of id-RNAs to the HBV life cycle.IMPORTANCE The relative abundance of integrant-derived HBV RNAs (id-RNAs) in chronically infected tissues suggest that id-RNAs coding for the envelope proteins may facilitate the production of a considerable fraction of surface antigens (HBsAg) in infected cells bearing HBV integrants. If the same cells support HBV replication, then a significant fraction of assembled HBV virions could bear id-RNA-derived HBsAg as a major component of their envelopes. Therefore, the infectivity of these HBV virions and their ability to facilitate virus cell-to-cell spread could be determined mainly by the properties of id-RNA-derived envelope proteins and not by the properties of replication-derived HBsAg. These interpretations suggest that id-RNAs may play a role in the maintenance of chronic HBV infection and therefore contribute to the HBV life cycle. Furthermore, the production of HBsAg from id-RNAs independently of viral replication may explain at least in part why treatment with interferon or nucleos(t)ides in most cases fails to achieve a loss of serum HBsAg.
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Affiliation(s)
- Natalia Freitas
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Tetyana Lukash
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Benjamin Chappell
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Betty L Slagle
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Severin O Gudima
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
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42
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Ramezani A, Nahad MP, Faghihloo E. The role of Nrf2 transcription factor in viral infection. J Cell Biochem 2018; 119:6366-6382. [DOI: 10.1002/jcb.26897] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 03/28/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Ali Ramezani
- Virology DepartmentSchool of MedicineAhvaz Jundishapur University of Medical SciencesAhvazIran
- Hepatitis Research CenterBirjand University of Medical SciencesBirjandIran
| | - Mehdi Parsa Nahad
- Virology DepartmentSchool of MedicineAhvaz Jundishapur University of Medical SciencesAhvazIran
| | - Ebrahim Faghihloo
- Department of MicrobiologySchool of MedicineShahid Beheshti University of Medical SciencesTehranIran
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43
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Chen BF. Hepatitis B virus pre-S/S variants in liver diseases. World J Gastroenterol 2018; 24:1507-1520. [PMID: 29662289 PMCID: PMC5897855 DOI: 10.3748/wjg.v24.i14.1507] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 03/29/2018] [Accepted: 03/30/2018] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B is a global health problem. The clinical outcomes of chronic hepatitis B infection include asymptomatic carrier state, chronic hepatitis (CH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Because of the spontaneous error rate inherent to viral reverse transcriptase, the hepatitis B virus (HBV) genome evolves during the course of infection under the antiviral pressure of host immunity. The clinical significance of pre-S/S variants has become increasingly recognized in patients with chronic HBV infection. Pre-S/S variants are often identified in hepatitis B carriers with CH, LC, and HCC, which suggests that these naturally occurring pre-S/S variants may contribute to the development of progressive liver damage and hepatocarcinogenesis. This paper reviews the function of the pre-S/S region along with recent findings related to the role of pre-S/S variants in liver diseases. According to the mutation type, five pre-S/S variants have been identified: pre-S deletion, pre-S point mutation, pre-S1 splice variant, C-terminus S point mutation, and pre-S/S nonsense mutation. Their associations with HBV genotype and the possible pathogenesis of pre-S/S variants are discussed. Different pre-S/S variants cause liver diseases through different mechanisms. Most cause the intracellular retention of HBV envelope proteins and induction of endoplasmic reticulum stress, which results in liver diseases. Pre-S/S variants should be routinely determined in HBV carriers to help identify individuals who may be at a high risk of less favorable liver disease progression. Additional investigations are required to explore the molecular mechanisms of the pre-S/S variants involved in the pathogenesis of each stage of liver disease.
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Affiliation(s)
- Bing-Fang Chen
- School of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan
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44
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Li Y, Sun Y, Sun F, Hua R, Li C, Chen L, Guo D, Mu J. Mechanisms and Effects on HBV Replication of the Interaction between HBV Core Protein and Cellular Filamin B. Virol Sin 2018; 33:162-172. [PMID: 29594956 DOI: 10.1007/s12250-018-0023-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 01/12/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is one of the major problems that threatens global health. There have been many studies on HBV, but the relationship between HBV and host factors is largely unexplored and more studies are needed to clarify these interactions. Filamin B is an actin-binding protein that acts as a cytoskeleton protein, and it is involved in cell development and several signaling pathways. In this study, we showed that filamin B interacted with HBV core protein, and the interaction promoted HBV replication. The interaction between filamin B and core protein was observed in HEK 293T, Huh7 and HepG2 cell lines by co-immunoprecipitation and co-localization immnofluoresence. Overexpression of filamin B increased the levels of HBV total RNAs and pre-genome RNA (pgRNA), and improved the secretion level of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). In contrast, filamin B knockdown inhibited HBV replication, decreased the level of HBV total RNAs and pgRNA, and reduced the secretion level of HBsAg and HBeAg. In addition, we found that filamin B and core protein may interact with each other via four blocks of argentine residues at the C-terminus of core protein. In conclusion, we identify filamin B as a novel host factor that can interact with core protein to promote HBV replication in hepatocytes. Our study provides new insights into the relationship between HBV and host factors and may provide new strategies for the treatment of HBV infection.
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Affiliation(s)
- Yilin Li
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yishuang Sun
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Fuyun Sun
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Rong Hua
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Chenlin Li
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Lang Chen
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Deyin Guo
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China. .,School of Basic Medicine (Shenzhen), Sun Yat-sen University, Guangzhou, 510081, China.
| | - Jingfang Mu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
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45
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Zhen Y, Wu Q, Ding Y, Zhang W, Zhai Y, Lin X, Weng Y, Guo R, Zhang Y, Feng J, Lei Y, Chen J. Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway. Oncol Lett 2018; 15:6562-6570. [PMID: 29725404 DOI: 10.3892/ol.2018.8154] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Accepted: 04/21/2017] [Indexed: 12/20/2022] Open
Abstract
The effects of hydrogen sulfide (H2S) on cancer are controversial. Our group previously demonstrated that exogenous H2S promotes the development of cancer via amplifying the activation of the nuclear factor-κB signaling pathway in hepatocellular carcinoma (HCC) cells (PLC/PRF/5). The present study aimed to further investigate the hypothesis that exogenous H2S promotes PLC/PRF/5 cell proliferation and migration, and inhibits apoptosis by activating the signal transducer and activator of transcription 3 (STAT3)-cyclooxygenase-2 (COX-2) signaling pathway. PLC/PRF/5 cells were treated with 500 µmol/l NaHS (a donor of H2S) for 24 h. The expression levels of phosphorylated (p)-STAT3, STAT3, cleaved caspase-3 and COX-2 were measured by western blot assay. Cell viability was detected by Cell Counting kit-8 assay. Apoptotic cells were observed by Hoechst 33258 staining. The expression of STAT3 and COX-2 messenger RNA (mRNA) was detected by semiquantitative reverse transcription-polymerase chain reaction. The production of vascular endothelial growth factor (VEGF) was evaluated by ELISA. The results indicated that treatment of PLC/PRF/5 cells with 500 µmol/l NaHS for 24 h markedly increased the expression levels of p-STAT3 and STAT3 mRNA, leading to COX-2 and COX-2 mRNA overexpression, VEGF induction, decreased cleaved caspase-3 production, increased cell viability and migration, and decreased number of apoptotic cells. However, co-treatment of PLC/PRF/5 cells with 500 µmol/l NaHS and 30 µmol/l AG490 (an inhibitor of STAT3) or 20 µmol/l NS-398 (an inhibitor of COX-2) for 24 h significantly reverted the effects induced by NaHS. Furthermore, co-treatment of PLC/PRF/5 cells with 500 µmol/l NaHS and 30 µmol/l AG490 markedly decreased the NaHS-induced increase in the expression level of COX-2. By contrast, co-treatment of PLC/PRF/5 cells with 500 µmol/l NaHS and 20 µmol/l NS-398 inhibited the NaHS-induced increase in the expression level of p-STAT3. In conclusion, the findings of the present study provide evidence that the STAT3-COX-2 signaling pathway is involved in NaHS-induced cell proliferation, migration, angiogenesis and anti-apoptosis in PLC/PRF/5 cells, and suggest that the positive feedback between STAT3 and COX-2 may serve a crucial role in hepatocellular carcinoma carcinogenesis.
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Affiliation(s)
- Yulan Zhen
- Department of Oncology, The Third People's Hospital of Dongguan Dongguan City, Guangdong 523326, P.R. China
| | - Qiaomei Wu
- Department of Anesthesiology, Oral Subsidiary Sun Yat-Sen University Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China
| | - Yiqian Ding
- Grade 2013, Medical Imaging, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510000, P.R. China
| | - Wei Zhang
- Department of Cardiovasology and Cardiac Care Unit, Huangpu Division of The First Affiliated Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Yuansheng Zhai
- Department of Cardiovasology and Cardiac Care Unit, Huangpu Division of The First Affiliated Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Xiaoxiong Lin
- Department of Cardiovasology and Cardiac Care Unit, Huangpu Division of The First Affiliated Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Yunxia Weng
- Department of Cardiovasology and Cardiac Care Unit, Huangpu Division of The First Affiliated Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Ruixian Guo
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China
| | - Ying Zhang
- Department of Oncology, Affiliated Hospital, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China
| | - Jianqiang Feng
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China
| | - Yiyan Lei
- Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jingfu Chen
- Department of Cardiovascular Medicine and Dongguan Cardiovascular Institute, The Third People's Hospital of Dongguan City, Dongguan, Guangdong 523326, P.R. China
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46
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Luo W, Wang J, Xu D, Bai H, Zhang Y, Zhang Y, Li X. Engineered zinc-finger transcription factors inhibit the replication and transcription of HBV in vitro and in vivo. Int J Mol Med 2018; 41:2169-2176. [PMID: 29344646 DOI: 10.3892/ijmm.2018.3396] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 01/05/2018] [Indexed: 01/12/2023] Open
Abstract
In the present study, an artificial zinc-finger transcription factor eukaryotic expression vector specifically recognizing and binding to the hepatitis B virus (HBV) enhancer (Enh) was constructed, which inhibited the replication and expression of HBV DNA. The HBV EnhI‑specific pcDNA3.1‑artificial transcription factor (ATF) vector was successfully constructed, and then transformed or injected into HepG2.2.15 cells and HBV transgenic mice, respectively. The results demonstrated that the HBV EnhI (1,070‑1,234 bp)‑specific ATF significantly inhibited the replication and transcription of HBV DNA in vivo and in vitro. The HBV EnhI‑specific ATF may be a meritorious component of progressive combination therapies for eliminating HBV DNA in infected patients. A radical cure for chronic HBV infection may become feasible by using this bioengineering technology.
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Affiliation(s)
- Wei Luo
- Department of General Surgery, The Second Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Junxia Wang
- Department of Neonatology, The Second Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Dengfeng Xu
- Department of Ophthalmology, Chongqing General Hospital, Chongqing 400014, P.R. China
| | - Huili Bai
- Department of Molecular Diagnostics, Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yangli Zhang
- Department of Molecular Diagnostics, Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yuhong Zhang
- Department of Molecular Diagnostics, Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xiaosong Li
- Department of Molecular Diagnostics, Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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47
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Cao M, Zhao Z, Tang Y, Wei Q, Wang L, Xiang Q, Zhang Y, Zhang H, Lai G. A new hepatitis B virus e antigen-negative strain gene used as a reference sequence in an animal model. Biochem Biophys Res Commun 2018; 496:502-507. [PMID: 29339154 DOI: 10.1016/j.bbrc.2018.01.081] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 01/11/2018] [Indexed: 12/16/2022]
Abstract
Infection with hepatitis B virus (HBV) e-antigen (HBeAg)-negative strains is increasingly prevalent. Currently, detailed information of the obtained natural HBV strain is not available except for the B genotype and HBeAg-negative. The aim of the present study was to characterize the natural genetic variation of the HBeAg-negative strain and investigate its function. The genic sequence was determined using Sanger sequencing, and compared to related sequences using alignment and phylogenetic analysis. In vivo, virus-specific serum markers were investigated in CBA/CaJ mice. The sequence had a full genome length of 3215 nucleotides. Sites 122, 125, 127, and 160 in S regions were identified as lysine, threonine, proline, and lysine respectively. The main four point variants including A1762T, G1764A, G1896A, and G1899A were detected in the full-length genome. The genotype of the sequence was B, with sub-genotype B2 and serological subtype adw2. The characterize of the natural genetic variation strain showed no reported drug-resistant variant in P region and no reported immune escape site in S region. The strain will increase viral replication and infection for mutations A1762T and G1764A in the basal core promoter region, and mutations G1896A and G1899A in the pre-core region. The G1896A variant resulted in a premature stop codon and abolished HBeAg expression. HBsAg persisted for 26 weeks and HBeAg was still negative in CBA/CaJ mice. The present sequence is representative of the HBeAg-negative genome and may serve as a valuable reference for studying HBeAg-negative strains. The present findings were successfully verified in CBA/CaJ mice, demonstrating good applicability of the sequence.
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Affiliation(s)
- Min Cao
- Chongqing Medical University Laboratory Animal Center, Chongqing, China
| | - Zhonghua Zhao
- Chongqing Academy of Science and Technology, Chongqing, China
| | - Yuwei Tang
- Chongqing Academy of Science and Technology, Chongqing, China
| | - Qinglv Wei
- Chongqing Academy of Science and Technology, Chongqing, China
| | - Lei Wang
- Chongqing Medical University Laboratory Animal Center, Chongqing, China
| | - Qin Xiang
- Chongqing Medical University Laboratory Animal Center, Chongqing, China
| | - Yunmei Zhang
- The Nursing College of Chongqing Medical University, Chongqing, China
| | - Huatang Zhang
- Chongqing Academy of Science and Technology, Chongqing, China
| | - Guoqi Lai
- Chongqing Medical University Laboratory Animal Center, Chongqing, China.
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48
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Siddiqui ZI, Farooqui SR, Azam SA, Afroz M, Wajid S, Parveen S, Kazim SN. A comparative study of hepatitis B virus X protein mutants K130M, V131I and KV130/131MI to investigate their roles in fibrosis, cirrhosis and hepatocellular carcinoma. J Viral Hepat 2017; 24:1121-1131. [PMID: 28654219 DOI: 10.1111/jvh.12747] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 06/06/2017] [Indexed: 01/04/2023]
Abstract
Hepatitis B virus (HBV) genomic mutations A1762T, G1764A and AG1762/1764TA cause production of HBV X protein (HBx) mutants, namely K130M, V131I and KV130/131MI. These mutations are important biomarkers for the development of cirrhosis and hepatocellular carcinoma (HCC) in chronic HBV patients. This study comparatively analyses the impact of intracellular expression of HBx mutants on HCC cell line Huh7. It was found that expression of KV130/131MI induced: cell proliferation, altered expression of cell cycle regulatory genes in favour of cell proliferation, intracellular reactive oxygen species (ROS) production and mitochondrial depolarization. KV130/131MI may be directly involved in host cell proliferation and hepatocarcinogenesis via altering expression of cell cycle regulatory genes. KV130/131MI may also play pivotal roles in fibrosis and cirrhosis via inducing ROS production and mitochondrial depolarization. Furthermore, these might be the possible reasons for higher occurrence of AG1762/1764TA as compared to A1762T and G1764A in cirrhosis and HCC patients.
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Affiliation(s)
- Z I Siddiqui
- Hepatitis Research Lab, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - S R Farooqui
- Hepatitis Research Lab, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - S A Azam
- Hepatitis Research Lab, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - M Afroz
- Hepatitis Research Lab, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - S Wajid
- Department of Biotechnology, Jamia Hamdard, New Delhi, India
| | - S Parveen
- Hepatitis Research Lab, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - S N Kazim
- Hepatitis Research Lab, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
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49
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Al-Qahtani AA, Al-Anazi MR, Nazir N, Wani K, Abdo AA, Sanai FM, Khan MQ, Al-Ashgar HI, Albenmousa A, Al-Hamoudi WK, Alswat KA, Al-Ahdal MN. Association of single nucleotide polymorphisms in microRNAs with susceptibility to hepatitis B virus infection and HBV-related liver complications: A study in a Saudi Arabian population. J Viral Hepat 2017; 24:1132-1142. [PMID: 28685993 DOI: 10.1111/jvh.12749] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 05/26/2017] [Indexed: 12/14/2022]
Abstract
The aim of this study was to evaluate the association of 10 SNPs in different microRNAs (miRNAs) with susceptibility to hepatitis B virus (HBV) infection, HBV clearance, persistence of chronic HBV infection, and progression to liver cirrhosis and hepatocellular carcinoma (HCC). Patients were categorized into the following groups: inactive HBV carrier, active HBV carrier, HBV-cleared subject and cirrhosis+HCC. Samples were analysed for 10 SNPs in microRNAs using either PCR-based genotyping or the TaqMan assay. We found that rs1358379 was associated with susceptibility to HBV infection, HBV clearance, persistent chronic HBV infection and liver cirrhosis+HCC. In addition, we found that rs2292832 and rs11614913 were associated with risk of HBV infection, viral clearance and cirrhosis+HCC, whereas rs2910164 was associated with proneness to HBV infection, and ability to clear the virus. There was evidence of associations between rs6505162 and HBV clearance and the development of liver disease, whereas a single association was found between rs2289030 and HBV clearance. Similarly, rs7372209 and rs4919510 were specifically associated with the development of HBV-induced liver complications. SNPs in miRNAs affect the susceptibility, clearance and progression of HBV infection in Saudi Arabian patients. We found, using Gene Ontology or pathway analyses, that these genes may contribute to the pathophysiology of HBV infection and related liver complications. However, differences in the association of examined SNPs with various clinical stages indicate variations in the respective functional roles of these polymorphisms and their miRNAs, and thus, further investigation to fully explore their therapeutic potential is warranted.
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Affiliation(s)
- A A Al-Qahtani
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.,Department of Microbiology and Immunology, Alfaisal University School of Medicine, Riyadh, Saudi Arabia
| | - M R Al-Anazi
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - N Nazir
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - K Wani
- Biomarkers Research Program, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - A A Abdo
- Gastroenterology Section, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
| | - F M Sanai
- Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia.,Gastroenterology Section, Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - M Q Khan
- Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - H I Al-Ashgar
- Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - A Albenmousa
- Department of Gastroenterology & Hepatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - W K Al-Hamoudi
- Gastroenterology Section, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
| | - K A Alswat
- Gastroenterology Section, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
| | - M N Al-Ahdal
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.,Department of Microbiology and Immunology, Alfaisal University School of Medicine, Riyadh, Saudi Arabia
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50
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Hepatitis B virus (HBV) X gene mutations and their association with liver disease progression in HBV-infected patients. Oncotarget 2017; 8:105115-105125. [PMID: 29285238 PMCID: PMC5739625 DOI: 10.18632/oncotarget.22428] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/17/2017] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B virus (HBV) is one of the most widespread human pathogens causing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). This study investigated the clinical impact of single and combinational mutations in HBx gene on the pathogenesis of HCC during progressive stages of liver disease. The patients were categorized into inactive HBV carriers, active carriers, cirrhosis and HCC groups based on disease severity. Male sex, age > 50 years, and high serum alanine aminotransferase level were associated with risk of progressive liver disease. I127T, V131I, and F132Y/I/R mutations showed a significant increasing trend associated with the disease progression to HCC. H94Y and K130M mutations were also significantly associated with severe liver disease. One double mutation (K130M+V131I) and two triple mutations (I127T+K130M+V131L and K130M+V131I+F132Y) were observed, with significant rising prevalence through progressive clinical phases of liver disease to HCC. Several single and combinational mutations in HBx correlating with severity and progressive clinical phases of HBV infection were identified. The mutational combinations may have a synergistic effect in accelerating the progression to HCC. These specific patterns of HBx mutations can be useful in predicting the clinical outcome of HBV-infected patients and may serve as early markers of high risk of developing HCC.
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