|
1
|
Qiu Q, Tong X, Zhu M, Liu Z, Pang H, Li L, Feng Y, Hu X, Gong C. Changes in gene expression levels caused by H3K9me3/H3K9ac modifications are associated with BmCPV infection in Bombyx mori. Virulence 2025; 16:2510535. [PMID: 40418637 DOI: 10.1080/21505594.2025.2510535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 05/02/2025] [Accepted: 05/19/2025] [Indexed: 05/28/2025] Open
Abstract
Changes in chromatin accessibility caused by histone modifications regulate gene transcription. However, little is known about associations between gene expression changes caused by histone modifications and viral infections. We investigate the midguts of silkworms infected with Bombyx mori cypovirus (BmCPV) at 48 h and 96 h post infection (CPV48 and CPV96), and corresponding midguts of uninfected silkworms (GUT48 and GUT96) using CUT&Tag-seq and RNA-seq. We report H3K9me3, H3K9ac, and gene expression profiles at the genome-wide level to change with BmCPV infection. Differential H3K9me3 peak-related genes were mainly enriched in MAPK, Wnt, and Hippo signalling pathways; Differential H3K9ac peaks-related genes were mainly enriched in the Hippo signalling, apoptosis, and citrate cycle pathways; and differentially expressed genes (DEGs) were mainly enriched in carbon metabolism, protein processing in endoplasmic reticulum, and glycolysis/gluconeogenesis pathways. Integration analysis between H3K9me3/H3K9ac peaks and gene expression revealed changes in gene expression profiles to be associated with alteration of H3K9me3/H3K9ac at promoters; gene expression correlates negatively with corresponding H3K9me3 signals in gene bodies, and positively with corresponding H3K9ac signals at the transcription start site. Intersection genes with log2foldchange of both CUT&Tag-seq peak and RNA-seq FPKM > 1 were screened and annotated. Genes shared by differential H3K9me3 peak-related genes and DEGs were enriched in insect hormone biosynthesis, MAPK signalling, and TGF-beta signalling pathways, and genes shared by differential H3K9ac peak-related genes and DEGs were enriched in glycolysis/gluconeogenesis, TGF-beta signalling, and mitophagy pathways. These results indicate that BmCPV regulates gene expression through H3K9me3/H3K9ac.
Collapse
Affiliation(s)
- Qunnan Qiu
- School of Life Sciences, Soochow University, Suzhou, China
- Agricultural Biotechnology Research Institute, Agricultural Biotechnology and Ecological Research Institute, Soochow University, Suzhou, China
| | - Xinyu Tong
- School of Life Sciences, Soochow University, Suzhou, China
| | - Min Zhu
- School of Life Sciences, Soochow University, Suzhou, China
- Agricultural Biotechnology Research Institute, Agricultural Biotechnology and Ecological Research Institute, Soochow University, Suzhou, China
| | - Zhe Liu
- School of Life Sciences, Soochow University, Suzhou, China
| | - Huilin Pang
- School of Life Sciences, Soochow University, Suzhou, China
| | - Liuyang Li
- School of Life Sciences, Soochow University, Suzhou, China
| | - Yongjie Feng
- School of Life Sciences, Soochow University, Suzhou, China
| | - Xiaolong Hu
- School of Life Sciences, Soochow University, Suzhou, China
- Agricultural Biotechnology Research Institute, Agricultural Biotechnology and Ecological Research Institute, Soochow University, Suzhou, China
| | - Chengliang Gong
- School of Life Sciences, Soochow University, Suzhou, China
- Agricultural Biotechnology Research Institute, Agricultural Biotechnology and Ecological Research Institute, Soochow University, Suzhou, China
| |
Collapse
|
|
2
|
Lin HY, Jeon AJ, Chen K, Lee CJM, Wu L, Chong SL, Anene-Nzelu CG, Foo RSY, Chow PKH. The epigenetic basis of hepatocellular carcinoma - mechanisms and potential directions for biomarkers and therapeutics. Br J Cancer 2025; 132:869-887. [PMID: 40057667 DOI: 10.1038/s41416-025-02969-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/23/2025] [Accepted: 02/20/2025] [Indexed: 05/17/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis is often late as current screening methods have limited sensitivity for early HCC. Moreover, current treatment regimens for intermediate-to-advanced HCC have high resistance rates, no robust predictive biomarkers, and limited survival benefits. A deeper understanding of the molecular biology of HCC may enhance tumor characterization and targeting of key carcinogenic signatures. The epigenetic landscape of HCC includes complex hallmarks of 1) global DNA hypomethylation of oncogenes and hypermethylation of tumor suppressors; 2) histone modifications, altering chromatin accessibility to upregulate oncogene expression, and/or suppress tumor suppressor gene expression; 3) genome-wide rearrangement of chromatin loops facilitating distal enhancer-promoter oncogenic interactions; and 4) RNA regulation via translational repression by microRNAs (miRNAs) and RNA modifications. Additionally, it is useful to consider etiology-specific epigenetic aberrancies, especially in viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are the main risk factors of HCC. This article comprehensively explores the epigenetic signatures in HCC, highlighting their potential as biomarkers and therapeutic targets. Additionally, we examine how etiology-specific epigenetic patterns and the integration of epigenetic therapies with immunotherapy could advance personalized HCC treatment strategies.
Collapse
Affiliation(s)
- Hong-Yi Lin
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Ah-Jung Jeon
- Department of Research and Development, Mirxes, Singapore, Singapore
| | - Kaina Chen
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Chang Jie Mick Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
| | - Lingyan Wu
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | - Shay-Lee Chong
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Roger Sik-Yin Foo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, Singapore, Singapore
| | - Pierce Kah-Hoe Chow
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore.
- Department of Hepato-pancreato-biliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore.
- Surgery Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore.
| |
Collapse
|
|
3
|
Du X, Xiao Q, Yang L, Shan Y, Hu Y, Bao W, Wu S, Wu Z. DNMT3B inhibits PCV2 replication via targeting TMEM37 to regulate Ca 2 + influx in PK15 cells. Vet Microbiol 2025; 304:110480. [PMID: 40112691 DOI: 10.1016/j.vetmic.2025.110480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/10/2025] [Accepted: 03/12/2025] [Indexed: 03/22/2025]
Abstract
Porcine circovirus type 2 (PCV2) is the main pathogen causing postweaning multisystemic wasting syndrome, which leads to enormous losses for porcine industry. However, the regulatory mechanism of PCV2 replication in host cells remains not been clarified. Here, pig DNMT3B was identified as be a host regulator associated with PCV2 infection via RNA-seq analysis. We demonstrated that upregulation of DNMT3B expression can effectively inhibit PCV2 replication in PK15 cells. Besides, TMEM37 acts as a key downstream target of DNMT3B in PCV2-infected PK15 cells. TMEM37 knockdown significantly slowed Ca2+ influx, and thus inhibited PCV2 replication. Taken together, DNMT3B is required for the PCV2-based infection regulation in host cells. Our findings indicated that DNMT3B inhibits PCV2 replication via targeting TMEM37 to regulate Ca2+ influx in PK15 cells, which offering a theoretical foundation for the use of this gene as a key biomarker for breeding strategies seeking to improve porcine disease resistance.
Collapse
Affiliation(s)
- Xiaomei Du
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.
| | - Qi Xiao
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, Jiangsu, China.
| | - Li Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.
| | - Yiyi Shan
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.
| | - Yueqing Hu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.
| | - Wenbin Bao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China.
| | - Shenglong Wu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China.
| | - Zhengchang Wu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China.
| |
Collapse
|
|
4
|
Liu X, Dong S, Ding Y, Li J, Wang J. Hepatitis B virus impacts embryonic development and methylation of maternal genes in assisted reproductive technology patients. J Assist Reprod Genet 2025; 42:809-815. [PMID: 39730946 PMCID: PMC11950455 DOI: 10.1007/s10815-024-03359-4] [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: 07/01/2024] [Accepted: 12/12/2024] [Indexed: 12/29/2024] Open
Abstract
PURPOSE In China, the prevalence of hepatitis B virus (HBV) infection among infertile couples is a significant clinical problem. It is necessary to determine the effect of HBV infection on embryo development. METHODS The 4301 fresh cycles and 5763 frozen embryo transfer (FET) cycles were grouped according to the couple with or without HBV infection. The embryo fertilization rate, cleavage rate, transplantable embryo rate, and rate of high-quality embryos were analysed. The methylation status of maternal antigen that embryos require (MATER), zygote arrest 1 (ZAR1) and growth differentiation factor 9 (GDF9) genes in the peripheral blood of assisted reproductive technology (ART) women was detected by methylation-specific polymerase chain reaction (MSP). RESULTS The pregnancy rate of the female HBV-positive group was significantly lower than that of the HBV-negative group. The fertilization rate of intracytoplasmic sperm injection (ICSI) cycles in the male HBV-positive group was significantly lower than that of the male HBV-negative group. There were no differences in biochemistry or clinical pregnancy rates among the FET groups. The promoter methylation of GDF9 in HBV-positive ART women was higher than that in HBV-negative ART women, and that of ZAR1 in HBV-positive ART women was lower than that in HBV-negative ART women. CONCLUSION It was a detrimental effect of HBV infection on in vitro fertilization (IVF) and ICSI treatment outcomes in women. The HBV infection was associated with the maternal genes promoting methylation.
Collapse
Affiliation(s)
- Xia Liu
- Department of Reproductive Medicine, the Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266000, China.
| | - Shixiang Dong
- Department of Obstetrics and Gynecology, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266061, China
| | - Yu Ding
- Department of Reproductive Medicine, the Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266000, China
| | - Jinjin Li
- Department of Hepatology, Qingdao Sixth People's Hospital, 9 Fushun Road, Qingdao, 266000, China
| | - Jingyuan Wang
- Department of Reproduction, Qingdao Municipal Hospital, 5 Donghaizhong Road, Qingdao, 266071, China
| |
Collapse
|
|
5
|
Tan X, Xun L, Yin Q, Chen C, Zhang T, Shen T. Epigenetic Modifications in HBV-Related Hepatocellular Carcinoma. J Viral Hepat 2025; 32:e14044. [PMID: 39868653 DOI: 10.1111/jvh.14044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/13/2024] [Accepted: 11/30/2024] [Indexed: 01/28/2025]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Hepatitis B virus (HBV) is the main pathogen for HCC development. HBV covalently closed circular DNA (cccDNA) forms extra-host chromatin-like minichromosomes in the nucleus of hepatocytes with host histones, non-histones, HBV X protein (HBx) and HBV core protein (HBc). Epigenetic alterations are dynamic and reversible, which regulate gene expression without altering the DNA sequence and play a pivotal role in the regulation of HCC onset and progression. The aim of this review is to elucidate the deregulation of epigenetic mechanisms involved in the pathogenesis of HBV-related HCC (HBV-HCC), including post-translational histone and non-histone modifications, DNA hypermethylation and hypomethylation, non-coding RNA modification on HBV cccDNA minichromosomes and host factors, effecting the replication/transcription of HBV cccDNA and transcription/translation of host genes, and thus HBV-HCC progression. It is expected that the epigenetic regulation perspective provides new ways for more in-depth development of therapeutic control of HBV-HCC.
Collapse
Affiliation(s)
- Xiaoqing Tan
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, Peoples republic of China, China
| | - Linting Xun
- Department of Gastroenterology, the First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People's Republic of China
| | - Qi Yin
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, People's Republic of China, China
| | - Chaohui Chen
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Tao Zhang
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, Peoples republic of China, China
| | - Tao Shen
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, Peoples republic of China, China
| |
Collapse
|
|
6
|
Magnani E, Macchi F, Randic T, Chen C, Madakashira B, Ranjan S, Eski SE, Singh SP, Sadler KC. Epigenetic Disordering Drives Stemness, Senescence Escape and Tumor Heterogeneity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.29.629346. [PMID: 39763773 PMCID: PMC11703240 DOI: 10.1101/2024.12.29.629346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Tumor heterogeneity is the substrate for tumor evolution and the linchpin of treatment resistance. Cancer cell heterogeneity is largely attributed to distinct genetic changes within each cell population. However, the widespread epigenome repatterning that characterizes most cancers is also highly heterogenous within tumors and could generate cells with diverse identities and malignant features. We show that high levels of the epigenetic regulator and oncogene, UHRF1, in zebrafish hepatocytes rapidly induced methylome disordering, loss of heterochromatin, and DNA damage, resulting in cell cycle arrest, senescence, and acquisition of stemness. Reducing UHRF1 expression transitions these cells from senescent to proliferation-competent. The expansion of these damaged cells results in hepatocellular carcinomas (HCC) that have immature cancer cells intermingled with fibroblasts, immune and senescent cells expressing high UHRF1 levels, which serve as reservoirs for new cancer cells. This defines a distinct and heterogenous HCC subtype resulting from epigenetic changes, stemness and senescence escape.
Collapse
Affiliation(s)
- Elena Magnani
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Filippo Macchi
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Tijana Randic
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Charlene Chen
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Bhavani Madakashira
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Shashi Ranjan
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Sema Elif Eski
- Laboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de Bruxelles, 1070 Brussels, Belgium
| | - Sumeet P. Singh
- Laboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de Bruxelles, 1070 Brussels, Belgium
| | - Kirsten C. Sadler
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
- Center for Genomics and Systems Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| |
Collapse
|
|
7
|
Chen Y, Liang R, Li Y, Jiang L, Ma D, Luo Q, Song G. Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application. Signal Transduct Target Ther 2024; 9:340. [PMID: 39627201 PMCID: PMC11615378 DOI: 10.1038/s41392-024-02030-9] [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: 03/11/2024] [Revised: 08/04/2024] [Accepted: 10/17/2024] [Indexed: 12/06/2024] Open
Abstract
The dynamic regulation of chromatin accessibility is one of the prominent characteristics of eukaryotic genome. The inaccessible regions are mainly located in heterochromatin, which is multilevel compressed and access restricted. The remaining accessible loci are generally located in the euchromatin, which have less nucleosome occupancy and higher regulatory activity. The opening of chromatin is the most important prerequisite for DNA transcription, replication, and damage repair, which is regulated by genetic, epigenetic, environmental, and other factors, playing a vital role in multiple biological progresses. Currently, based on the susceptibility difference of occupied or free DNA to enzymatic cleavage, solubility, methylation, and transposition, there are many methods to detect chromatin accessibility both in bulk and single-cell level. Through combining with high-throughput sequencing, the genome-wide chromatin accessibility landscape of many tissues and cells types also have been constructed. The chromatin accessibility feature is distinct in different tissues and biological states. Research on the regulation network of chromatin accessibility is crucial for uncovering the secret of various biological processes. In this review, we comprehensively introduced the major functions and mechanisms of chromatin accessibility variation in different physiological and pathological processes, meanwhile, the targeted therapies based on chromatin dynamics regulation are also summarized.
Collapse
Affiliation(s)
- Yang Chen
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Rui Liang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Yong Li
- Hepatobiliary Pancreatic Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, PR China
| | - Lingli Jiang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Di Ma
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Qing Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Guanbin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China.
| |
Collapse
|
|
8
|
Zhang Y, Cao W, Wang S, Zhang L, Li X, Zhang Z, Xie Y, Li M. Epigenetic modification of hepatitis B virus infection and related hepatocellular carcinoma. Virulence 2024; 15:2421231. [PMID: 39460469 PMCID: PMC11583590 DOI: 10.1080/21505594.2024.2421231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 09/18/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatitis B virus (HBV) infection poses a challenge to global public health. Persistent liver infection with HBV is associated with an increased risk of developing severe liver disease. The complex interaction between the virus and the host is the reason for the persistent presence of HBV and the risk of tumor development. Chronic liver inflammation, integration of viral genome with host genome, expression of HBx protein, and viral genotype are all key participants in the pathogenesis of hepatocellular carcinoma (HCC). Epigenetic regulation in HBV-associated HCC involves complex interactions of molecular mechanisms that control gene expression and function without altering the underlying DNA sequence. These epigenetic modifications can significantly affect the onset and progression of HCC. This review summarizes recent research on the epigenetic regulation of HBV persistent infection and HBV-HCC development, including DNA methylation, histone modification, RNA modification, non-coding RNA, etc. Enhanced knowledge of these mechanisms will offer fresh perspectives and potential targets for intervention tactics in HBV-HCC.
Collapse
Affiliation(s)
- Yaqin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Weihua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shiyu Wang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xinxin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ziyu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| |
Collapse
|
|
9
|
Chen T, Mahdadi S, Vidal M, Desbène-Finck S. Non-nucleoside inhibitors of DNMT1 and DNMT3 for targeted cancer therapy. Pharmacol Res 2024; 207:107328. [PMID: 39079576 DOI: 10.1016/j.phrs.2024.107328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/26/2024] [Accepted: 07/26/2024] [Indexed: 08/02/2024]
Abstract
DNA methylation can deactivate tumor suppressor genes thus causing cancers. Two DNA methylation inhibitors have been approved by the Food and Drug Administration (FDA) and have entered clinical use. However, these inhibitors are nucleoside analogues that can be incorporated into DNA or RNA and induce significant side effects. DNMT1 and DNMT3 are key enzymes involved in DNA methylation. In the acute myeloid leukemia model, a non-nucleoside DNMT1-specific inhibitor has shown lower toxicity and improved pharmacokinetics compared to traditional nucleoside drugs. DNMT3 is also implicated in certain specific cancers. Thus, developing non-nucleoside inhibitors for DNMT1 or DNMT3 can help in understanding their roles in carcinogenesis and provide targeted treatment options in certain cancers. Although no non-nucleoside inhibitors have yet entered clinical trials, in this review, we focus on DNMT1 or DNMT3 selective inhibitors. For DNMT1 selective inhibitors, we have compiled information on the repurposed drugs, derivative compounds and selective inhibitors identified through virtual screening. Additionally, we have outlined potential targets for DNMT1, including protein-protein complex, RNA mimics and aptamers. Compared to DNMT1, research on DNMT3-specific inhibitors has been less extensive. In this context, our exploration has identified a limited number of molecular inhibitors, and we have proposed specific long non-coding RNAs (lncRNAs) as potential contributors to the selective inhibition of DNMT3. This collective effort aims to offer valuable insights into the development of non-nucleoside inhibitors that selectively target DNMT1 or DNMT3.
Collapse
Affiliation(s)
- Ting Chen
- UMR 8038 CNRS, U1268 INSERM, UFR de pharmacie, Université Paris cité, 75270, France
| | - Syrine Mahdadi
- UMR 8038 CNRS, U1268 INSERM, UFR de pharmacie, Université Paris cité, 75270, France
| | - Michel Vidal
- UMR 8038 CNRS, U1268 INSERM, UFR de pharmacie, Université Paris cité, 75270, France; Toxicology, Cochin Hospital, HUPC, APHP, Paris 75014, France
| | | |
Collapse
|
|
10
|
Naully PG, Tan MI, Agustiningsih A, Sukowati C, Giri-Rachman EA. cccDNA epigenetic regulator as target for therapeutical vaccine development against hepatitis B. Ann Hepatol 2024; 30:101533. [PMID: 39147134 DOI: 10.1016/j.aohep.2024.101533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/21/2024] [Accepted: 08/01/2024] [Indexed: 08/17/2024]
Abstract
Chronic hepatitis B virus infection (CHB) remains a global health concern, with currently available antiviral therapies demonstrating limited effectiveness in preventing hepatocellular carcinoma (HCC) development. Two primary challenges in CHB treatment include the persistence of the minichromosome, covalently closed circular DNA (cccDNA) of the hepatitis B virus (HBV), and the failure of the host immune response to eliminate cccDNA. Recent findings indicate several host and HBV proteins involved in the epigenetic regulation of cccDNA, including HBV core protein (HBc) and HBV x protein (HBx). Both proteins might contribute to the stability of the cccDNA minichromosome and interact with viral and host proteins to support transcription. One potential avenue for CHB treatment involves the utilization of therapeutic vaccines. This paper explores HBV antigens suitable for epigenetic manipulation of cccDNA, elucidates their mechanisms of action, and evaluates their potential as key components of epigenetically-driven vaccines for CHB therapy. Molecular targeted agents with therapeutic vaccines offer a promising strategy for addressing CHB by targeting the virus and enhancing the host's immunological response. Despite challenges, the development of these vaccines provides new hope for CHB patients by emphasizing the need for HBV antigens that induce effective immune responses without causing T cell exhaustion.
Collapse
Affiliation(s)
- Patricia Gita Naully
- School of Life Science and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; Faculty of Health Sciences and Technology, Jenderal Achmad Yani University, Cimahi 40525, Indonesia
| | - Marselina Irasonia Tan
- School of Life Science and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia
| | - Agustiningsih Agustiningsih
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Caecilia Sukowati
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia; Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park, Basovizza 34049, Trieste, Italy
| | | |
Collapse
|
|
11
|
Sun X, Liu Y, Cheng C, Sun H, Tian L. CTHRC1 modulates cell proliferation and invasion in hepatocellular carcinoma by DNA methylation. Discov Oncol 2024; 15:347. [PMID: 39134747 PMCID: PMC11319694 DOI: 10.1007/s12672-024-01194-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 07/25/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND Collagen triple helix repeat containing-1 (CTHRC1), an extracellular matrix protein, is highly expressed in hepatocellular carcinoma (HCC) and linked to poor prognosis. Nevertheless, the precise mechanism of CTHRC1 in HCC is unclear. METHODS Agena MassARRAY® Methylation Analysis assessed the methylation level of CTHRC1 in the promoter region. Functional assays were conducted to investigate the effects of CTHRC1 knockdown in Hep3B2.1 cells. RNA sequencing identified differentially expressed genes and lncRNAs associated with angiogenesis after CTHRC1 knockdown. Furthermore, differential alternative splicing (AS) and gene fusion events were analyzed using rMATS and Arriba. RESULTS In HCC cell lines, CTHRC1 was highly expressed and associated with hypomethylation. Downregulation of CTHRC1 inhibited Hep3B2.1 cell proliferation, migration, and invasion, blocked cells in the G1/S phase, and promoted apoptosis. We obtained 34 mRNAs and 7 lncRNAs differentially expressed between the NC and CTHRC1 inhibitor groups. Additionally, we found 4 angiogenesis-related mRNAs and lncRNAs significantly correlated with CTHRC1. RT-qPCR results showed that knockdown of CTHRC1 in Hep3B2.1 cells resulted in significantly aberrant expression of CXCL6, LINC02127, and AC020978.8. Moreover, the role of CTHRC1 in HCC development may be associated with events, like 12 AS events and 5 pairs of fusion genes. CONCLUSIONS High expressed CTHRC1 is associated with hypomethylation and may promote HCC development, involving events like angiogenesis, alternative splicing, and gene fusion.
Collapse
Affiliation(s)
- Xiangjun Sun
- Department of Hepatobiliary Surgery, Linyi People's Hospital, Linyi, 276000, China
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Ye Liu
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Changdong Cheng
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Haoyu Sun
- Weifang Medical University, Weifang, 261053, China
| | - Liqiang Tian
- Department of Neurosurgery, Linyi People's Hospital, Lanshan District, Wohu Mountain Road and Wuhan Road Interchange, Linyi, 276000, China.
| |
Collapse
|
|
12
|
Oropeza-de Lara SA, Garza-Veloz I, Berthaud-González B, Tirado-Navarro TG, Gurrola-Carlos R, Bonilla-Rocha B, Delgado-Enciso I, Martinez-Fierro ML. Comparative Assessment of miR-185-5p and miR-191-5p Expression: From Normal Endometrium to High-Grade Endometrial Cancer. Cells 2024; 13:1099. [PMID: 38994952 PMCID: PMC11240595 DOI: 10.3390/cells13131099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 06/11/2024] [Accepted: 06/18/2024] [Indexed: 07/13/2024] Open
Abstract
Endometrial cancer (EC) is a significant cause of cancer-related deaths in women. MicroRNAs (miRs) play a role in cancer development, acting as oncogenes or tumor suppressors. This study evaluated the diagnostic potential of hsa-miR-185-5p and hsa-miR-191-5p in EC and their correlation with clinical and histopathological features. A cross-sectional study analyzed formalin-fixed, paraffin-embedded tissue samples from 59 patients: 18 with EC, 21 with endometrial hyperplasia (EH), 17 with normal endometrium (NE), and 3 with endometrial polyps (EPs). Quantitative reverse transcription-polymerase chain reaction and TaqMan probes were used for miR expression analysis. The Shapiro-Wilk test was used to analyze the normal distribution of the data. Subsequently, parametric or non-parametric tests were used to evaluate the associations between the expression levels of each miR and clinical parameters. Both miRs were underexpressed in some precursor and malignant lesions compared to certain NE subtypes and benign lesions. Specifically, hsa-miR-185-5p showed underexpression in grade 3 EC compared to some NE and EH subtypes (FC: -57.9 to -8.5, p < 0.05), and hsa-miR-191-5p was underexpressed in EH and EC compared to secretory endometrium and EPs (FC: -4.2 to -32.8, p < 0.05). SETD1B, TJP1, and MSI1 were common predicted target genes. In conclusion, hsa-miR-185-5p and hsa-miR-191-5p are underexpressed in EC tissues, correlating with histopathological grades, highlighting their potential as diagnostic biomarkers and their role as tumor suppressors in EC.
Collapse
Affiliation(s)
- Sergio Antonio Oropeza-de Lara
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autonoma de Zacatecas, Carretera Zacatecas-Guadalajara Km 6 Ejido la Escondida, Zacatecas 98160, Mexico; (S.A.O.-d.L.); (T.G.T.-N.); (R.G.-C.); (B.B.-R.)
| | - Idalia Garza-Veloz
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autonoma de Zacatecas, Carretera Zacatecas-Guadalajara Km 6 Ejido la Escondida, Zacatecas 98160, Mexico; (S.A.O.-d.L.); (T.G.T.-N.); (R.G.-C.); (B.B.-R.)
| | - Bertha Berthaud-González
- Hospital General “Luz González Cosío”, Circuito el Orito, Cd. Administrativa, Zacatecas 98160, Mexico;
| | - Tania Guillermina Tirado-Navarro
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autonoma de Zacatecas, Carretera Zacatecas-Guadalajara Km 6 Ejido la Escondida, Zacatecas 98160, Mexico; (S.A.O.-d.L.); (T.G.T.-N.); (R.G.-C.); (B.B.-R.)
| | - Reinaldo Gurrola-Carlos
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autonoma de Zacatecas, Carretera Zacatecas-Guadalajara Km 6 Ejido la Escondida, Zacatecas 98160, Mexico; (S.A.O.-d.L.); (T.G.T.-N.); (R.G.-C.); (B.B.-R.)
| | - Bernardo Bonilla-Rocha
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autonoma de Zacatecas, Carretera Zacatecas-Guadalajara Km 6 Ejido la Escondida, Zacatecas 98160, Mexico; (S.A.O.-d.L.); (T.G.T.-N.); (R.G.-C.); (B.B.-R.)
| | - Ivan Delgado-Enciso
- Department of Molecular Medicine, School of Medicine, University of Colima, Av. Universidad No. 333, Las Viboras, Colima 28040, Mexico;
- Department of Research, Colima Cancerology State Institute, IMSS-Bienestar Colima, Colima 28085, Mexico
| | - Margarita L. Martinez-Fierro
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autonoma de Zacatecas, Carretera Zacatecas-Guadalajara Km 6 Ejido la Escondida, Zacatecas 98160, Mexico; (S.A.O.-d.L.); (T.G.T.-N.); (R.G.-C.); (B.B.-R.)
| |
Collapse
|
|
13
|
Yan W, Rao D, Fan F, Liang H, Zhang Z, Dong H. Hepatitis B virus X protein and TGF-β: partners in the carcinogenic journey of hepatocellular carcinoma. Front Oncol 2024; 14:1407434. [PMID: 38962270 PMCID: PMC11220127 DOI: 10.3389/fonc.2024.1407434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/21/2024] [Indexed: 07/05/2024] Open
Abstract
Hepatitis B infection is substantially associated with the development of liver cancer globally, with the prevalence of hepatocellular carcinoma (HCC) cases exceeding 50%. Hepatitis B virus (HBV) encodes the Hepatitis B virus X (HBx) protein, a pleiotropic regulatory protein necessary for the transcription of the HBV covalently closed circular DNA (cccDNA) microchromosome. In previous studies, HBV-associated HCC was revealed to be affected by HBx in multiple signaling pathways, resulting in genetic mutations and epigenetic modifications in proto-oncogenes and tumor suppressor genes. In addition, transforming growth factor-β (TGF-β) has dichotomous potentials at various phases of malignancy as it is a crucial signaling pathway that regulates multiple cellular and physiological processes. In early HCC, TGF-β has a significant antitumor effect, whereas in advanced HCC, it promotes malignant progression. TGF-β interacts with the HBx protein in HCC, regulating the pathogenesis of HCC. This review summarizes the respective and combined functions of HBx and TGB-β in HCC occurrence and development.
Collapse
Affiliation(s)
- Wei Yan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Dean Rao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Feimu Fan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Zunyi Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Hanhua Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| |
Collapse
|
|
14
|
Peruhova M, Banova-Chakarova S, Miteva DG, Velikova T. Genetic screening of liver cancer: State of the art. World J Hepatol 2024; 16:716-730. [PMID: 38818292 PMCID: PMC11135278 DOI: 10.4254/wjh.v16.i5.716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/14/2024] [Accepted: 04/09/2024] [Indexed: 05/22/2024] Open
Abstract
Liver cancer, primarily hepatocellular carcinoma, remains a global health challenge with rising incidence and limited therapeutic options. Genetic factors play a pivotal role in the development and progression of liver cancer. This state-of-the-art paper provides a comprehensive review of the current landscape of genetic screening strategies for liver cancer. We discuss the genetic underpinnings of liver cancer, emphasizing the critical role of risk-associated genetic variants, somatic mutations, and epigenetic alterations. We also explore the intricate interplay between environmental factors and genetics, highlighting how genetic screening can aid in risk stratification and early detection via using liquid biopsy, and advancements in high-throughput sequencing technologies. By synthesizing the latest research findings, we aim to provide a comprehensive overview of the state-of-the-art genetic screening methods for liver cancer, shedding light on their potential to revolutionize early detection, risk assessment, and targeted therapies in the fight against this devastating disease.
Collapse
Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital "Heart and Brain", Burgas 8000, Bulgaria
| | - Sonya Banova-Chakarova
- Department of Gastroenterology, University Hospital "Heart and Brain", Burgas 8000, Bulgaria.
| | - Dimitrina Georgieva Miteva
- Department of Genetics, Faculty of Biology, Sofia University" St. Kliment Ohridski, Sofia 1164, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| |
Collapse
|
|
15
|
Dong W, Wang H, Li M, Li P, Ji S. Virus-induced host genomic remodeling dysregulates gene expression, triggering tumorigenesis. Front Cell Infect Microbiol 2024; 14:1359766. [PMID: 38572321 PMCID: PMC10987825 DOI: 10.3389/fcimb.2024.1359766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 03/01/2024] [Indexed: 04/05/2024] Open
Abstract
Virus-induced genomic remodeling and altered gene expression contribute significantly to cancer development. Some oncogenic viruses such as Human papillomavirus (HPV) specifically trigger certain cancers by integrating into the host's DNA, disrupting gene regulation linked to cell growth and migration. The effect can be through direct integration of viral genomes into the host genome or through indirect modulation of host cell pathways/proteins by viral proteins. Viral proteins also disrupt key cellular processes like apoptosis and DNA repair by interacting with host molecules, affecting signaling pathways. These disruptions lead to mutation accumulation and tumorigenesis. This review focuses on recent studies exploring virus-mediated genomic structure, altered gene expression, and epigenetic modifications in tumorigenesis.
Collapse
Affiliation(s)
- Weixia Dong
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Huiqin Wang
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Menghui Li
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Ping Li
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Shaoping Ji
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
- Department of Biochemistry and Molecular Biology, Medical School, Henan University, Kaifeng, Henan, China
| |
Collapse
|
|
16
|
Agustiningsih A, Rasyak MR, Turyadi, Jayanti S, Sukowati C. The oncogenic role of hepatitis B virus X gene in hepatocarcinogenesis: recent updates. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:120-134. [PMID: 38464387 PMCID: PMC10918233 DOI: 10.37349/etat.2024.00209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 11/21/2023] [Indexed: 03/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancers with high mortality rate. Among its various etiological factors, one of the major risk factors for HCC is a chronic infection of hepatitis B virus (HBV). HBV X protein (HBx) has been identified to play an important role in the HBV-induced HCC pathogenesis since it may interfere with several key regulators of many cellular processes. HBx localization within the cells may be beneficial to HBx multiple functions at different phases of HBV infection and associated hepatocarcinogenesis. HBx as a regulatory protein modulates cellular transcription, molecular signal transduction, cell cycle, apoptosis, autophagy, protein degradation pathways, and host genetic stability via interaction with various factors, including its association with various non-coding RNAs. A better understanding on the regulatory mechanism of HBx on various characteristics of HCC would provide an overall picture of HBV-associated HCC. This article addresses recent data on HBx role in the HBV-associated hepatocarcinogenesis.
Collapse
Affiliation(s)
- Agustiningsih Agustiningsih
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Muhammad Rezki Rasyak
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
- Post Graduate School, Faculty of Medicine, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Turyadi
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Sri Jayanti
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Caecilia Sukowati
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy
| |
Collapse
|
|
17
|
Wang F, Song H, Xu F, Xu J, Wang L, Yang F, Zhu Y, Tan G. Role of hepatitis B virus non-structural protein HBx on HBV replication, interferon signaling, and hepatocarcinogenesis. Front Microbiol 2023; 14:1322892. [PMID: 38188582 PMCID: PMC10767994 DOI: 10.3389/fmicb.2023.1322892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/07/2023] [Indexed: 01/09/2024] Open
Abstract
Hepatitis B, a global health concern caused by the hepatitis B virus (HBV), infects nearly 2 billion individuals worldwide, as reported by the World Health Organization (WHO). HBV, a hepatotropic DNA virus, predominantly targets and replicates within hepatocytes. Those carrying the virus are at increased risk of liver cirrhosis and hepatocellular carcinoma, resulting in nearly 900,000 fatalities annually. The HBV X protein (HBx), encoded by the virus's open reading frame x, plays a key role in its virulence. This protein is integral to viral replication, immune modulation, and liver cancer progression. Despite its significance, the precise molecular mechanisms underlying HBx remain elusive. This review investigates the HBx protein's roles in HBV replication, interferon signaling regulation, and hepatocellular carcinoma progression. By understanding the complex interactions between the virus and its host mediated by HBx, we aim to establish a solid foundation for future research and the development of HBx-targeted therapeutics.
Collapse
Affiliation(s)
- Fei Wang
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Hongxiao Song
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Fengchao Xu
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jing Xu
- Health Examination Center, The First Hospital of Jilin University, Changchun, China
| | - Le Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Fan Yang
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yujia Zhu
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Guangyun Tan
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| |
Collapse
|
|
18
|
Nuermaimaiti A, Chang L, Yan Y, Sun H, Xiao Y, Song S, Feng K, Lu Z, Ji H, Wang L. The role of sex hormones and receptors in HBV infection and development of HBV-related HCC. J Med Virol 2023; 95:e29298. [PMID: 38087447 DOI: 10.1002/jmv.29298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/02/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023]
Abstract
Gender disparity in hepatitis B virus (HBV)-related diseases has been extensively documented. Epidemiological studies consistently reported that males have a higher prevalence of HBV infection and incidence of hepatocellular carcinoma (HCC). Further investigations have revealed that sex hormone-related signal transductions play a significant role in gender disparity. Sex hormone axes showed significantly different responses to virus entry and replication. The sex hormones axes change the HBV-specific immune responses and antitumor immunity. Additionally, Sex hormone axes showed different effects on the development of HBV-related disease. But the role of sex hormones remains controversial, and researchers have not reached a consensus on the role of sex hormones and the use of hormone therapies in HCC treatment. In this review, we aim to summarize the experimental findings on sex hormones and provide a comprehensive understanding of their roles in the development of HCC and their implications for hormone-related HCC treatment.
Collapse
Affiliation(s)
- Abudulimutailipu Nuermaimaiti
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Le Chang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Ying Yan
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huizhen Sun
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yingzi Xiao
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shi Song
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Kaihao Feng
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhuoqun Lu
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huimin Ji
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Lunan Wang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| |
Collapse
|
|
19
|
Reyes A, Ortiz G, Duarte LF, Fernández C, Hernández-Armengol R, Palacios PA, Prado Y, Andrade CA, Rodriguez-Guilarte L, Kalergis AM, Simon F, Carreño LJ, Riedel CA, Cáceres M, González PA. Contribution of viral and bacterial infections to senescence and immunosenescence. Front Cell Infect Microbiol 2023; 13:1229098. [PMID: 37753486 PMCID: PMC10518457 DOI: 10.3389/fcimb.2023.1229098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 08/24/2023] [Indexed: 09/28/2023] Open
Abstract
Cellular senescence is a key biological process characterized by irreversible cell cycle arrest. The accumulation of senescent cells creates a pro-inflammatory environment that can negatively affect tissue functions and may promote the development of aging-related diseases. Typical biomarkers related to senescence include senescence-associated β-galactosidase activity, histone H2A.X phosphorylation at serine139 (γH2A.X), and senescence-associated heterochromatin foci (SAHF) with heterochromatin protein 1γ (HP-1γ protein) Moreover, immune cells undergoing senescence, which is known as immunosenescence, can affect innate and adaptative immune functions and may elicit detrimental effects over the host's susceptibility to infectious diseases. Although associations between senescence and pathogens have been reported, clear links between both, and the related molecular mechanisms involved remain to be determined. Furthermore, it remains to be determined whether infections effectively induce senescence, the impact of senescence and immunosenescence over infections, or if both events coincidently share common molecular markers, such as γH2A.X and p53. Here, we review and discuss the most recent reports that describe cellular hallmarks and biomarkers related to senescence in immune and non-immune cells in the context of infections, seeking to better understand their relationships. Related literature was searched in Pubmed and Google Scholar databases with search terms related to the sections and subsections of this review.
Collapse
Affiliation(s)
- Antonia Reyes
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gerardo Ortiz
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luisa F. Duarte
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile
| | - Christian Fernández
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile
| | - Rosario Hernández-Armengol
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile
| | - Pablo A. Palacios
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Yolanda Prado
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile
| | - Catalina A. Andrade
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Linmar Rodriguez-Guilarte
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Felipe Simon
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile
| | - Leandro J. Carreño
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Claudia A. Riedel
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile
| | - Mónica Cáceres
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| |
Collapse
|
|
20
|
Fu S, Debes JD, Boonstra A. DNA methylation markers in the detection of hepatocellular carcinoma. Eur J Cancer 2023; 191:112960. [PMID: 37473464 DOI: 10.1016/j.ejca.2023.112960] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/22/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and has a poor prognosis. Epigenetic modification has been shown to be deregulated during HCC development by dramatically impacting the differentiation, proliferation, and function of cells. One important epigenetic modification is DNA methylation during which methyl groups are added to cytosines without changing the DNA sequence itself. Studies found that methylated DNA markers can be specific for detection of HCC. On the basis of these findings, the utility of methylated DNA markers as novel biomarkers for early-stage HCC has been measured in blood, and indeed superior sensitivity and specificity have been found in several studies when compared to current surveillance methods. However, a variety of factors currently limit the immediate application of these exciting biomarkers. In this review, we provide a detailed rationalisation of the approach and basis for the use of methylation biomarkers for HCC detection and summarise recent studies on methylated DNA markers in HCC focusing on the importance of the aetiological cause of liver disease in the mechanisms leading to cancer.
Collapse
Affiliation(s)
- Siyu Fu
- Erasmus MC University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands
| | - José D Debes
- Erasmus MC University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands; Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - André Boonstra
- Erasmus MC University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands.
| |
Collapse
|
|
21
|
Lominadze Z, Shaik MR, Choi D, Zaffar D, Mishra L, Shetty K. Hepatocellular Carcinoma Genetic Classification. Cancer J 2023; 29:249-258. [PMID: 37796642 PMCID: PMC10686192 DOI: 10.1097/ppo.0000000000000682] [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] [Indexed: 10/07/2023]
Abstract
ABSTRACT Hepatocellular carcinoma (HCC) represents a significant global burden, with management complicated by its heterogeneity, varying presentation, and relative resistance to therapy. Recent advances in the understanding of the genetic, molecular, and immunological underpinnings of HCC have allowed a detailed classification of these tumors, with resultant implications for diagnosis, prognostication, and selection of appropriate treatments. Through the correlation of genomic features with histopathology and clinical outcomes, we are moving toward a comprehensive and unifying framework to guide our diagnostic and therapeutic approach to HCC.
Collapse
Affiliation(s)
- Zurabi Lominadze
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
| | | | - Dabin Choi
- Department of Medicine, University of Maryland Medical Center
| | - Duha Zaffar
- Department of Medicine, University of Maryland Midtown Medical Center
| | - Lopa Mishra
- Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory; Divisions of Gastroenterology and Hepatology, Northwell Health
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
| |
Collapse
|
|
22
|
Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
Collapse
Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
| |
Collapse
|
|
23
|
Xue C, Gu X, Zheng Q, Shi Q, Yuan X, Su Y, Jia J, Jiang J, Lu J, Li L. ALYREF mediates RNA m 5C modification to promote hepatocellular carcinoma progression. Signal Transduct Target Ther 2023; 8:130. [PMID: 36934090 PMCID: PMC10024699 DOI: 10.1038/s41392-023-01395-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 02/07/2023] [Accepted: 02/20/2023] [Indexed: 03/20/2023] Open
Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qiuxian Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yuanshuai Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Junjun Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jianwen Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| |
Collapse
|
|
24
|
Relevance of HBx for Hepatitis B Virus-Associated Pathogenesis. Int J Mol Sci 2023; 24:ijms24054964. [PMID: 36902395 PMCID: PMC10003785 DOI: 10.3390/ijms24054964] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/20/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
The hepatitis B virus (HBV) counts as a major global health problem, as it presents a significant causative factor for liver-related morbidity and mortality. The development of hepatocellular carcinomas (HCC) as a characteristic of a persistent, chronic infection could be caused, among others, by the pleiotropic function of the viral regulatory protein HBx. The latter is known to modulate an onset of cellular and viral signaling processes with emerging influence in liver pathogenesis. However, the flexible and multifunctional nature of HBx impedes the fundamental understanding of related mechanisms and the development of associated diseases, and has even led to partial controversial results in the past. Based on the cellular distribution of HBx-nuclear-, cytoplasmic- or mitochondria-associated-this review encompasses the current knowledge and previous investigations of HBx in context of cellular signaling pathways and HBV-associated pathogenesis. In addition, particular focus is set on the clinical relevance and potential novel therapeutic applications in the context of HBx.
Collapse
|
|
25
|
Karakousis ND, Chrysavgis L, Papatheodoridi A, Legaki AI, Lembessis P, Cholongitas E, Chatzigeorgiou A, Papatheodoridis G. Significance of Circulating Cell-Free DNA Biomarkers in HBeAg-Negative Chronic Hepatitis B Virus Infection and Their Changes after Treatment Initiation. Pathogens 2023; 12:394. [PMID: 36986316 PMCID: PMC10053129 DOI: 10.3390/pathogens12030394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/25/2023] [Accepted: 02/28/2023] [Indexed: 03/05/2023] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is a common chronic liver disease that is closely associated with increased morbidity and mortality. Circulating cell-free DNA (cf-DNA) and global DNA methylation, expressed as circulating levels of 5-methyl-2'-deoxycytidine, are increasingly used to monitor chronic inflammatory diseases of several etiologies. This study attempts to investigate the serum levels of circulating cf-DNA and 5-methyl-2'-deoxycytidine in HBeAg-negative patients with chronic infection (carriers) and chronic hepatitis B (CHB), as well as their changes after treatment initiation in CHB. METHODS Serum samples from a total of 61 HBeAg-negative patients (30 carriers and 31 CHB patients) were included in order to quantify the levels of circulating cf-DNA and 5-methyl-2'-deoxycytidine. In addition, serum samples from 17 CHB patients in complete virological and biochemical remission after initiation of treatment with a nucleos(t)ide analogue were included. RESULTS Circulating cf-DNA concentration was significantly increased after the initiation of treatment (15 vs. 10 ng/mL, p = 0.022). There was a trend in higher mean levels of circulating 5-methyl-2'-deoxycytidine in carriers compared to CHB patients (211.02 vs. 175.66 ng/mL, p = 0.089), as well as a trend in increasing 5-methyl-2'-deoxycytidine levels after treatment initiation in CHB patients compared to pre-treatment levels (215 vs. 173 ng/mL, p = 0.079). CONCLUSIONS Both circulating levels of cf-DNA and 5-methyl-2'-deoxycytidine might be useful biomarkers in order to monitor liver disease activity and response to antiviral treatment in HBeAg-negative chronic HBV patients, but further studies are essential in order to validate these intriguing findings.
Collapse
Affiliation(s)
- Nikolaos D. Karakousis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Lampros Chrysavgis
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Alkistis Papatheodoridi
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, 11527 Athens, Greece
- Department of Clinical Therapeutics, Medical School of National and Kapodistrian University of Athens, “Alexandra” General Hospital of Athens, 11528 Athens, Greece
| | - Aigli-Ioanna Legaki
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Panagiotis Lembessis
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
| |
Collapse
|
|
26
|
Islam B, Yu HY, Duan TQ, Pan J, Li M, Zhang RQ, Masroor M, Huang JF. Cell cycle kinases (AUKA, CDK1, PLK1) are prognostic biomarkers and correlated with tumor-infiltrating leukocytes in HBV related HCC. J Biomol Struct Dyn 2023; 41:11845-11861. [PMID: 36634158 DOI: 10.1080/07391102.2022.2164056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 12/24/2022] [Indexed: 01/14/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the high incidence cancers and third leading cause of cancer-related mortality. HBV is the top most risk factor accounting for 50-80% of the HCC cases. Kinases: Aurora kinase A (AURKA), cyclin-dependent kinase (CDK1) and Polo-like kinase 1 (PLK1), the key regulators of cell mitosis are overexpressed in varieties of cancers including HCC. However, the exact role of these genes in prognosis of HCC is not fully unveiled. In addition, there is no such an accurate prognostic biomarker for HBV-related HCC. To address this issue, we performed a multidimensional analysis of AURKA, CDK1 and PLK1 with a series of publicly available databases in multiple cancers and with experimental validation in HBV-related HCC tissues. Overexpression of AURKA, CDK1 and PLK1 was found in multiple cancers including HCC. Elevated expression of these genes could result from lowered DNA methylation and genomic alterations. Transcriptional overexpression was significantly correlated with poor prognosis of HCC patients. The expression levels were also significantly positively associated with tumor grades and stages. Furthermore, the expression levels of these genes had a strong correlation with infiltration of immune cells. Our analysis shows that AURKA, CDK1 and PLK1 are correlated with immune infiltration and are the prognostic biomarkers for HBV-induced HCC.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Baitul Islam
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Hai-Yang Yu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Tian-Qi Duan
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jing Pan
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Min Li
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Ru-Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Matiullah Masroor
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ju-Fang Huang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| |
Collapse
|
|
27
|
Bhattacharya A. Epigenetic modifications and regulations in gastrointestinal diseases. EPIGENETICS IN ORGAN SPECIFIC DISORDERS 2023:497-543. [DOI: 10.1016/b978-0-12-823931-5.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
28
|
Yoon H, Han J, Jang KL. Hepatitis B Virus X Protein Stimulates Hepatitis C Virus (HCV) Replication by Protecting HCV Core Protein from E6AP-Mediated Proteasomal Degradation. Microbiol Spectr 2022; 10:e0143222. [PMID: 36374094 PMCID: PMC9784765 DOI: 10.1128/spectrum.01432-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 10/21/2022] [Indexed: 11/16/2022] Open
Abstract
Most clinical and experimental studies have suggested that hepatitis C virus (HCV) is dominant over hepatitis B virus (HBV) during coinfection, although the underlying mechanism remains unclear. In this study, we found that the HBV X protein (HBx) upregulates the levels of the HCV core protein to stimulate HCV replication during coinfection in human hepatoma cells. For this purpose, HBx upregulated both the protein levels and enzyme activities of cellular DNA methyltransferase 1 (DNMT1) and DNMT3b, and this subsequently reduced the expression levels of the E6-associated protein (E6AP), an E3 ligase of the HCV core protein, via DNA methylation. The ubiquitin-dependent proteasomal degradation of the HCV core protein was severely impaired in the presence of HBx, whereas this effect was not observed when E6AP was either ectopically expressed or restored by treatment with 5-aza-2'dC or DNMT1 knockdown. The effect of HBx on the HCV core protein was accurately reproduced in HBV/HCV coinfection systems, which were established by either monoinfection by HCV in Huh7D cells transfected with a 1.2-mer HBV replicon or coinfection by HBV and HCV in Huh7D-Na+-taurocholate cotransporting polypeptide cells, providing evidence for the stimulation of HCV replication by HBx. The present study may provide insights into understanding HCV dominance during HBV/HCV coinfection in patients. IMPORTANCE Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major human pathogens that cause a substantial proportion of liver diseases worldwide. As the two hepatotropic viruses have the same modes of transmission, coinfection is often observed, especially in areas and populations where HBV is endemic. High-risk populations include people who inject drugs. Both clinical and experimental studies have shown that HCV is more dominant than HBV during coinfection, but the underlying mechanism remains unclear. In this study, we show that HBV X protein (HBx) stimulates HCV replication by inhibiting the expression of E6-associated protein (E6AP) via DNA methylation, thereby protecting the HCV core protein from proteasomal degradation, which can contribute to HCV dominance during HBV/HCV coinfection.
Collapse
Affiliation(s)
- Hyunyoung Yoon
- Department of Integrated Biological Science, The Graduate School, Pusan National University, Busan, Republic of Korea
| | - Jiwoo Han
- Department of Integrated Biological Science, The Graduate School, Pusan National University, Busan, Republic of Korea
| | - Kyung Lib Jang
- Department of Integrated Biological Science, The Graduate School, Pusan National University, Busan, Republic of Korea
- Department of Microbiology, College of Natural Science, Pusan National University, Busan, Republic of Korea
- Microbiological Resource Research Institute, Pusan National University, Busan, Republic of Korea
| |
Collapse
|
|
29
|
The Role of Lead and Cadmium in Gynecological Malignancies. Antioxidants (Basel) 2022; 11:antiox11122468. [PMID: 36552675 PMCID: PMC9774668 DOI: 10.3390/antiox11122468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/10/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Lead and cadmium are non-essential and toxic heavy metals. Their presence and elevated levels can lead to many pathologies. They disrupt the antioxidant properties of many enzymes, consume the resources of antioxidant cells, and thus participate in the generation of oxidative stress, which may result in DNA damage. In addition, they have been found to be carcinogenic through their genotoxic properties. They have been shown to be present in various types of cancer, including cancer of the female reproductive system. Both metals have been recognized as metalloestrogens, which are important in hormone-related cancers. Participation in the oncogenesis of ovarian, endometrial and cervical cancer was analysed in detail, using the available research in this field. We emphasize their role as potential biomarkers in cancer risk and diagnosis as well as advancement of gynaecological malignancies.
Collapse
|
|
30
|
Sae-Lee C, Barrow TM, Colicino E, Choi SH, Rabanal-Ruiz Y, Green D, Korolchuk VI, Mathers JC, Byun HM. Genomic targets and selective inhibition of DNA methyltransferase isoforms. Clin Epigenetics 2022; 14:103. [PMID: 35987848 PMCID: PMC9392947 DOI: 10.1186/s13148-022-01325-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 08/11/2022] [Indexed: 11/10/2022] Open
Abstract
Background DNA methylation in the human genome is established and maintained by DNA methyltransferases (DNMTs). DNMT isoforms show differential expression by cell lineage and during development, but much remains to be elucidated about their shared and unique genomic targets. Results We examined changes in the epigenome following overexpression of 13 DNMT isoforms in HEK293T cells. We observed increased methylation (Δβ > 0.2) at 43,405 CpG sites, with expression of DNMT3A2, DNMTΔ3B4 and DNMTΔ3B2 associated with the greatest impact. De novo methylation occurred primarily within open sea regions and at loci with intermediate methylation levels (β: 0.2–0.6). 53% of differentially methylated loci showed specificity towards a single DNMT subfamily, primarily DNMTΔ3B and DNMT3A and 39% towards a single isoform. These loci were significantly enriched for pathways related to neuronal development (DNMTΔ3B4), calcium homeostasis (DNMTΔ3B3) and ion transport (DNMT3L). Repetitive elements did not display differential sensitivity to overexpressed DNMTs, but hypermethylation of Alu elements was associated with their evolutionary age following overexpression of DNMT3A2, DNMT3B1, DNMT3B2 and DNMT3L. Differential methylation (Δβ > 0.1) was observed at 121 of the 353 loci associated with the Horvath ‘epigenetic clock’ model of ageing, with 51 showing isoform specificity, and was associated with reduction of epigenetic age by 5–15 years following overexpression of seven isoforms. Finally, we demonstrate the potential for dietary constituents to modify epigenetic marks through isoform-specific inhibition of methylation activity. Conclusions Our results provide insight into regions of the genome methylated uniquely by specific DNMT isoforms and demonstrate the potential for dietary intervention to modify the epigenome. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-022-01325-4.
Collapse
|
|
31
|
Baidya A, Khatun M, Mondal RK, Ghosh S, Chakraborty BC, Mallik S, Ahammed SKM, Chowdhury A, Banerjee S, Datta S. Hepatitis B virus suppresses complement C9 synthesis by limiting the availability of transcription factor USF-1 and inhibits formation of membrane attack complex: implications in disease pathogenesis. J Biomed Sci 2022; 29:97. [PMID: 36376872 PMCID: PMC9664717 DOI: 10.1186/s12929-022-00876-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 10/29/2022] [Indexed: 11/15/2022] Open
Abstract
Background The complement system functions primarily as a first-line host defense against invading microbes, including viruses. However, the interaction of Hepatitis B virus (HBV) with the complement-components during chronic HBV infection remains largely unknown. We investigated the mechanism by which HBV inhibits the formation of cytolytic complement membrane-attack complex (MAC) and studied its impact on MAC-mediated microbicidal activity and disease pathogenesis. Methods Blood/liver tissues were collected from chronically HBV-infected patients and controls. HepG2hNTCP cells were infected with HBV particles and Huh7 cells were transfected with full-length linear HBV-monomer or plasmids containing different HBV-ORFs and expression of complement components or other host genes were evaluated. Additionally, ELISA, Real-time PCR, Western blot, bioinformatics analysis, gene overexpression/knock-down, mutagenesis, chromatin immunoprecipitation, epigenetic studies, immunofluorescence, and quantification of serum HBV-DNA, bacterial-DNA and endotoxin were performed. Results Among the MAC components (C5b-C9), significant reduction was noted in the expression of C9, the major constituent of MAC, in HBV-infected HepG2hNTCP cells and in Huh7 cells transfected with full-length HBV as well as HBX. C9 level was also marked low in sera/liver of chronic hepatitis B (CHB) and Immune-tolerant (IT) patients than inactive carriers and healthy controls. HBX strongly repressed C9-promoter activity in Huh7 cells but CpG-island was not detected in C9-promoter. We identified USF-1 as the key transcription factor that drives C9 expression and demonstrated that HBX-induced hypermethylation of USF-1-promoter is the leading cause of USF-1 downregulation that in turn diminished C9 transcription. Reduced MAC formation and impaired lysis of HBV-transfected Huh7 and bacterial cells were observed following incubation of these cells with C9-deficient CHB sera but was reversed upon C9 supplementation. Significant inverse correlation was noted between C9 concentration and HBV-DNA, bacterial-DNA and endotoxin content in HBV-infected patients. One-year Tenofovir therapy resulted in improvement in C9 level and decline in viral/bacterial/endotoxin load in CHB patients. Conclusion Collectively, HBX suppressed C9 transcription by restricting the availability of USF-1 through hypermethylation of USF-1-promoter and consequently hinder the formation and lytic functions of MAC. Early therapy is needed for both CHB and IT to normalize the aberrant complement profile and contain viral and bacterial infection and limit disease progression. Supplementary Information The online version contains supplementary material available at 10.1186/s12929-022-00876-1.
Collapse
|
|
32
|
Wang D, Hu X, Chen J, Liang B, Zhang L, Qin P, Wu D. Bioinformatics Analysis and Validation of the Role of Lnc-RAB11B-AS1 in the Development and Prognosis of Hepatocellular Carcinoma. Cells 2022; 11:3517. [PMID: 36359911 PMCID: PMC9657516 DOI: 10.3390/cells11213517] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/01/2022] [Accepted: 11/03/2022] [Indexed: 01/26/2024] Open
Abstract
Lnc-RAB11B-AS1 is reported to be dysregulated in several types of cancers and can function as both an oncogene and tumor suppressor gene. To evaluate the potential role of lnc-RAB11B-AS1 in hepatocellular carcinoma (HCC), we investigated and evaluated its expression in HCC based on the data mining of a series of public databases, including TCGA, GEO, ICGC, HPA, DAVID, cBioPortal, GeneMIANA, TIMER, and ENCORI. The data showed downregulation of lnc-RAB11B-AS1 in HCC and was accompanied by the synchronous downregulation of the targeted RAB11B mRNA and its protein. Low expression of lnc-RAB11B-AS1 was associated with shorter overall survival (OS) and disease-free survival (DFS) of HCC patients, PD1/PD-L1 was correlated with low expression of RAB11B. Furthermore, Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed a correlation between immune cell change and non-alcoholic fatty liver disease. The above findings revealed that lnc-RAB11B-AS1 was down-regulated in HCC and closely associated with the clinical stage of the HCC patients, suggesting that lnc-RAB11B-AS1 could be a possible predictor for HCC and a potential new therapeutic target for the treatment of HCC.
Collapse
Affiliation(s)
- Dedong Wang
- Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
- Institute of Public Health, Guangzhou Medical University & Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Xiangzhi Hu
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Jinbin Chen
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 510180, China
| | - Boheng Liang
- Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
- Institute of Public Health, Guangzhou Medical University & Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
| | - Lin Zhang
- Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
- Institute of Public Health, Guangzhou Medical University & Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
| | - Pengzhe Qin
- Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
- Institute of Public Health, Guangzhou Medical University & Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
| | - Di Wu
- Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
- Institute of Public Health, Guangzhou Medical University & Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
| |
Collapse
|
|
33
|
Boycott C, Beetch M, Yang T, Lubecka K, Ma Y, Zhang J, Kurzava Kendall L, Ullmer M, Ramsey BS, Torregrosa-Allen S, Elzey BD, Cox A, Lanman NA, Hui A, Villanueva N, de Conti A, Huan T, Pogribny I, Stefanska B. Epigenetic aberrations of gene expression in a rat model of hepatocellular carcinoma. Epigenetics 2022; 17:1513-1534. [PMID: 35502615 PMCID: PMC9586690 DOI: 10.1080/15592294.2022.2069386] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/22/2022] [Accepted: 04/14/2022] [Indexed: 11/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is mostly triggered by environmental and life-style factors and may involve epigenetic aberrations. However, a comprehensive documentation of the link between the dysregulated epigenome, transcriptome, and liver carcinogenesis is lacking. In the present study, Fischer-344 rats were fed a choline-deficient (CDAA, cancer group) or choline-sufficient (CSAA, healthy group) L-amino acid-defined diet. At the end of 52 weeks, transcriptomic alterations in livers of rats with HCC tumours and healthy livers were investigated by RNA sequencing. DNA methylation and gene expression were assessed by pyrosequencing and quantitative reverse-transcription PCR (qRT-PCR), respectively. We discovered 1,848 genes that were significantly differentially expressed in livers of rats with HCC tumours (CDAA) as compared with healthy livers (CSAA). Upregulated genes in the CDAA group were associated with cancer-related functions, whereas macronutrient metabolic processes were enriched by downregulated genes. Changes of highest magnitude were detected in numerous upregulated genes that govern key oncogenic signalling pathways, including Notch, Wnt, Hedgehog, and extracellular matrix degradation. We further detected perturbations in DNA methylating and demethylating enzymes, which was reflected in decreased global DNA methylation and increased global DNA hydroxymethylation. Four selected upregulated candidates, Mmp12, Jag1, Wnt4, and Smo, demonstrated promoter hypomethylation with the most profound decrease in Mmp12. MMP12 was also strongly overexpressed and hypomethylated in human HCC HepG2 cells as compared with primary hepatocytes, which coincided with binding of Ten-eleven translocation 1 (TET1). Our findings provide comprehensive evidence for gene expression changes and dysregulated epigenome in HCC pathogenesis, potentially revealing novel targets for HCC prevention/treatment.
Collapse
Affiliation(s)
- Cayla Boycott
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| | - Megan Beetch
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tony Yang
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| | - Katarzyna Lubecka
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Lodz, Lodz, Poland
| | - Yuexi Ma
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jiaxi Zhang
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| | - Lucinda Kurzava Kendall
- Department of Nutrition Science, College of Health and Human Sciences, Purdue University, Indiana, USA
- Department of Internal Medicine, Ascension St. Vincent Hospital, Indianapolis, Indiana, USA
| | - Melissa Ullmer
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Benjamin S. Ramsey
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
| | - Sandra Torregrosa-Allen
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
| | - Bennett D. Elzey
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, Indiana, USA
| | - Abigail Cox
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, Indiana, USA
| | - Nadia Atallah Lanman
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, Indiana, USA
| | - Alisa Hui
- Department of Chemistry, Faculty of Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Nathaniel Villanueva
- Department of Chemistry, Faculty of Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Aline de Conti
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, Arkansas, USA
| | - Tao Huan
- Department of Chemistry, Faculty of Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Igor Pogribny
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, Arkansas, USA
| | - Barbara Stefanska
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| |
Collapse
|
|
34
|
Yang Z, Sun B, Xiang J, Wu H, Kan S, Hao M, Chang L, Liu H, Wang D, Liu W. Role of epigenetic modification in interferon treatment of hepatitis B virus infection. Front Immunol 2022; 13:1018053. [PMID: 36325353 PMCID: PMC9618964 DOI: 10.3389/fimmu.2022.1018053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/27/2022] [Indexed: 11/28/2022] Open
Abstract
Human hepatitis B virus (HBV) is a small, enveloped DNA virus that causes acute and chronic hepatitis. Chronic hepatitis B (CHB) is associated with hepatocellular carcinoma pathogenesis. Interferons (IFNs) have been used for the treatment of CHB for a long time, with advantages including less treatment duration and sustained virological response. Presently, various evidence suggests that epigenetic modification of the viral covalently closed circular DNA (cccDNA) and the host genome is crucial for the regulation of viral activity. This modification includes histone acetylation, DNA methylation, N6-methyladenosine, and non-coding RNA modification. IFN treatment for CHB can stimulate multiple IFN-stimulated genes for inhibiting virus replication. IFNs can also affect the HBV life cycle through epigenetic modulation. In this review, we summarized the different mechanisms through which IFN-α inhibits HBV replication, including epigenetic regulation. Moreover, the mechanisms underlying IFN activity are discussed, which indicated its potential as a novel treatment for CHB. It is proposed that epigenetic changes such as histone acetylation, DNA methylation, m6A methylation could be the targets of IFN, which may offer a novel approach to HBV treatment.
Collapse
Affiliation(s)
- Zhijing Yang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Baozhen Sun
- Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jingcheng Xiang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Han Wu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Shaoning Kan
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Ming Hao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Lu Chang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Huimin Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
| | - Weiwei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
| |
Collapse
|
|
35
|
Tian Z, Xu C, Yang P, Lin Z, Wu W, Zhang W, Ding J, Ding R, Zhang X, Dou K. Molecular pathogenesis: Connections between viral hepatitis-induced and non-alcoholic steatohepatitis-induced hepatocellular carcinoma. Front Immunol 2022; 13:984728. [PMID: 36189208 PMCID: PMC9520190 DOI: 10.3389/fimmu.2022.984728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/31/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma(HCC) is the sixth most common cancer in the world and is usually caused by viral hepatitis (HBV and HCV), alcoholic, and non-alcoholic fatty liver disease(NAFLD). Viral hepatitis accounts for 80% of HCC cases worldwide. In addition, With the increasing incidence of metabolic diseases, NAFLD is now the most common liver disease and a major risk factor for HCC in most developed countries. This review mainly described the specificity and similarity between the pathogenesis of viral hepatitis(HBV and HCV)-induced HCC and NAFLD-induced HCC. In general, viral hepatitis promotes HCC development mainly through specific encoded viral proteins. HBV can also exert its tumor-promoting mechanism by integrating into the host chromosome, while HCV cannot. Viral hepatitis-related HCC and NASH-related HCC differ in terms of genetic factors, and epigenetic modifications (DNA methylation, histone modifications, and microRNA effects). In addition, both of them can lead to HCC progression through abnormal lipid metabolism, persistent inflammatory response, immune and intestinal microbiome dysregulation.
Collapse
Affiliation(s)
- Zelin Tian
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Chen Xu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Peijun Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Zhibin Lin
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenlong Wu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- Chinese Education Ministry’s Key Laboratory of Western Resources and Modern Biotechnology, Key Laboratory of Biotechnology Shaanxi Province, College of Life Sciences, Northwest University, Xi’an, China
| | - Jian Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Rui Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
| |
Collapse
|
|
36
|
Identification of Estradiol Benzoate as an Inhibitor of HBx Using Inducible Stably Transfected HepG2 Cells Expressing HiBiT Tagged HBx. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27155000. [PMID: 35956950 PMCID: PMC9370419 DOI: 10.3390/molecules27155000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 11/16/2022]
Abstract
HBx plays a significant role in the cccDNA epigenetic modification regulating the hepatitis B virus (HBV) life cycle and in hepatocyte proliferation and carcinogenesis. By using the sleeping-beauty transposon system, we constructed a tetracycline-induced HBx-expressing stable cell line, SBHX21. HBx with a HiBiT tag can be quickly detected utilizing a NanoLuc-based HiBiT detection system. By screening a drug library using SBHX21 cells, we identified estradiol benzoate as a novel anti-HBx agent. Estradiol benzoate also markedly reduced the production of HBeAg, HBsAg, HBV pgRNA, and HBV DNA in a dose-dependent manner, suggesting that estradiol benzoate could be an anti-HBV agent. Docking model results revealed that estradiol benzoate binds to HBx at TRP87 and TRP107. Collectively, our results suggest that estradiol benzoate inhibits the HBx protein and HBV transcription and replication, which may serve as a novel anti-HBV molecular compound for investigating new treatment strategies for HBV infection.
Collapse
|
|
37
|
IFN-α inhibits HBV transcription and replication by promoting HDAC3-mediated de-2-hydroxyisobutyrylation of histone H4K8 on HBV cccDNA minichromosome in liver. Acta Pharmacol Sin 2022; 43:1484-1494. [PMID: 34497374 PMCID: PMC9160025 DOI: 10.1038/s41401-021-00765-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023]
Abstract
The epigenetic modification of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a crucial role in cccDNA transcription and viral persistence. Interferon-α (IFN-α) is a pivotal agent against HBV cccDNA. However, the mechanism by which IFN-α modulates the epigenetic regulation of cccDNA remains poorly understood. In this study, we report that IFN-α2b enhances the histone deacetylase 3 (HDAC3)-mediated de-2-hydroxyisobutyrylation of histone H4 lysine 8 (H4K8) on HBV cccDNA minichromosome to restrict the cccDNA transcription in liver. By screening acetyltransferases and deacetylases, we identified that HDAC3 was an effective restrictor of HBV transcription and replication. Moreover, we found that HDAC3 was able to mediate the de-2-hydroxyisobutyrylation of H4K8 in HBV-expressing hepatoma cells. Then, the 2-hydroxyisobutyrylation of histone H4K8 (H4K8hib) was identified on the HBV cccDNA minichromosome, promoting the HBV transcription and replication. The H4K8hib was regulated by HDAC3 depending on its deacetylase domain in the system. The low level of HDAC3 and high level of H4K8hib were observed in the liver tissues from HBV-infected human liver-chimeric mice. The levels of H4K8hib on HBV cccDNA minichromosome were significantly elevated in the liver biopsy specimens from clinical hepatitis B patients, which was consistent with the high transcriptional activity of cccDNA. Strikingly, IFN-α2b effectively facilitated the histone H4K8 de-2-hydroxyisobutyrylation mediated by HDAC3 on the HBV cccDNA minichromosome in primary human hepatocytes and hepatoma cells, leading to the inhibition of HBV transcription and replication. Our finding provides new insights into the mechanism by which IFN-α modulates the epigenetic regulation of HBV cccDNA minichromosome.
Collapse
|
|
38
|
Yang L, Zou T, Chen Y, Zhao Y, Wu X, Li M, Du F, Chen Y, Xiao Z, Shen J. Hepatitis B virus X protein mediated epigenetic alterations in the pathogenesis of hepatocellular carcinoma. Hepatol Int 2022; 16:741-754. [PMID: 35648301 DOI: 10.1007/s12072-022-10351-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/25/2022] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide health problem. Hepatitis B virus X protein (HBx), a pleiotropic regulatory protein encoded by HBV, is necessary for the transcription of HBV covalently closed circular DNA (cccDNA) minichromosomes, and affects the epigenetic regulation of host cells. The epigenetic reprogramming of HBx on host cell genome is strongly involved in HBV-related HCC carcinogenesis. Here, we review the latest findings of the epigenetic regulation induced by HBx protein in hepatocellular carcinoma (HCC), including DNA methylation, histone modification and non-coding RNA expression. The influence of HBx on the epigenetic regulation of cccDNA is also summarized. In addition, preliminary studies of targeted drugs for epigenetic changes induced by HBx are also discussed. The exploration of epigenetic markers as potential targets will help to develop new prevention and/or treatment methods for HBx-related HCC.
Collapse
Affiliation(s)
- Liqiong Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Tao Zou
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Yao Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China.
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China.
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China.
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China.
| |
Collapse
|
|
39
|
Mahapatra S, Mohanty S, Mishra R, Prasad P. An overview of cancer and the human microbiome. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2022; 191:83-139. [DOI: 10.1016/bs.pmbts.2022.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
40
|
Zhang D, Guo S, Schrodi SJ. Mechanisms of DNA Methylation in Virus-Host Interaction in Hepatitis B Infection: Pathogenesis and Oncogenetic Properties. Int J Mol Sci 2021; 22:9858. [PMID: 34576022 PMCID: PMC8466338 DOI: 10.3390/ijms22189858] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV), the well-studied oncovirus that contributes to the majority of hepatocellular carcinomas (HCC) worldwide, can cause a severe inflammatory microenvironment leading to genetic and epigenetic changes in hepatocyte clones. HBV replication contributes to the regulation of DNA methyltransferase gene expression, particularly by X protein (HBx), and subsequent methylation changes may lead to abnormal transcription activation of adjacent genes and genomic instability. Undoubtedly, the altered expression of these genes has been known to cause diverse aspects of infected hepatocytes, including apoptosis, proliferation, reactive oxygen species (ROS) accumulation, and immune responses. Additionally, pollutant-induced DNA methylation changes and aberrant methylation of imprinted genes in hepatocytes also complicate the process of tumorigenesis. Meanwhile, hepatocytes also contribute to epigenetic modification of the viral genome to affect HBV replication or viral protein production. Meanwhile, methylation levels of HBV integrants and surrounding host regions also play crucial roles in their ability to produce viral proteins in affected hepatocytes. Both host and viral changes can provide novel insights into tumorigenesis, individualized responses to therapeutic intervention, disease progress, and early diagnosis. As such, DNA methylation-mediated epigenetic silencing of cancer-related genes and viral replication is a compelling therapeutic goal to reduce morbidity and mortality from liver cancer caused by chronic HBV infection. In this review, we summarize the most recent research on aberrant DNA methylation associated with HBV infection, which is involved in HCC development, and provide an outlook on the future direction of the research.
Collapse
Affiliation(s)
- Dake Zhang
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Shicheng Guo
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA;
| | - Steven J. Schrodi
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA;
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
| |
Collapse
|
|
41
|
Epigenetic Changes Affecting the Development of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13164237. [PMID: 34439391 PMCID: PMC8392268 DOI: 10.3390/cancers13164237] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/15/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma is a life-threatening disease. Despite many efforts to understand the exact pathogenesis and the signaling pathways involved in its formation, treatment remains unsatisfactory. Currently, an important function in the development of neoplastic diseases and treatment effects is attributed to changes taking place at the epigenetic level. Epigenetic studies revealed modified methylation patterns in HCC, dysfunction of enzymes engaged in the DNA methylation process, the aberrant function of non-coding RNAs, and a set of histone modifications that influence gene expression. The aim of this review is to summarize the current knowledge on the role of epigenetics in the formation of hepatocellular carcinoma. Abstract Hepatocellular carcinoma (HCC) remains a serious oncologic issue with still a dismal prognosis. So far, no key molecular mechanism that underlies its pathogenesis has been identified. Recently, by specific molecular approaches, many genetic and epigenetic changes arising during HCC pathogenesis were detected. Epigenetic studies revealed modified methylation patterns in HCC tumors, dysfunction of enzymes engaged in the DNA methylation process, and a set of histone modifications that influence gene expression. HCC cells are also influenced by the disrupted function of non-coding RNAs, such as micro RNAs and long non-coding RNAs. Moreover, a role of liver cancer stem cells in HCC development is becoming evident. The reversibility of epigenetic changes offers the possibility of influencing them and regulating their undesirable effects. All these data can be used not only to identify new therapeutic targets but also to predict treatment response. This review focuses on epigenetic changes in hepatocellular carcinoma and their possible implications in HCC therapy.
Collapse
|
|
42
|
Pietropaolo V, Prezioso C, Moens U. Role of Virus-Induced Host Cell Epigenetic Changes in Cancer. Int J Mol Sci 2021; 22:ijms22158346. [PMID: 34361112 PMCID: PMC8346956 DOI: 10.3390/ijms22158346] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized.
Collapse
Affiliation(s)
- Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy;
- Correspondence: (V.P.); (U.M.)
| | - Carla Prezioso
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy;
- IRCSS San Raffaele Roma, Microbiology of Chronic Neuro-Degenerative Pathologies, 00161 Rome, Italy
| | - Ugo Moens
- Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø—The Arctic University of Norway, 9037 Tromsø, Norway
- Correspondence: (V.P.); (U.M.)
| |
Collapse
|
|
43
|
Lu H, Yi W, Sun F, Zeng Z, Zhang L, Li M, Xie Y. Comprehensive investigation of HBV-related hepatocellular carcinoma and choice of anti-HBV therapy. BIOSAFETY AND HEALTH 2021. [DOI: 10.1016/j.bsheal.2021.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
|
|
44
|
Li F, Ou Q, Lai Z, Pu L, Chen X, Wang L, Sun L, Liang X, Wang Y, Xu H, Wei J, Wu F, Zhu H, Wang L. The Co-occurrence of Chronic Hepatitis B and Fibrosis Is Associated With a Decrease in Hepatic Global DNA Methylation Levels in Patients With Non-alcoholic Fatty Liver Disease. Front Genet 2021; 12:671552. [PMID: 34335686 PMCID: PMC8318039 DOI: 10.3389/fgene.2021.671552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 06/01/2021] [Indexed: 01/23/2023] Open
Abstract
Global DNA hypomethylation has been reported in patients with chronic hepatitis B (CHB) and non-alcoholic fatty-liver disease (NAFLD). However, the global DNA methylation profile of patients with concurrent NAFLD and CHB (NAFLD + CHB) is still unclear. We aimed to detect the hepatic global DNA methylation levels of NAFLD + CHB patients and assess the associated risk factors. Liver biopsies were collected from 55 NAFLD patients with or without CHB. The histological characteristics of the biopsy were then assessed. Hepatic global DNA methylation levels were quantified by fluorometric method. The hepatic global DNA methylation levels in NAFLD + CHB group were significantly lower than that in NAFLD group. Participants with fibrosis showed lower levels of hepatic global DNA methylation than those without fibrosis. Participants with both CHB and fibrosis had lower levels of hepatic global DNA methylation than those without either CHB or fibrosis. The co-occurrence of CHB and fibrosis was significantly associated with a reduction in global DNA methylation levels compared to the absence of both CHB and fibrosis. Our study suggests that patients with NAFLD + CHB exhibited lower levels of global DNA methylation than patients who had NAFLD alone. The co-occurrence of CHB and liver fibrosis in NAFLD patients was associated with a decrease in global DNA methylation levels.
Collapse
Affiliation(s)
- FangYuan Li
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - Qian Ou
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - ZhiWei Lai
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - LiuZhen Pu
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - XingYi Chen
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - LiRong Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - LiuQiao Sun
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - XiaoPing Liang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - YaoYao Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - Hang Xu
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - Jun Wei
- Department of Science and Technology, Guangzhou Customs, Guangzhou, China
| | - Feng Wu
- Department of Science and Technology, Guangzhou Customs, Guangzhou, China
| | - HuiLian Zhu
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - LiJun Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| |
Collapse
|
|
45
|
Singh P, Kairuz D, Arbuthnot P, Bloom K. Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach. World J Gastroenterol 2021; 27:3182-3207. [PMID: 34163105 PMCID: PMC8218364 DOI: 10.3748/wjg.v27.i23.3182] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/23/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Global prophylactic vaccination programmes have helped to curb new hepatitis B virus (HBV) infections. However, it is estimated that nearly 300 million people are chronically infected and have a high risk of developing hepatocellular carcinoma. As such, HBV remains a serious health priority and the development of novel curative therapeutics is urgently needed. Chronic HBV infection has been attributed to the persistence of the covalently closed circular DNA (cccDNA) which establishes itself as a minichromosome in the nucleus of hepatocytes. As the viral transcription intermediate, the cccDNA is responsible for producing new virions and perpetuating infection. HBV is dependent on various host factors for cccDNA formation and the minichromosome is amenable to epigenetic modifications. Two HBV proteins, X (HBx) and core (HBc) promote viral replication by modulating the cccDNA epigenome and regulating host cell responses. This includes viral and host gene expression, chromatin remodeling, DNA methylation, the antiviral immune response, apoptosis, and ubiquitination. Elimination of the cccDNA minichromosome would result in a sterilizing cure; however, this may be difficult to achieve. Epigenetic therapies could permanently silence the cccDNA minichromosome and promote a functional cure. This review explores the cccDNA epigenome, how host and viral factors influence transcription, and the recent epigenetic therapies and epigenome engineering approaches that have been described.
Collapse
Affiliation(s)
- Prashika Singh
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Dylan Kairuz
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Patrick Arbuthnot
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Kristie Bloom
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| |
Collapse
|
|
46
|
Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis. Microorganisms 2021; 9:microorganisms9061179. [PMID: 34070716 PMCID: PMC8227491 DOI: 10.3390/microorganisms9061179] [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: 04/28/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022] Open
Abstract
Tumorigenesis due to viral infection accounts for a high fraction of the total global cancer burden (15–20%) of all human cancers. A comprehensive understanding of the mechanisms by which viral infection leads to tumor development is extremely important. One of the main mechanisms by which viruses induce host cell proliferation programs is through controlling the host’s epigenetic machinery. In this review, we dissect the epigenetic pathways through which oncogenic viruses can integrate their genome into host cell chromosomes and lead to tumor progression. In addition, we highlight the potential use of drugs based on histone modifiers in reducing the global impact of cancer development due to viral infection.
Collapse
|
|
47
|
Jiang Y, Han Q, Zhao H, Zhang J. The Mechanisms of HBV-Induced Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:435-450. [PMID: 34046368 PMCID: PMC8147889 DOI: 10.2147/jhc.s307962] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy, and the hepatitis B virus (HBV) is its major pathogenic factor. Over the past decades, it has been confirmed that HBV infection could promote disease progression through a variety of mechanisms, ultimately leading to the malignant transformation of liver cells. Many factors have been identified in the pathogenesis of HBV-associated HCC (HBV-HCC), including HBV gene integration, genomic instability caused by mutation, and activation of cancer-promoting signaling pathways. As research in the progression of HBV-HCC progresses, the role of many new mechanisms, such as epigenetics, exosomes, autophagy, metabolic regulation, and immune suppression, is also being continuously explored. The occurrence of HBV-HCC is a complex process caused by interactions across multiple genes and multiple steps, where the synergistic effects of various cancer-promoting mechanisms accelerate the process of disease evolution from inflammation to tumorigenesis. In this review, we aim to provide a brief overview of the mechanisms involved in the occurrence and development of HBV-HCC, which may contribute to a better understanding of the role of HBV in the occurrence and development of HCC.
Collapse
Affiliation(s)
- Yu Jiang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China
| | - Huajun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China
| |
Collapse
|
|
48
|
Sekiba K, Otsuka M, Koike K. Potential of HBx Gene for Hepatocarcinogenesis in Noncirrhotic Liver. Semin Liver Dis 2021; 41:142-149. [PMID: 33984871 DOI: 10.1055/s-0041-1723033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Current treatments for hepatitis B virus (HBV) using nucleos(t)ide analogs cannot eliminate the risk of hepatocellular carcinoma (HCC) development. As HBV-associated HCC can develop even in the absence of liver cirrhosis, HBV is regarded to possess direct oncogenic potential. HBV regulatory protein X (HBx) has been identified as a primary mediator of HBV-mediated hepatocarcinogenesis. A fragment of the HBV genome that contains the coding region of HBx is commonly integrated into the host genome, resulting in the production of aberrant proteins and subsequent hepatocarcinogenesis. Besides, HBx interferes with the host DNA or deoxyribonucleic acid damage repair pathways, signal transduction, epigenetic regulation of gene expression, and cancer immunity, thereby promoting carcinogenesis in the noncirrhotic liver. However, numerous molecules and pathways have been implicated in the development of HBx-associated HCC, suggesting that the mechanisms underlying HBx-mediated hepatocarcinogenesis remain to be elucidated.
Collapse
Grants
- Japan Agency for Medical Research and Development, AMED JP20fk0210054
- Japan Agency for Medical Research and Development, AMED JP20fk0210080h0001
- Japan Agency for Medical Research and Development, AMED JP20fk0310102
- The Ministry of Education, Culture, Sports, Science, and Technology, Japan 19H03430
- The Ministry of Education, Culture, Sports, Science, and Technology, Japan 19J11829
Collapse
Affiliation(s)
- Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
49
|
Zeisel MB, Guerrieri F, Levrero M. Host Epigenetic Alterations and Hepatitis B Virus-Associated Hepatocellular Carcinoma. J Clin Med 2021; 10:jcm10081715. [PMID: 33923385 PMCID: PMC8071488 DOI: 10.3390/jcm10081715] [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: 02/18/2021] [Revised: 04/06/2021] [Accepted: 04/12/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary malignancy of the liver and a leading cause of cancer-related deaths worldwide. Although much progress has been made in HCC drug development in recent years, treatment options remain limited. The major cause of HCC is chronic hepatitis B virus (HBV) infection. Despite the existence of a vaccine, more than 250 million individuals are chronically infected by HBV. Current antiviral therapies can repress viral replication but to date there is no cure for chronic hepatitis B. Of note, inhibition of viral replication reduces but does not eliminate the risk of HCC development. HBV contributes to liver carcinogenesis by direct and indirect effects. This review summarizes the current knowledge of HBV-induced host epigenetic alterations and their association with HCC, with an emphasis on the interactions between HBV proteins and the host cell epigenetic machinery leading to modulation of gene expression.
Collapse
Affiliation(s)
- Mirjam B. Zeisel
- Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), 69003 Lyon, France;
- Correspondence: (M.B.Z.); (M.L.)
| | - Francesca Guerrieri
- Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), 69003 Lyon, France;
| | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), 69003 Lyon, France;
- Hospices Civils de Lyon, Hôpital Croix Rousse, Service d’Hépato-Gastroentérologie, 69004 Lyon, France
- Correspondence: (M.B.Z.); (M.L.)
| |
Collapse
|
|
50
|
Papatheodoridi A, Chatzigeorgiou A, Chrysavgis L, Lembessis P, Loglio A, Facchetti F, Cholongitas E, Koutsilieris M, Lampertico P, Papatheodoridis G. Circulating cell-free DNA species affect the risk of hepatocellular carcinoma in treated chronic hepatitis B patients. J Viral Hepat 2021; 28:464-474. [PMID: 33260272 DOI: 10.1111/jvh.13446] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 11/16/2020] [Indexed: 01/08/2023]
Abstract
Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients even under effective long-term oral antiviral therapy, but its pathogenesis in the setting of long-standing inhibition of viral replication has not been completely elucidated. We investigated whether species of circulating cell-free DNA (cfDNA) may be involved in the process of hepatocarcinogenesis in treated CHB patients. Serum samples were obtained from HBeAg-negative CHB patients with (HCC cases, n = 37) or without HCC development during the first 5 years of oral antiviral therapy (controls, n = 74). HCC cases and controls were matched 1:2 for age, sex and platelets. Determination of different circulating cfDNA species (before HCC diagnosis in HCC cases) including total cfDNA quantity, levels of Alu repeat DNA and RNase P coding DNA, copies of mitochondrial DNA and levels of 5-methyl-2'-deoxycytidine as an indicator of DNA methylation was performed. HCC cases compared with controls had higher median levels of Alu247 (123 vs 69 genomic equivalent, p = .042) and RNase P coding DNA (68 vs 15 genomic equivalent, p < .001). In contrast, median cfDNA concentration, Alu115 levels, Alu247/Alu115 ratio as an index of DNA integrity and mitochondrial DNA copies did not differ significantly between HCC cases and controls. Receiver operating characteristic curve analysis showed that levels RNase P coding DNA offered good prediction of subsequent HCC development (c-statistic: 0.80, p < .001). In conclusion, serum levels of RNase P coding DNA are increased years before HCC diagnosis and could be potentially helpful in the prediction of the HCC risk in treated HBeAg-negative CHB patients.
Collapse
Affiliation(s)
- Alkistis Papatheodoridi
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
- Department of Clinical Therapeutics, 'Alexandra' General Hospital of Athens, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Lampros Chrysavgis
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Lembessis
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Alessandro Loglio
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC 'A. M. and A. Migliavacca' Center for Liver Disease, Milan, Italy
| | - Floriana Facchetti
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC 'A. M. and A. Migliavacca' Center for Liver Disease, Milan, Italy
| | - Evangelos Cholongitas
- 1st Department of Internal Medicine, General Hospital of Athens 'Laiko', Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Michael Koutsilieris
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC 'A. M. and A. Migliavacca' Center for Liver Disease, Milan, Italy
| | - George Papatheodoridis
- Department of Gastroenterology, General Hospital of Athens 'Laiko', Medical School of National and Kapodistrian University of Athens, Athens, Greece
| |
Collapse
|