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Lin TS, Zhu Z, Lin X, Huang HY, Li LP, Li J, Ni J, Li P, Chen L, Tang W, Liu H, Se X, Xie M, Long C, Chiu CM, Fang SH, Zhao J, Lin YCD, Yu X, Huang HD. Enhancing bloodstream infection diagnostics: a novel filtration and targeted next-generation sequencing approach for precise pathogen identification. Front Microbiol 2025; 16:1538265. [PMID: 40182288 PMCID: PMC11965694 DOI: 10.3389/fmicb.2025.1538265] [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: 12/02/2024] [Accepted: 03/06/2025] [Indexed: 04/05/2025] Open
Abstract
Bloodstream infections (BSIs) pose a significant diagnostic challenge, largely due to the limitations of traditional methods such as blood cultures. These methods often yield low positive rates, have lengthy processing times that delay treatment, and are limited in detecting only a narrow range of pathogens. Such delays and inaccuracies can critically impede timely clinical interventions, potentially compromising patient outcomes. Next-generation sequencing (NGS) is a powerful tool for rapid, precise pathogen identification. While metagenomic NGS (mNGS) offers broad pathogen coverage, it is often costly and complex. Targeted NGS (tNGS), however, focuses on key regions of clinically relevant pathogens, reducing costs and simplifying workflows while maintaining high sensitivity, making it more practical for routine diagnostics. In this study, we introduce a novel approach combining a human cell-specific filtration membrane with a multiplex tNGS panel to overcome these challenges. The filtration membrane, designed with surface charge properties to be electrostatically attractive to leukocytes for the selective capture of specific cells, demonstrated high efficiency in removing host cells and nucleic acids, achieving over a 98% reduction in host DNA and thereby minimizing background interference in pathogen detection. Additionally, we developed an effective multiplex tNGS panel targeting over 330 clinically relevant pathogens and verified its consistency with mNGS and blood culture results, demonstrating a significant improvement in detection sensitivity. By integrating these two methods, we achieved a synergistic enhancement in diagnostic capability, boosting pathogen reads by 6- to 8-fold, which enabled reliable identification even in cases of low-abundance pathogens. This approach provides faster, more accurate, and more sensitive detection of BSIs, enabling earlier identification of infections. This facilitates timely and targeted treatment, ultimately improving patient outcomes in critical care settings. Given the unique properties of the filtration membrane and the strengths of the tNGS panel, this approach shows promising applications in prenatal and genetic health support, as well as in advancing early cancer screening strategies.
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Affiliation(s)
- Ting-Syuan Lin
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - ZiHao Zhu
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - XiaoHong Lin
- Department of Critical Care Medicine, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - Hsi-Yuan Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Li-Ping Li
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Jing Li
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Jie Ni
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - PeiZhi Li
- Shanya life-tech Co. Ltd., Guangzhou, Guangdong, China
| | - LanChun Chen
- Department of Critical Care Medicine, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - WeiXin Tang
- Department of Critical Care Medicine, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - HuiXin Liu
- Department of Critical Care Medicine, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - XiaoLong Se
- Department of Critical Care Medicine, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - MingFei Xie
- Department of Critical Care Medicine, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - Canling Long
- Central Laboratory, The Second Affiliated Hospital, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen, China
| | - Chih-Min Chiu
- Health SwifTech Co. Ltd., Shenzhen, Guangdong, China
| | - Szu-Han Fang
- Health SwifTech Co. Ltd., Shenzhen, Guangdong, China
| | - JiaMing Zhao
- Health SwifTech Co. Ltd., Shenzhen, Guangdong, China
| | - Yang-Chi-Dung Lin
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - XueTao Yu
- Department of Critical Care Medicine, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - Hsien-Da Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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La Frazia S, Pauciullo S, Zulian V, Garbuglia AR. Viral Oncogenesis: Synergistic Role of Genome Integration and Persistence. Viruses 2024; 16:1965. [PMID: 39772271 PMCID: PMC11728759 DOI: 10.3390/v16121965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/12/2025] Open
Abstract
Persistence is a strategy used by many viruses to evade eradication by the immune system, ensuring their permanence and transmission within the host and optimizing viral fitness. During persistence, viruses can trigger various phenomena, including target organ damage, mainly due to an inflammatory state induced by infection, as well as cell proliferation and/or immortalization. In addition to immune evasion and chronic inflammation, factors contributing to viral persistence include low-level viral replication, the accumulation of viral mutants, and, most importantly, maintenance of the viral genome and reliance on viral oncoprotein production. This review focuses on the process of genome integration, which may occur at different stages of infection (e.g., HBV), during the chronic phase of infection (e.g., HPV, EBV), or as an essential part of the viral life cycle, as seen in retroviruses (HIV, HTLV-1). It also explores the close relationship between integration, persistence, and oncogenesis. Several models have been proposed to describe the genome integration process, including non-homologous recombination, looping, and microhomology models. Integration can occur either randomly or at specific genomic sites, often leading to genome destabilization. In some cases, integration results in the loss of genomic regions or impairs the regulation of oncogene and/or oncosuppressor expression, contributing to tumor development.
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Affiliation(s)
- Simone La Frazia
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
| | - Silvia Pauciullo
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.); (A.R.G.)
| | - Verdiana Zulian
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.); (A.R.G.)
| | - Anna Rosa Garbuglia
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.); (A.R.G.)
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Wu Z, Dong Z, Luo J, Hu W, Tong Y, Gao X, Yao W, Tian H, Wang X. A comprehensive comparison of molecular and phenotypic profiles between hepatitis B virus (HBV)-infected and non-HBV-infected hepatocellular carcinoma by multi-omics analysis. Genomics 2024; 116:110831. [PMID: 38513875 DOI: 10.1016/j.ygeno.2024.110831] [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: 08/01/2023] [Revised: 11/22/2023] [Accepted: 03/14/2024] [Indexed: 03/23/2024]
Abstract
Hepatitis B virus (HBV) infection is a major etiology of hepatocellular carcinoma (HCC). An interesting question is how different are the molecular and phenotypic profiles between HBV-infected (HBV+) and non-HBV-infected (HBV-) HCCs? Based on the publicly available multi-omics data for HCC, including bulk and single-cell data, and the data we collected and sequenced, we performed a comprehensive comparison of molecular and phenotypic features between HBV+ and HBV- HCCs. Our analysis showed that compared to HBV- HCCs, HBV+ HCCs had significantly better clinical outcomes, higher degree of genomic instability, higher enrichment of DNA repair and immune-related pathways, lower enrichment of stromal and oncogenic signaling pathways, and better response to immunotherapy. Furthermore, in vitro experiments confirmed that HBV+ HCCs had higher immunity, PD-L1 expression and activation of DNA damage response pathways. This study may provide insights into the profiles of HBV+ and HBV- HCCs, and guide rational therapeutic interventions for HCC patients.
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Affiliation(s)
- Zijie Wu
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Zehua Dong
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China
| | - Jiangti Luo
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China
| | - Weiwei Hu
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Yue Tong
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Xiangdong Gao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Wenbing Yao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
| | - Hong Tian
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China.
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Naim D, Ahsan A, Imtiaj A, Mollah NH. Genome-wide identification and in silico characterization of major RNAi gene families in date palm (Phoenix dactylifera). BMC Genom Data 2024; 25:31. [PMID: 38491426 PMCID: PMC10943882 DOI: 10.1186/s12863-024-01217-x] [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: 05/13/2023] [Accepted: 03/06/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Dates contain various minerals that are essential for good health. The major RNA interference (RNAi) gene families play a vital role in plant growth and development by controlling the expression of protein-coding genes against different biotic and abiotic stresses. However, these gene families for date palm are not yet studied. Therefore, this study has explored major RNAi genes and their characteristics in date palm. RESULTS We have identified 4 PdDCLs, 7 PdAGOs, and 3 PdRDRs as RNAi proteins from the date palm genome by using AtRNAi genes as query sequences in BLASTp search. Domain analysis of predicted RNAi genes has revealed the Helicase_C, Dicer_dimer, PAZ, RNase III, and Piwi domains that are associated with the gene silencing mechanisms. Most PdRNAi proteins have been found in the nucleus and cytosol associated with the gene silencing actions. The gene ontology (GO) enrichment analysis has revealed some important GO terms including RNA interference, dsRNA fragmentation, and ribonuclease_III activity that are related to the protein-coding gene silencing mechanisms. Gene regulatory network (GRN) analysis has identified PAZ and SNF2 as the transcriptional regulators of PdRNAi genes. Top-ranked 10 microRNAs including Pda-miR156b, Pda-miR396a, Pda-miR166a, Pda-miR167d, and Pda-miR529a have been identified as the key post-transcriptional regulators of PdRNAi genes that are associated with different biotic/abiotic stresses. The cis-acting regulatory element analysis of PdRNAi genes has detected some vital cis-acting elements including ABRE, MBS, MYB, MYC, Box-4, G-box, I-box, and STRE that are linked with different abiotic stresses. CONCLUSION The results of this study might be valuable resources for the improvement of different characteristics in date palm by further studies in wet-lab.
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Affiliation(s)
- Darun Naim
- Bioinformatics Lab, Department of Statistics, Faculty of Science, University of Rajshahi, 6205, Rajshahi, Bangladesh
- Department of Botany, Faculty of Biological Sciences, University of Rajshahi, 6205, Rajshahi, Bangladesh
| | - Asif Ahsan
- Bioinformatics Lab, Department of Statistics, Faculty of Science, University of Rajshahi, 6205, Rajshahi, Bangladesh
| | - Ahmed Imtiaj
- Department of Botany, Faculty of Biological Sciences, University of Rajshahi, 6205, Rajshahi, Bangladesh
| | - Nurul Haque Mollah
- Bioinformatics Lab, Department of Statistics, Faculty of Science, University of Rajshahi, 6205, Rajshahi, Bangladesh.
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Wu Q, Kinoti WM, Habili N, Tyerman SD, Rinaldo A, Constable FE. Genetic Diversity of Grapevine Virus A in Three Australian Vineyards Using Amplicon High Throughput Sequencing (Amplicon-HTS). Viruses 2023; 16:42. [PMID: 38257742 PMCID: PMC10819895 DOI: 10.3390/v16010042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/18/2023] [Accepted: 12/25/2023] [Indexed: 01/24/2024] Open
Abstract
Shiraz disease (SD) is one of the most destructive viral diseases of grapevines in Australia and is known to cause significant economic loss to local growers. Grapevine virus A (GVA) was reported to be the key pathogen associated with this disease. This study aimed to better understand the diversity of GVA variants both within and between individual SD and grapevine leafroll disease (LRD) affected grapevines located at vineyards in South Australia. Amplicon high throughput sequencing (Amplicon-HTS) combined with median-joining networks (MJNs) was used to analyze the variability in specific gene regions of GVA variants. Several GVAII variant groups contain samples from both vineyards studied, suggesting that these GVAII variants were from a common origin. Variant groups analyzed by MJNs using the overall data set denote that there may be a possible relationship between variant groups of GVA and the geographical location of the grapevines.
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Affiliation(s)
- Qi Wu
- School of Agriculture, Food and Wine, University of Adelaide, Waite Precinct, PMB 1, Glen Osmond, SA 5064, Australia (S.D.T.)
- Australian Wine Research Institute, Wine Innovation Central Building, Hartley Grove crn Paratoo Road, Urrbrae, SA 5064, Australia
| | - Wycliff M. Kinoti
- Agriculture Victoria Research, Department of Energy, Environment and Climate Action, AgriBio, Centre for AgriBioscience, 5 Ring Road, Bundoora, VIC 3083, Australia
| | - Nuredin Habili
- School of Agriculture, Food and Wine, University of Adelaide, Waite Precinct, PMB 1, Glen Osmond, SA 5064, Australia (S.D.T.)
- Australian Wine Research Institute, Wine Innovation Central Building, Hartley Grove crn Paratoo Road, Urrbrae, SA 5064, Australia
| | - Stephen D. Tyerman
- School of Agriculture, Food and Wine, University of Adelaide, Waite Precinct, PMB 1, Glen Osmond, SA 5064, Australia (S.D.T.)
| | - Amy Rinaldo
- Australian Wine Research Institute, Wine Innovation Central Building, Hartley Grove crn Paratoo Road, Urrbrae, SA 5064, Australia
| | - Fiona E. Constable
- Agriculture Victoria Research, Department of Energy, Environment and Climate Action, AgriBio, Centre for AgriBioscience, 5 Ring Road, Bundoora, VIC 3083, Australia
- School of Applied Systems Biology, La Trobe University, Bundoora, VIC 3086, Australia
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Fukano K, Wakae K, Nao N, Saito M, Tsubota A, Toyoshima T, Aizaki H, Iijima H, Matsudaira T, Kimura M, Watashi K, Sugiura W, Muramatsu M. A versatile method to profile hepatitis B virus DNA integration. Hepatol Commun 2023; 7:e0328. [PMID: 38051537 PMCID: PMC10697629 DOI: 10.1097/hc9.0000000000000328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 09/26/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND HBV DNA integration into the host genome is frequently found in HBV-associated HCC tissues and is associated with hepatocarcinogenesis. Multiple detection methods, including hybrid capture-sequencing, have identified integration sites and provided clinical implications; however, each has advantages and disadvantages concerning sensitivity, cost, and throughput. Therefore, methods that can comprehensively and cost-effectively detect integration sites with high sensitivity are required. Here, we investigated the efficiency of RAISING (Rapid Amplification of Integration Site without Interference by Genomic DNA contamination) as a simple and inexpensive method to detect viral integration by amplifying HBV-integrated fragments using virus-specific primers covering the entire HBV genome. METHODS AND RESULTS Illumina sequencing of RAISING products from HCC-derived cell lines (PLC/PRF/5 and Hep3B cells) identified HBV-human junction sequences as well as their frequencies. The HBV-human junction profiles identified using RAISING were consistent with those determined using hybrid capture-sequencing, and the representative junctions could be validated by junction-specific nested PCR. The comparison of these detection methods revealed that RAISING-sequencing outperforms hybrid capture-sequencing in concentrating junction sequences. RAISING-sequencing was also demonstrated to determine the sites of de novo integration in HBV-infected HepG2-NTCP cells, primary human hepatocytes, liver-humanized mice, and clinical specimens. Furthermore, we made use of xenograft mice subcutaneously engrafted with PLC/PRF/5 or Hep3B cells, and HBV-human junctions determined by RAISING-sequencing were detectable in the plasma cell-free DNA using droplet digital PCR. CONCLUSIONS RAISING successfully profiles HBV-human junction sequences with smaller amounts of sequencing data and at a lower cost than hybrid capture-sequencing. This method is expected to aid basic HBV integration and clinical diagnosis research.
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Affiliation(s)
- Kento Fukano
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kousho Wakae
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Naganori Nao
- Division of International Research Promotion, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- One Health Research Center, Hokkaido University, Sapporo, Japan
- Institute for Vaccine Research and Development, HU-IVReD, Hokkaido University, Sapporo, Japan
| | - Masumichi Saito
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Center for Emergency Preparedness and Response, National Institute of Infectious Diseases, Tokyo, Japan
| | - Akihito Tsubota
- Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Takae Toyoshima
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hideki Aizaki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroko Iijima
- Department of Internal Medicine, Division of Hepatobiliary and Pancreatic Disease, Hyogo Medical University, Hyogo, Japan
| | - Takahiro Matsudaira
- Biotechnological Research Support Division, FASMAC Co., Ltd., Kanagawa, Japan
| | - Moto Kimura
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan
| | - Wataru Sugiura
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Department of Infectious Disease Research, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
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Katoh H, Honda T. Roles of Human Endogenous Retroviruses and Endogenous Virus-Like Elements in Cancer Development and Innate Immunity. Biomolecules 2023; 13:1706. [PMID: 38136578 PMCID: PMC10741599 DOI: 10.3390/biom13121706] [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: 10/28/2023] [Revised: 11/18/2023] [Accepted: 11/21/2023] [Indexed: 12/24/2023] Open
Abstract
Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the host genome. Although mutations and silencing mechanisms impair their original role in viral replication, HERVs are believed to play roles in various biological processes. Long interspersed nuclear elements (LINEs) are non-LTR retrotransposons that have a lifecycle resembling that of retroviruses. Although LINE expression is typically silenced in somatic cells, it also contributes to various biological processes. The aberrant expression of HERVs and LINEs is closely associated with the development of cancer and/or immunological diseases, suggesting that they are integrated into various pathways related to the diseases. HERVs/LINEs control gene expression depending on the context as promoter/enhancer elements. Some RNAs and proteins derived from HERVs/LINEs have oncogenic potential, whereas others stimulate innate immunity. Non-retroviral endogenous viral elements (nrEVEs) are a novel type of virus-like element in the genome. nrEVEs may also be involved in host immunity. This article provides a current understanding of how these elements impact cellular physiology in cancer development and innate immunity, and provides perspectives for future studies.
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Affiliation(s)
- Hirokazu Katoh
- Department of Virology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan;
| | - Tomoyuki Honda
- Department of Virology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan;
- Department of Virology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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Long J, Gong J, Zhu H, Liu X, Li L, Chen B, Ren H, Liu C, Lu H, Zhang J, Wang B. Difference of gut microbiota between patients with negative and positive HBeAg in chronic hepatitis B and the effect of tenofovir alafenamide on intestinal flora. Front Microbiol 2023; 14:1232180. [PMID: 37799607 PMCID: PMC10548823 DOI: 10.3389/fmicb.2023.1232180] [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: 05/31/2023] [Accepted: 08/24/2023] [Indexed: 10/07/2023] Open
Abstract
Background Severe liver diseases, such as liver fibrosis, cirrhosis, and liver cancer, are mainly caused by hepatitis B virus (HBV). This study investigated the differences between gut microbiota in HBeAg-positive and negative groups of patients with chronic hepatitis B (CHB) and investigated the effect of tenofovir alafenamide (TAF) on gut microbiota. Methods This prospective study included patients with CHB not taking nucleoside antivirals (No-NAs group, n = 95) and those taking TAF (TAF group, n = 60). We divided CHB patients into two groups according to the HBeAg status of the subjects on the day of data collection. Phase 1 are HBeAg-negative patients and phase 2 are HBeAg-positive patients. We investigated the improvement of clinical symptoms by TAF, as well as differences in gut microbiota between different groups by 16S rRNA high-throughput sequencing. Results Gut microbiota demonstrated significant differences between patients with HBeAg-positive and -negative CHB. Both the No-NAs and TAF Phase 2 subgroups demonstrated significantly increased microbiota richness and diversity, showing greater heterogeneity. Additionally, the Phase 2 subgroup exhibited a low abundance of pathways associated with glucose metabolism and amino acid metabolism. The TAF group demonstrated a significantly decreased HBV load, alanine aminotransferase, and aspartate aminotransferase and a significant increase in prealbumin compared with the No-NAs group. No significant difference was found in uric acid, creatinine, blood calcium, inorganic phosphorus, eGFR, and β2-microglobulin concentrations between the two groups. Additionally, the urea level in the TAF group was significantly lower than that in the No-NAs group, but with no significant effect on other indicators such as eGFR and β2-microglobulin. Conclusion This study revealed significant differences in gut microbiota composition and function between patients with HBeAg-positive and -negative CHB.
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Affiliation(s)
- Jianfei Long
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingru Gong
- Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Han Zhu
- Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Xiaolin Liu
- Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Ling Li
- Department of Pharmacy, Jing’an District Central Hospital, Fudan University, Shanghai, China
| | - Bicui Chen
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Hongyan Ren
- Shanghai Mobio Biomedical Technology Co., Ltd., Shanghai, China
| | - Chao Liu
- Shanghai Mobio Biomedical Technology Co., Ltd., Shanghai, China
| | - Huiping Lu
- Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Infectious Diseases and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China
- Department of Infectious Diseases, Jing’An Branch of Huashan Hospital, Fudan University, Shanghai, China
| | - Bin Wang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
- Department of Pharmacy, Jing’an District Central Hospital, Fudan University, Shanghai, China
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Mancino M, Lai G, De Grossi F, Cuomo A, Manganaro L, Butta GM, Ferrari I, Vicenzi E, Poli G, Pesce E, Oliveto S, Biffo S, Manfrini N. FAM46C Is an Interferon-Stimulated Gene That Inhibits Lentiviral Particle Production by Modulating Autophagy. Microbiol Spectr 2023; 11:e0521122. [PMID: 37358411 PMCID: PMC10434054 DOI: 10.1128/spectrum.05211-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 06/02/2023] [Indexed: 06/27/2023] Open
Abstract
FAM46C is a multiple myeloma (MM) tumor suppressor whose function is only starting to be elucidated. We recently showed that in MM cells FAM46C triggers apoptosis by inhibiting autophagy and altering intracellular trafficking and protein secretion. To date, both a physiological characterization of FAM46C role and an assessment of FAM46C-induced phenotypes outside of MM are lacking. Preliminary reports suggested an involvement of FAM46C with regulation of viral replication, but this was never confirmed. Here, we show that FAM46C is an interferon-stimulated gene and that the expression of wild-type FAM46C in HEK-293T cells, but not of its most frequently found mutant variants, inhibits the production of both HIV-1-derived and HIV-1 lentiviruses. We demonstrate that this effect does not require transcriptional regulation and does not depend on inhibition of either global or virus-specific translation but rather mostly relies on FAM46C-induced deregulation of autophagy, a pathway that we show to be required for efficient lentiviral particle production. These studies not only provide new insights on the physiological role of the FAM46C protein but also could help in implementing more efficient antiviral strategies on one side and lentiviral particle production approaches on the other. IMPORTANCE FAM46C role has been thoroughly investigated in MM, but studies characterizing its role outside of the tumoral environment are still lacking. Despite the success of antiretroviral therapy in suppressing HIV load to undetectable levels, there is currently no HIV cure, and treatment is lifelong. Indeed, HIV continues to be a major global public health issue. Here, we show that FAM46C expression in HEK-293T cells inhibits the production of both HIV and HIV-derived lentiviruses. We also demonstrate that such inhibitory effect relies, at least in part, on the well-established regulatory role that FAM46C exerts on autophagy. Deciphering the molecular mechanism underlying this regulation will not only facilitate the understanding of FAM46C physiological role but also give new insights on the interplay between HIV and the cellular environment.
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Affiliation(s)
- Marilena Mancino
- INGM, Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
| | - Giancarlo Lai
- INGM, Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
| | | | - Alessandro Cuomo
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Lara Manganaro
- INGM, Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Giacomo M. Butta
- INGM, Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Ivan Ferrari
- INGM, Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
| | - Elisa Vicenzi
- Viral Pathogenesis and Biosafety Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Guido Poli
- Viral Pathogenesis and Biosafety Unit, San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University School of Medicine, Milan, Italy
| | - Elisa Pesce
- INGM, Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
| | - Stefania Oliveto
- INGM, Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
- Department of Biosciences, University of Milan, Milan, Italy
| | - Stefano Biffo
- INGM, Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
- Department of Biosciences, University of Milan, Milan, Italy
| | - Nicola Manfrini
- INGM, Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
- Department of Biosciences, University of Milan, Milan, Italy
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10
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Giosa D, Lombardo D, Musolino C, Chines V, Raffa G, Casuscelli di Tocco F, D'Aliberti D, Caminiti G, Saitta C, Alibrandi A, Aiese Cigliano R, Romeo O, Navarra G, Raimondo G, Pollicino T. Mitochondrial DNA is a target of HBV integration. Commun Biol 2023; 6:684. [PMID: 37400627 DOI: 10.1038/s42003-023-05017-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 06/05/2023] [Indexed: 07/05/2023] Open
Abstract
Hepatitis B virus (HBV) may integrate into the genome of infected cells and contribute to hepatocarcinogenesis. However, the role of HBV integration in hepatocellular carcinoma (HCC) development remains unclear. In this study, we apply a high-throughput HBV integration sequencing approach that allows sensitive identification of HBV integration sites and enumeration of integration clones. We identify 3339 HBV integration sites in paired tumour and non-tumour tissue samples from 7 patients with HCC. We detect 2107 clonally expanded integrations (1817 in tumour and 290 in non-tumour tissues), and a significant enrichment of clonal HBV integrations in mitochondrial DNA (mtDNA) preferentially occurring in the oxidative phosphorylation genes (OXPHOS) and D-loop region. We also find that HBV RNA sequences are imported into the mitochondria of hepatoma cells with the involvement of polynucleotide phosphorylase (PNPASE), and that HBV RNA might have a role in the process of HBV integration into mtDNA. Our results suggest a potential mechanism by which HBV integration may contribute to HCC development.
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Affiliation(s)
- Domenico Giosa
- Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy
- Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Daniele Lombardo
- Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy
- Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Cristina Musolino
- Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
- Department of Human Pathology, University Hospital of Messina, Messina, Italy
| | - Valeria Chines
- Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy
- Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Giuseppina Raffa
- Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy
- Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Francesca Casuscelli di Tocco
- Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy
- Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Deborah D'Aliberti
- Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy
- Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Giuseppe Caminiti
- Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Carlo Saitta
- Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy
| | | | | | - Orazio Romeo
- Department of ChiBioFarAm, University of Messina, Messina, Italy
| | - Giuseppe Navarra
- Department of Human Pathology, University Hospital of Messina, Messina, Italy
| | - Giovanni Raimondo
- Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy
| | - Teresa Pollicino
- Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy.
- Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy.
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11
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Svicher V, Salpini R, D’Anna S, Piermatteo L, Iannetta M, Malagnino V, Sarmati L. New insights into hepatitis B virus lymphotropism: Implications for HBV-related lymphomagenesis. Front Oncol 2023; 13:1143258. [PMID: 37007163 PMCID: PMC10050604 DOI: 10.3389/fonc.2023.1143258] [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: 01/12/2023] [Accepted: 03/02/2023] [Indexed: 03/17/2023] Open
Abstract
HBV is one of the most widespread hepatitis viruses worldwide, and a correlation between chronic infection and liver cancer has been clearly reported. The carcinogenic capacity of HBV has been reported for other solid tumors, but the largest number of studies focus on its possible lymphomagenic role. To update the correlation between HBV infection and the occurrence of lymphatic or hematologic malignancies, the most recent evidence from epidemiological and in vitro studies has been reported. In the context of hematological malignancies, the strongest epidemiological correlations are with the emergence of lymphomas, in particular non-Hodgkin's lymphoma (NHL) (HR 2.10 [95% CI 1.34-3.31], p=0.001) and, more specifically, all NHL B subtypes (HR 2.14 [95% CI 1.61-2.07], p<0.001). Questionable and unconfirmed associations are reported between HBV and NHL T subtypes (HR 1.11 [95% CI 0.88-1.40], p=0.40) and leukemia. The presence of HBV DNA in peripheral blood mononuclear cells has been reported by numerous studies, and its integration in the exonic regions of some genes is considered a possible source of carcinogenesis. Some in vitro studies have shown the ability of HBV to infect, albeit not productively, both lymphomonocytes and bone marrow stem cells, whose differentiation is halted by the virus. As demonstrated in animal models, HBV infection of blood cells and the persistence of HBV DNA in peripheral lymphomonocytes and bone marrow stem cells suggests that these cellular compartments may act as HBV reservoirs, allowing replication to resume later in the immunocompromised patients (such as liver transplant recipients) or in subjects discontinuing effective antiviral therapy. The pathogenetic mechanisms at the basis of HBV carcinogenic potential are not known, and more in-depth studies are needed, considering that a clear correlation between chronic HBV infection and hematological malignancies could benefit both antiviral drugs and vaccines.
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Affiliation(s)
- Valentina Svicher
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Romina Salpini
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Stefano D’Anna
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Lorenzo Piermatteo
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Marco Iannetta
- Clinical Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Vincenzo Malagnino
- Clinical Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Loredana Sarmati
- Clinical Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
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12
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Tümen D, Heumann P, Gülow K, Demirci CN, Cosma LS, Müller M, Kandulski A. Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma. Biomedicines 2022; 10:3202. [PMID: 36551958 PMCID: PMC9775527 DOI: 10.3390/biomedicines10123202] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation and progression are favored by different etiological risk factors including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, non-/and alcoholic fatty liver disease (N/AFLD), and tobacco smoking. In molecular pathogenesis, endogenous alteration in genetics (TP53, TERT, CTNNB1, etc.), epigenetics (DNA-methylation, miRNA, lncRNA, etc.), and dysregulation of key signaling pathways (Wnt/β-catenin, JAK/STAT, etc.) strongly contribute to the development of HCC. The multitude and complexity of different pathomechanisms also reflect the difficulties in tailored medical therapy of HCC. Treatment options for HCC are strictly dependent on tumor staging and liver function, which are structured by the updated Barcelona Clinic Liver Cancer classification system. Surgical resection, local ablative techniques, and liver transplantation are valid and curative therapeutic options for early tumor stages. For multifocal and metastatic diseases, systemic therapy is recommended. While Sorafenib had been the standalone HCC first-line therapy for decades, recent developments had led to the approval of new treatment options as first-line as well as second-line treatment. Anti-PD-L1 directed combination therapies either with anti-VEGF directed agents or with anti-CTLA-4 active substances have been implemented as the new treatment standard in the first-line setting. However, data from clinical trials indicate different responses on specific therapeutic regimens depending on the underlying pathogenesis of hepatocellular cancer. Therefore, histopathological examinations have been re-emphasized by current international clinical guidelines in addition to the standardized radiological diagnosis using contrast-enhanced cross-sectional imaging. In this review, we emphasize the current knowledge on molecular pathogenesis of hepatocellular carcinoma. On this occasion, the treatment sequences for early and advanced tumor stages according to the recently updated Barcelona Clinic Liver Cancer classification system and the current algorithm of systemic therapy (first-, second-, and third-line treatment) are summarized. Furthermore, we discuss novel precautional and pre-therapeutic approaches including therapeutic vaccination, adoptive cell transfer, locoregional therapy enhancement, and non-coding RNA-based therapy as promising treatment options. These novel treatments may prolong overall survival rates in regard with quality of life and liver function as mainstay of HCC therapy.
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Affiliation(s)
| | | | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
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13
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Sun X, Feng W, Cui P, Ruan R, Ma W, Han Z, Sun J, Pan Y, Zhu J, Zhong X, Li J, Ma M, Hu R, Lv M, Huang Q, Zhang W, Feng M, Zhuang X, Huang B, Zhou X. Detection and monitoring of HBV-related hepatocellular carcinoma from plasma cfDNA fragmentation profiles. Genomics 2022; 114:110502. [PMID: 36220554 DOI: 10.1016/j.ygeno.2022.110502] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/30/2022] [Accepted: 10/04/2022] [Indexed: 01/15/2023]
Abstract
Most hepatocellular carcinomas (HCCs) are associated with hepatitis B virus infection (HBV) in China. Early detection of HCC can significantly improve prognosis but is not yet fully clinically feasible. This study aims to develop methods for detecting HCC and studying the carcinogenesis of HBV using plasma cell-free DNA (cfDNA) whole-genome sequencing (WGS) data. Low coverage WGS was performed for 452 participants, including healthy individuals, hepatitis B patients, cirrhosis patients, and HCC patients. Then the sequencing data were processed using various machine learning models based on cfDNA fragmentation profiles for cancer detection. Our best model achieved a sensitivity of 87.10% and a specificity of 88.37%, and it showed an increased sensitivity with higher BCLC stages of HCC. Overall, this study proves the potential of a non-invasive assay based on cfDNA fragmentation profiles for the detection and prognosis of HCC and provides preliminary data on the carcinogenic mechanism of HBV.
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Affiliation(s)
- Xinfeng Sun
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Wenxing Feng
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Pin Cui
- Shenzhen Rapha Biotechnology Incorporate, Shenzhen 518118, China
| | - Ruyun Ruan
- College of Big Data and Internet, Shenzhen Technology University, Shenzhen 518118, China
| | - Wenfeng Ma
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Zhiyi Han
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Jialing Sun
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Yuanke Pan
- College of Big Data and Internet, Shenzhen Technology University, Shenzhen 518118, China
| | - Jinxin Zhu
- College of Big Data and Internet, Shenzhen Technology University, Shenzhen 518118, China
| | - Xin Zhong
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Jing Li
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Mengqing Ma
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Rui Hu
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Minling Lv
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Qi Huang
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Wei Zhang
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Mingji Feng
- Shenzhen Rapha Biotechnology Incorporate, Shenzhen 518118, China
| | - Xintao Zhuang
- Shenzhen Rapha Biotechnology Incorporate, Shenzhen 518118, China
| | - Bingding Huang
- College of Big Data and Internet, Shenzhen Technology University, Shenzhen 518118, China.
| | - Xiaozhou Zhou
- Department of Liver Disease, the fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China.
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14
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Li SS, Zhai XH, Liu HL, Liu TZ, Cao TY, Chen DM, Xiao LX, Gan XQ, Cheng K, Hong WJ, Huang Y, Lian YF, Xiao J. Whole-exome sequencing analysis identifies distinct mutational profile and novel prognostic biomarkers in primary gastrointestinal diffuse large B-cell lymphoma. Exp Hematol Oncol 2022; 11:71. [PMID: 36243813 PMCID: PMC9569083 DOI: 10.1186/s40164-022-00325-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 09/29/2022] [Indexed: 11/10/2022] Open
Abstract
Background Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, and about 10% of DLBCL cases primarily occur in the gastrointestinal tract. Previous reports have revealed that primary gastrointestinal-DLBCL (pGI-DLBCL) harbors different genetic mutations from other nodal or extranodal DLBCL. However, the exonic mutation profile of pGI-DLBCL has not been fully addressed. Methods We performed whole-exome sequencing of matched tumor tissues and blood samples from 53 pGI-DLBCL patients. The exonic mutation profiles were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Results A total of 6,588 protein-altering events were found and the five most frequent mutated genes in our pGI-DLBCL cohort were IGLL5 (47%), TP53 (42%), BTG2 (28%), P2RY8 (26%) and PCLO (23%). Compared to the common DLBCL, significantly less or absence of MYD88 (0%), EZH2 (0%), BCL2 (2%) or CD79B (8%) mutations were identified in pGI-DLBCL. The recurrent potential driver genes were mainly enriched in pathways related to signal transduction, infectious disease and immune regulation. In addition, HBV infection had an impact on the mutational signature in pGI-DLBCL, as positive HBsAg was significantly associated with the TP53 and LRP1B mutations, two established tumor suppressor genes in many human cancers. Moreover, IGLL5 and LRP1B mutations were significantly correlated with patient overall survival and could serve as two novel prognostic biomarkers in pGI-DLBCL. Conclusions Our study provides a comprehensive view of the exonic mutation profile of the largest pGI-DLBCL cohort to date. The results could facilitate the clinical development of novel therapeutic and prognostic biomarkers for pGI-DLBCL. Supplementary Information The online version contains supplementary material available at 10.1186/s40164-022-00325-7.
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Affiliation(s)
- Shan-Shan Li
- Department of Medical Oncology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Xiao-Hui Zhai
- Department of Medical Oncology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Hai-Ling Liu
- Department of Pathology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Ting-Zhi Liu
- Department of Hematology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Tai-Yuan Cao
- Department of Medical Oncology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Dong-Mei Chen
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Le-Xin Xiao
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Xiao-Qin Gan
- Department of Medical Oncology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Ke Cheng
- Department of Medical Oncology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Wan-Jia Hong
- Department of Medical Oncology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China
| | - Yan Huang
- Department of Pathology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China. .,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
| | - Yi-Fan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
| | - Jian Xiao
- Department of Medical Oncology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China. .,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
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15
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Su Y, Ding J, Yang F, He C, Xu Y, Zhu X, Zhou H, Li H. The regulatory role of PDE4B in the progression of inflammatory function study. Front Pharmacol 2022; 13:982130. [PMID: 36278172 PMCID: PMC9582262 DOI: 10.3389/fphar.2022.982130] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/22/2022] [Indexed: 11/20/2022] Open
Abstract
Inflammation is a response of the body to external stimuli (eg. chemical irritants, bacteria, viruses, etc.), and when the stimuli are persistent, they tend to trigger chronic inflammation. The presence of chronic inflammation is an important component of the tumor microenvironment produced by a variety of inflammatory cells (eg. macrophages, neutrophils, leukocytes, etc.). The relationship between chronic inflammation and cancer development has been widely accepted, and chronic inflammation has been associated with the development of many cancers, including chronic bronchitis and lung cancer, cystitis inducing bladder cancer. Moreover, chronic colorectitis is more likely to develop into colorectal cancer. Therefore, the specific relationship and cellular mechanisms between inflammation and cancer are a hot topic of research. Recent studies have identified phosphodiesterase 4B (PDE4B), a member of the phosphodiesterase (PDEs) protein family, as a major cyclic AMP (cAMP) metabolizing enzyme in inflammatory cells, and the therapeutic role of PDE4B as chronic inflammation, cancer. In this review, we will present the tumors associated with chronic inflammation, and PDE4B potential clinical application.
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Affiliation(s)
- Yue Su
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Public Foundation, Bengbu Medical University, Bengbu, China
| | - Jiaxiang Ding
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Public Foundation, Bengbu Medical University, Bengbu, China
| | - Fan Yang
- Department of Ophthalmology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Cuixia He
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Yuanyuan Xu
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Xingyu Zhu
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Huan Zhou
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Public Foundation, Bengbu Medical University, Bengbu, China
- School of Pharmacy, Bengbu Medical University, Bengbu, China
- *Correspondence: Hongtao Li, ; Huan Zhou,
| | - Hongtao Li
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- *Correspondence: Hongtao Li, ; Huan Zhou,
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16
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Hepatitis B virus polymerase restricts LINE-1 mobility. Gene 2022; 850:146943. [PMID: 36198378 DOI: 10.1016/j.gene.2022.146943] [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: 05/23/2022] [Revised: 09/06/2022] [Accepted: 09/28/2022] [Indexed: 11/21/2022]
Abstract
Long interspersed element-1 (LINE-1, L1) transposable element (TE) composes about 17% of the human genome. However, genetic and biochemical interactions between L1 and hepatitis B virus (HBV) remain poorly understood. In this study, I found that HBV restricts L1 retrotransposition in a reverse transcriptase (RT)-independent manner. Notably, HBV polymerase (Pol) strongly inhibited L1 retrotransposition. Indeed, the ribonuclease H (RNase H) domain was essential for inhibition of L1 retrotransposition. The L1 ORF1p RNA-binding protein predominantly localized into cytoplasmic RNA granule termed P-body. However, HBV Pol hijacked L1 ORF1p from P-body through an interaction with L1 ORF1p, when both proteins were co-expressed. Furthermore, HBV Pol repressed the L1 5' untranslated region (UTR). Altogether, HBV seems to restrict L1 mobility at multiple steps. Thus, these results suggest a novel function or activity of HBV Pol in regulation of L1 retrotransposition.
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TP53 and LRP1B Co-Wild Predicts Improved Survival for Patients with LUSC Receiving Anti-PD-L1 Immunotherapy. Cancers (Basel) 2022; 14:cancers14143382. [PMID: 35884443 PMCID: PMC9320428 DOI: 10.3390/cancers14143382] [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: 06/13/2022] [Revised: 07/02/2022] [Accepted: 07/06/2022] [Indexed: 02/04/2023] Open
Abstract
Immunotherapy brought long-term benefits for partial patients with lung squamous cell carcinoma (LUSC). The predictor of anti-PD-L1 therapy was controversial and limited in LUSC. We aimed to explore novel biomarker for LUSC immunotherapy and the potential mechanism. Five hundred and twenty-five Chinese patients (Geneplus cohort) with LUSC underwent targeted sequencing and were involved to explore the genomic profiling. TP53 and LRP1B were the most frequently recurrent genes and correlated to higher tumor mutational burden (TMB). We observed that LUSC patients with TP53 and LRP1B co-wild (co-wild type) were associated with better survival of anti-PD-L1 therapy compared with TP53 mutant or LRP1B mutant (mutant type) in POPAR/OAK cohort. Copy-number variation (CNV) and whole genome doubling (WGD) data from TCGA LUSC cohort were obtained to assess the CNV events. There were fewer CNV alterations and lower chromosome instability in patients with TP53/LRP1B co-wild compared with those with TP53/LRP1B mutant. RNA expression data from the TCGA LUSC cohort were collected to explore the differences in RNA expression and tumor immune microenvironment (TIME) between mutant and co-wild groups. The TP53/LRP1B co-wild type had a significantly increased proportion of multiple tumor-infiltrating lymphocytes (TILs), including activated CD8 T cell, activated dendritic cell (DC), and effector memory CD8 T cell. Immune-related gene sets including checkpoint, chemokine, immunostimulatory, MHC and receptors were enriched in the co-wild type. In conclusion, TP53/LRP1B co-wild LUSC conferred an elevated response rate in anti-PD-L1 therapy and improved survival, which was associated with a chromosome-stable phenotype and an activated immune microenvironment.
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Jia D, Zhang R, Shao J, Zhang W, Cai L, Sun W. Exposure to trace levels of metals and fluoroquinolones increases inflammation and tumorigenesis risk of zebrafish embryos. ENVIRONMENTAL SCIENCE AND ECOTECHNOLOGY 2022; 10:100162. [PMID: 36159734 PMCID: PMC9488011 DOI: 10.1016/j.ese.2022.100162] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 05/04/2023]
Abstract
Exposure to trace-level heavy metals and antibiotics may elicit metabolic disorder, alter protein expression, and then induce pathological changes in zebrafish embryos, despite negligible physiological and developmental toxicity. This study investigated the single and combined developmental toxicity of fluoroquinolones (enrofloxacin [ENR] and ciprofloxacin [CIP]) (≤0.5 μM) and heavy metals (Cu and Cd) (≤0.5 μM) to zebrafish embryos, and molecular responses of zebrafish larvae upon exposure to the single pollutant (0.2 μM) or a binary metal-fluoroquinolone mixture (0.2 μM). In all single and mixture exposure groups, no developmental toxicity was observed, but oxidative stress, inflammation, and lipid depletion were found in zebrafish embryos, which was more severe in the mixture exposure groups than in the single exposure groups, probably due to increased metal bioaccumulation in the presence of ENR or CIP. Metabolomics analysis revealed the up-regulation of amino acids and down-regulation of fatty acids, corresponding to an active response to oxidative stress and the occurrence of inflammation. The up-regulation of antioxidase and immune proteins revealed by proteomics analysis further confirmed the occurrence of oxidative stress and inflammation. Furthermore, the KEGG pathway enrichment analysis showed a significant disturbance of pathways related to immunity and tumor, indicating the potential risk of tumorigenesis in zebrafish larvae. The findings provide molecular-level insights into the adverse effects of heavy metals and antibiotics (especially in chemical mixtures) on zebrafish embryos, and highlight the potential ecotoxicological risks of trace-level heavy metals and antibiotics in the environment.
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Affiliation(s)
- Dantong Jia
- College of Environmental Sciences and Engineering, Peking University, The Key Laboratory of Water and Sediment Sciences, Ministry of Education, Beijing, 100871, China
- State Environmental Protection Key Laboratory of All Material Fluxes in River Ecosystems, International Joint Laboratory for Regional Pollution Control, Ministry of Education, Beijing, 100871, China
| | - Ruijie Zhang
- College of Environmental Sciences and Engineering, Peking University, The Key Laboratory of Water and Sediment Sciences, Ministry of Education, Beijing, 100871, China
- State Environmental Protection Key Laboratory of All Material Fluxes in River Ecosystems, International Joint Laboratory for Regional Pollution Control, Ministry of Education, Beijing, 100871, China
| | - Jian Shao
- College of Animal Science, Guizhou University, The Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guiyang, Guizhou, 550025, China
| | - Wei Zhang
- Department of Plant, Soil and Microbial Sciences, Environmental Science and Policy Program, Michigan State University, East Lansing, MI, 48824, United States
| | - Leilei Cai
- College of Safety and Environmental Engineering, Shandong University of Science and Technology, Qingdao, Shandong, 266590, China
| | - Weiling Sun
- College of Environmental Sciences and Engineering, Peking University, The Key Laboratory of Water and Sediment Sciences, Ministry of Education, Beijing, 100871, China
- State Environmental Protection Key Laboratory of All Material Fluxes in River Ecosystems, International Joint Laboratory for Regional Pollution Control, Ministry of Education, Beijing, 100871, China
- Corresponding author. Peking University. China.
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19
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Cheng Y, Tang R, Li X, Wang B, Cheng Y, Xiao S, Sun P, Yu W, Li C, Lin X, Zhu Y. LRP1B is a Potential Biomarker for Tumor Immunogenicity and Prognosis of HCC Patients Receiving ICI Treatment. J Hepatocell Carcinoma 2022; 9:203-220. [PMID: 35345553 PMCID: PMC8957351 DOI: 10.2147/jhc.s348785] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/05/2022] [Indexed: 12/11/2022] Open
Abstract
Background New predictors of the efficacy of hepatocellular carcinoma (HCC) immunotherapy are needed. The ability of a single gene mutation to predict the therapeutic effect of immune checkpoint inhibitors (ICI) in HCC remains unknown. Methods The most frequently mutated genes in HCC were analyzed using the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. Mutant genes that correlated with the tumor mutational burden (TMB) and prognosis were obtained. The mutation pattern and immunological function of one of the most frequently mutated genes, LRP1B, were determined. A pan-tumor analysis of LRP1B expression, association with cancer prognosis, and immunological role was also explored. A retrospective clinical study was conducted using 102 HCC patients who received ICI treatment to further verify whether gene mutations can predict the effectiveness of immunotherapy and prognosis of HCC. Results LRP1B is among the most frequently mutated genes in HCC cohorts in TCGA and ICGC datasets. TCGA data showed that the LRP1B mutation activated immune signaling pathways and promoted mast cell activation. Patients with LRP1B mutations had significantly higher TMB than those with wild-type LRP1B. LRP1B expression correlated with the cancer-immunity cycle and immune cell infiltration. High LRP1B expression was also associated with poor survival among HCC patients. Results from the clinical study showed that HCC patients in the LRP1B mutation group had a poor response to ICI and worse prognosis than the wild-type group. The LRP1B mutation group had significantly higher TMB and mast cell infiltration in tumor tissues. Conclusion This study is the first to report that a single gene LRP1B mutation is associated with a poor clinical response to ICI treatment and negative outcomes in HCC patients. HighLRP1B expression correlated with tumor immunity and HCC prognosis.
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Affiliation(s)
- Yang Cheng
- Digestive Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
- Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Rui Tang
- Digestive Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Xiangzhao Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Biao Wang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Yanling Cheng
- Digestive Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Shuzhe Xiao
- Digestive Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Penghui Sun
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Wenxuan Yu
- Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Cheng Li
- Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Xinsheng Lin
- Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Yun Zhu
- Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
- Correspondence: Yun Zhu, Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China, Email
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20
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Bousali M, Karamitros T. Hepatitis B Virus Integration into Transcriptionally Active Loci and HBV-Associated Hepatocellular Carcinoma. Microorganisms 2022; 10:microorganisms10020253. [PMID: 35208708 PMCID: PMC8879149 DOI: 10.3390/microorganisms10020253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/10/2022] [Accepted: 01/20/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatitis B Virus (HBV) DNA integrations into the human genome are considered major causative factors to HBV-associated hepatocellular carcinoma development. In the present study, we investigated whether HBV preferentially integrates parts of its genome in specific genes and evaluated the contribution of the integrations in HCC development per gene. We applied dedicated in-house developed pipelines on all of the available HBV DNA integration data and performed a statistical analysis to identify genes that could be characterized as hotspots of integrations, along with the evaluation of their association with HBV-HCC. Our results suggest that 15 genes are recurrently affected by HBV integrations and they are significantly associated with HBV-HCC. Further studies that focus on HBV integrations disrupting these genes are mandatory in order to understand the role of HBV integrations in clonal advantage gain and oncogenesis promotion, as well as to determine whether inhibition of the HBV-disrupted genes can provide a therapy strategy for HBV-HCC.
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Affiliation(s)
- Maria Bousali
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
- Correspondence: ; Tel.: +30-210-6478871
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21
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Wang Y, Tong Y, Zhang Z, Zheng R, Huang D, Yang J, Zong H, Tan F, Xie Y, Huang H, Zhang X. ViMIC: a database of human disease-related virus mutations, integration sites and cis-effects. Nucleic Acids Res 2022; 50:D918-D927. [PMID: 34500462 PMCID: PMC8728280 DOI: 10.1093/nar/gkab779] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/10/2021] [Accepted: 08/26/2021] [Indexed: 02/06/2023] Open
Abstract
Molecular mechanisms of virus-related diseases involve multiple factors, including viral mutation accumulation and integration of a viral genome into the host DNA. With increasing attention being paid to virus-mediated pathogenesis and the development of many useful technologies to identify virus mutations (VMs) and viral integration sites (VISs), much research on these topics is available in PubMed. However, knowledge of VMs and VISs is widely scattered in numerous published papers which lack standardization, integration and curation. To address these challenges, we built a pilot database of human disease-related Virus Mutations, Integration sites and Cis-effects (ViMIC), which specializes in three features: virus mutation sites, viral integration sites and target genes. In total, the ViMIC provides information on 31 712 VMs entries, 105 624 VISs, 16 310 viral target genes and 1 110 015 virus sequences of eight viruses in 77 human diseases obtained from the public domain. Furthermore, in ViMIC users are allowed to explore the cis-effects of virus-host interactions by surveying 78 histone modifications, binding of 1358 transcription regulators and chromatin accessibility on these VISs. We believe ViMIC will become a valuable resource for the virus research community. The database is available at http://bmtongji.cn/ViMIC/index.php.
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Affiliation(s)
- Ying Wang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
| | - Yuantao Tong
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Zeyu Zhang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Rongbin Zheng
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Danqi Huang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Jinxuan Yang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Hui Zong
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Fanglin Tan
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Yujia Xie
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Honglian Huang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Xiaoyan Zhang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
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22
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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]
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23
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Salpini R, D’Anna S, Benedetti L, Piermatteo L, Gill U, Svicher V, Kennedy PTF. Hepatitis B virus DNA integration as a novel biomarker of hepatitis B virus-mediated pathogenetic properties and a barrier to the current strategies for hepatitis B virus cure. Front Microbiol 2022; 13:972687. [PMID: 36118192 PMCID: PMC9478028 DOI: 10.3389/fmicb.2022.972687] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic infection with Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality worldwide. HBV-DNA integration into the human genome is recognized as a frequent event occurring during the early phases of HBV infection and characterizing the entire course of HBV natural history. The development of refined molecular biology technologies sheds new light on the functional implications of HBV-DNA integration into the human genome, including its role in the progression of HBV-related pathogenesis and in triggering the establishment of pro-oncogenic mechanisms, promoting the development of hepatocellular carcinoma. The present review provides an updated and comprehensive overview of the current body of knowledge on HBV-DNA integration, focusing on the molecular mechanisms underlying HBV-DNA integration and its occurrence throughout the different phases characterizing the natural history of HBV infection. Furthermore, here we discuss the main clinical implications of HBV integration as a biomarker of HBV-related pathogenesis, particularly in reference to hepatocarcinogenesis, and how integration may act as a barrier to the achievement of HBV cure with current and novel antiviral therapies. Overall, a more refined insight into the mechanisms and functionality of HBV integration is paramount, since it can potentially inform the design of ad hoc diagnostic tools with the ability to reveal HBV integration events perturbating relevant intracellular pathways and for identifying novel therapeutic strategies targeting alterations directly related to HBV integration.
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Affiliation(s)
- Romina Salpini
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Stefano D’Anna
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Livia Benedetti
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Lorenzo Piermatteo
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Upkar Gill
- Barts Liver Centre, Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Valentina Svicher
- Department of Biology, University of Rome Tor Vergata, Roma, Italy
- *Correspondence: Valentina Svicher,
| | - Patrick T. F. Kennedy
- Barts Liver Centre, Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
- Patrick T. F. Kennedy,
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24
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Cui D, Li W, Jiang D, Wu J, Xie J, Wu Y. Advances in Multi-Omics Applications in HBV-Associated Hepatocellular Carcinoma. Front Med (Lausanne) 2021; 8:754709. [PMID: 34660653 PMCID: PMC8514776 DOI: 10.3389/fmed.2021.754709] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 08/31/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) specifically infects liver cells, leading to progressive liver cirrhosis and significantly increasing the risk of hepatocellular carcinoma (HCC). The maturity of sequencing technology, improvement in bioinformatics data analysis and progress of omics technologies had improved research efficiency. The occurrence and progression of HCC are affected by multisystem and multilevel pathological changes. With the application of single-omics technologies, including genomics, transcriptomics, metabolomics and proteomics in tissue and body fluid samples, and even the novel development of multi-omics analysis on a single-cell platform, HBV-associated HCC changes can be better analyzed. The review summarizes the application of single omics and combined analysis of multi-omics data in HBV-associated HCC and proposes the importance of multi-omics analysis in the type of HCC, which provide the possibility for the precise diagnosis and therapy of HBV-associated HCC.
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Affiliation(s)
- Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Li
- Center of Research Laboratory, The First People's Hospital of Lianyungang, Lianyungang, China
| | - Daixi Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianguo Wu
- Department of Laboratory Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
| | - Jue Xie
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yingping Wu
- Department of Laboratory Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
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25
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Chen C, Wang T, Yang M, Song J, Huang M, Bai Y, Su H. Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Advanced Biliary Tract Cancer. Pathol Oncol Res 2021; 27:1609879. [PMID: 34720757 PMCID: PMC8553707 DOI: 10.3389/pore.2021.1609879] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 09/30/2021] [Indexed: 01/10/2023]
Abstract
Background: Biliary tract cancer is a highly lethal malignancy with poor clinical outcome. Accumulating evidence indicates targeted therapeutics may provide new hope for improving treatment response in BTC, hence better understanding the genomic profile is particularly important. Since tumor tissue may not be available for some patients, a complementary method is urgently needed. Circulating tumor DNA (ctDNA) provides a noninvasive means for detecting genomic alterations, and has been regarded as a promising tool to guide clinical therapies. Methods: Next-generation sequencing of 150 cancer-related genes was used to detect gene alterations in blood-derived ctDNA from 154 Chinese patients with BTC. Genomic alterations were analyzed and compared with an internal tissue genomic database and TCGA database. Results: 94.8% patients had at least one change detected in their ctDNA. The median maximum somatic allele frequency was 6.47% (ranging 0.1-34.8%). TP53 and KRAS were the most often mutated genes. The frequencies of single nucleotide variation in commonly mutated genes in ctDNA were similar to those detected in tissue samples, TP53 (35.1 vs. 40.4%) and KRAS (20.1 vs. 22.6%). Pathway analysis revealed that mutated genes were mapped to several key pathways including PI3K-Akt, p53, ErbB and Ras signaling pathway. In addition, patients harboring LRP1B, TP53, and ErbB family mutations presented significantly higher tumor mutation burden. Conclusions: These findings demonstrated that ctDNA testing by NGS was feasible in revealing genomic changes and could be a viable alternative to tissue biopsy in patients with metastatic BTC.
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Affiliation(s)
- Chen Chen
- Hepatobiliary Surgery, Hunan Provincial People’s Hospital (The First Affiliate Hospital of Hunan Normal University), Changsha, China
| | - Tao Wang
- Hepatobiliary Surgery, Hunan Provincial People’s Hospital (The First Affiliate Hospital of Hunan Normal University), Changsha, China
| | - Mengmei Yang
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Jia Song
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Mengli Huang
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Yuezong Bai
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Hao Su
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
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26
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Zhuo Z, Rong W, Li H, Li Y, Luo X, Liu Y, Tang X, Zhang L, Su F, Cui H, Xiao F. Long-read sequencing reveals the structural complexity of genomic integration of HBV DNA in hepatocellular carcinoma. NPJ Genom Med 2021; 6:84. [PMID: 34642322 PMCID: PMC8511263 DOI: 10.1038/s41525-021-00245-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 09/03/2021] [Indexed: 02/01/2023] Open
Abstract
The integration of HBV DNA into the human genome can disrupt its structure in hepatocellular carcinoma (HCC), but the complexity of HBV genomic integration remains elusive. Here we applied long-read sequencing to precisely elucidate the HBV integration pattern in the human hepatocellular genome. The DNA library was sequenced using the long-read sequencing on GridION and PacBio Sequel II, respectively. The DNA and mRNA were sequenced using next-generation sequencing on Illumina NextSeq. BLAST (Basic Local Alignment Search Tool) and local scripts were used to analyze HBV integration patterns. We established an analytical strategy based on the long-read sequences, and analyzed the complexity of HBV DNA integration into the hepatocellular genome. A total of 88 integrated breakpoints were identified. HBV DNA integration into human genomic DNA was mainly fragmented with different orientations, rarely with a complete genome. The same HBV integration breakpoints were identified among the three platforms. Most breakpoints were observed at P, X, and S genes in the HBV genome, and observed at introns, intergenic sequences, and exons in the human genome. Tumor tissue harbored a much higher integrated number than the adjacent tissue, and the distribution of HBV integrated into human chromosomes was more concentrated. HBV integration shows different patterns between cancer cells and adjacent normal cells. We for the first time obtained the entire HBV integration pattern through long-read sequencing and demonstrated the value of long-read sequencing in detecting the genomic integration structures of viruses in host cells.
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Affiliation(s)
- Zhongling Zhuo
- Peking University Fifth School of Clinical Medicine, Beijing, China.,The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Clinical Biobank, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Weiqi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
| | - Hexin Li
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Ying Li
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Xuanmei Luo
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Ye Liu
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaokun Tang
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Lili Zhang
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Fei Su
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Hongyuan Cui
- Department of Surgery, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
| | - Fei Xiao
- Peking University Fifth School of Clinical Medicine, Beijing, China. .,The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China. .,Clinical Biobank, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
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27
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Lin SY, Su YP, Trauger ER, Song BP, Thompson EGC, Hoffman MC, Chang TT, Lin YJ, Kao YL, Cui Y, Hann HW, Park G, Shieh FS, Song W, Su YH. Detection of Hepatitis B Virus-Host Junction Sequences in Urine of Infected Patients. Hepatol Commun 2021; 5:1649-1659. [PMID: 34558837 PMCID: PMC8485884 DOI: 10.1002/hep4.1783] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/24/2021] [Accepted: 06/20/2021] [Indexed: 01/25/2023] Open
Abstract
Integrated hepatitis B virus (HBV) DNA, found in more than 85% of HBV-associated hepatocellular carcinomas (HBV-HCCs), can play a significant role in HBV-related liver disease progression. HBV-host junction sequences (HBV-JSs), created through integration events, have been used to determine HBV-HCC clonality. Here, we investigate the feasibility of analyzing HBV integration in a noninvasive urine liquid biopsy. Using an HBV-targeted next-generation sequencing (NGS) assay, we first identified HBV-JSs in eight HBV-HCC tissues and designed short-amplicon junction-specific polymerase chain reaction assays to detect HBV-JSs in matched urine. We detected and validated tissue-derived junctions in five of eight matched urine samples. Next, we screened 32 urine samples collected from 25 patients infected with HBV (5 with hepatitis, 10 with cirrhosis, 4 with HCC, and 6 post-HCC). Encouragingly, all 32 urine samples contained HBV-JSs detectable by HBV-targeted NGS. Of the 712 total HBV-JSs detected in urine, 351 were in gene-coding regions, 11 of which, including TERT (telomerase reverse transcriptase), had previously been reported as recurrent integration sites in HCC tissue and were found only in the urine patients with cirrhosis or HCC. The integration breakpoints of HBV DNA detected in urine were found predominantly (~70%) at a previously identified integration hotspot, HBV DR1-2 (down-regulator of transcription 1-2). Conclusion: HBV viral-host junction DNA can be detected in urine of patients infected with HBV. This study demonstrates the potential for a noninvasive urine liquid biopsy of integrated HBV DNA to monitor patients infected with HBV for HBV-associated liver diseases and the efficacy of antiviral therapy.
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Affiliation(s)
| | - Yih-Ping Su
- The Baruch S. Blumberg Research InstituteDoylestownPAUSA
| | | | | | | | | | - Ting-Tsung Chang
- Department of Internal MedicineNational Cheng Kung University Hospital, College of MedicineTainanTaiwan, Republic of China
| | - Yih-Jyh Lin
- Department of SurgeryNational Cheng Kung University Hospital, College of MedicineTainanTaiwan, Republic of China
| | - Yu-Lan Kao
- The Baruch S. Blumberg Research InstituteDoylestownPAUSA
| | - Yixiao Cui
- The Baruch S. Blumberg Research InstituteDoylestownPAUSA
| | - Hie-Won Hann
- Liver Disease Prevention CenterDivision of Gastroenterology and HepatologyThomas Jefferson University HospitalPhiladelphiaPAUSA
| | - Grace Park
- Liver Disease Prevention CenterDivision of Gastroenterology and HepatologyThomas Jefferson University HospitalPhiladelphiaPAUSA
| | | | - Wei Song
- JBS Science, Inc.DoylestownPAUSA
| | - Ying-Hsiu Su
- The Baruch S. Blumberg Research InstituteDoylestownPAUSA
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28
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Tsuge M. Are Humanized Mouse Models Useful for Basic Research of Hepatocarcinogenesis through Chronic Hepatitis B Virus Infection? Viruses 2021; 13:v13101920. [PMID: 34696350 PMCID: PMC8541657 DOI: 10.3390/v13101920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/14/2021] [Accepted: 09/20/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a global health problem that can lead to liver dysfunction, including liver cirrhosis and hepatocellular carcinoma (HCC). Current antiviral therapies can control viral replication in patients with chronic HBV infection; however, there is a risk of HCC development. HBV-related proteins may be produced in hepatocytes regardless of antiviral therapies and influence intracellular metabolism and signaling pathways, resulting in liver carcinogenesis. To understand the mechanisms of liver carcinogenesis, the effect of HBV infection in human hepatocytes should be analyzed. HBV infects human hepatocytes through transfer to the sodium taurocholate co-transporting polypeptide (NTCP). Although the NTCP is expressed on the hepatocyte surface in several animals, including mice, HBV infection is limited to human primates. Due to this species-specific liver tropism, suitable animal models for analyzing HBV replication and developing antivirals have been lacking since the discovery of the virus. Recently, a humanized mouse model carrying human hepatocytes in the liver was developed based on several immunodeficient mice; this is useful for analyzing the HBV life cycle, antiviral effects of existing/novel antivirals, and intracellular signaling pathways under HBV infection. Herein, the usefulness of human hepatocyte chimeric mouse models in the analysis of HBV-associated hepatocarcinogenesis is discussed.
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Affiliation(s)
- Masataka Tsuge
- Natural Science Center for Basic Research and Development, Department of Biomedical Science, Research and Development Division, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; ; Tel.: +81-82-257-1510
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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29
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Midorikawa Y, Tatsuno K, Moriyama M. Genome-wide analysis of hepatitis B virus integration in hepatocellular carcinoma: Insights next generation sequencing. Hepatobiliary Surg Nutr 2021; 10:548-552. [PMID: 34430541 DOI: 10.21037/hbsn-21-228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 06/25/2021] [Indexed: 11/06/2022]
Affiliation(s)
- Yutaka Midorikawa
- Genome Science and Medicine, RCAST, University of Tokyo, Tokyo, Japan.,Department of Surgery, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Kenji Tatsuno
- Genome Science and Medicine, RCAST, University of Tokyo, Tokyo, Japan
| | - Mitsuhiko Moriyama
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
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30
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Príncipe C, Dionísio de Sousa IJ, Prazeres H, Soares P, Lima RT. LRP1B: A Giant Lost in Cancer Translation. Pharmaceuticals (Basel) 2021; 14:836. [PMID: 34577535 PMCID: PMC8469001 DOI: 10.3390/ph14090836] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/14/2021] [Accepted: 08/16/2021] [Indexed: 12/23/2022] Open
Abstract
Low-density lipoprotein receptor-related protein 1B (LRP1B) is a giant member of the LDLR protein family, which includes several structurally homologous cell surface receptors with a wide range of biological functions from cargo transport to cell signaling. LRP1B is among the most altered genes in human cancer overall. Found frequently inactivated by several genetic and epigenetic mechanisms, it has mostly been regarded as a putative tumor suppressor. Still, limitations in LRP1B studies exist, in particular associated with its huge size. Therefore, LRP1B expression and function in cancer remains to be fully unveiled. This review addresses the current understanding of LRP1B and the studies that shed a light on the LRP1B structure and ligands. It goes further in presenting increasing knowledge brought by technical and methodological advances that allow to better manipulate LRP1B expression in cells and to more thoroughly explore its expression and mutation status. New evidence is pushing towards the increased relevance of LRP1B in cancer as a potential target or translational prognosis and response to therapy biomarker.
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Affiliation(s)
- Catarina Príncipe
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (C.P.); (H.P.); (P.S.)
- Cancer Signalling and Metabolism Group, IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
| | - Isabel J. Dionísio de Sousa
- Department of Oncology, Centro Hospitalar Universitário de São João, 4200-450 Porto, Portugal;
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Hugo Prazeres
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (C.P.); (H.P.); (P.S.)
- IPO-Coimbra, Portuguese Oncology Institute of Coimbra, 3000-075 Coimbra, Portugal
| | - Paula Soares
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (C.P.); (H.P.); (P.S.)
- Cancer Signalling and Metabolism Group, IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Raquel T. Lima
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (C.P.); (H.P.); (P.S.)
- Cancer Signalling and Metabolism Group, IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
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31
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Bousali M, Papatheodoridis G, Paraskevis D, Karamitros T. Hepatitis B Virus DNA Integration, Chronic Infections and Hepatocellular Carcinoma. Microorganisms 2021; 9:1787. [PMID: 34442866 PMCID: PMC8398950 DOI: 10.3390/microorganisms9081787] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B Virus (HBV) is an Old World virus with a high mutation rate, which puts its origins in Africa alongside the origins of Homo sapiens, and is a member of the Hepadnaviridae family that is characterized by a unique viral replication cycle. It targets human hepatocytes and can lead to chronic HBV infection either after acute infection via horizontal transmission usually during infancy or childhood or via maternal-fetal transmission. HBV has been found in ~85% of HBV-related Hepatocellular Carcinomas (HCC), and it can integrate the whole or part of its genome into the host genomic DNA. The molecular mechanisms involved in the HBV DNA integration is not yet clear; thus, multiple models have been described with respect to either the relaxed-circular DNA (rcDNA) or the double-stranded linear DNA (dslDNA) of HBV. Various genes have been found to be affected by HBV DNA integration, including cell-proliferation-related genes, oncogenes and long non-coding RNA genes (lincRNAs). The present review summarizes the advances in the research of HBV DNA integration, focusing on the evolutionary and molecular side of the integration events along with the arising clinical aspects in the light of WHO's commitment to eliminate HBV and viral hepatitis by 2030.
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Affiliation(s)
- Maria Bousali
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - George Papatheodoridis
- Department of Gastroenterology, “Laiko” General Hospital of Athens, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Paraskevis
- Department of Hygiene Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
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32
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Huang CJ, Wang LHC, Wang YC. Identification of Therapeutic Targets for the Selective Killing of HBV-Positive Hepatocytes. J Pers Med 2021; 11:jpm11070649. [PMID: 34357116 PMCID: PMC8307716 DOI: 10.3390/jpm11070649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 11/16/2022] Open
Abstract
The hepatitis B virus (HBV) infection is a major risk factor for cirrhosis and hepatocellular carcinoma. Most infected individuals become lifelong carriers of HBV as the drugs currently used to treat the patients can only control the disease, thereby achieving functional cure (loss of the hepatitis B surface antigen) but not complete cure (elimination of infected hepatocytes). Therefore, we aimed to identify the target genes for the selective killing of HBV-positive hepatocytes to develop a novel therapy for the treatment of HBV infection. Our strategy was to recognize the conditionally essential genes that are essential for the survival of HBV-positive hepatocytes, but non-essential for the HBV-negative hepatocytes. Using microarray gene expression data curated from the Gene Expression Omnibus database and the known essential genes from the Online GEne Essentiality database, we used two approaches, comprising the random walk with restart algorithm and the support vector machine approach, to determine the potential targets for the selective killing of HBV-positive hepatocytes. The final candidate genes list obtained using these two approaches consisted of 36 target genes, which may be conditionally essential for the cell survival of HBV-positive hepatocytes; however, this requires further experimental validation. Therefore, the genes identified in this study can be used as potential drug targets to develop novel therapeutic strategies for the treatment of HBV, and may ultimately help in achieving the elusive goal of a complete cure for hepatitis B.
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Affiliation(s)
- Chien-Jung Huang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
| | - Lily Hui-Ching Wang
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300044, Taiwan;
- Department of Medical Science, National Tsing Hua University, Hsinchu 300044, Taiwan
| | - Yu-Chao Wang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
- Correspondence:
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33
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Wu C, Guo X, Li M, Shen J, Fu X, Xie Q, Hou Z, Zhai M, Qiu X, Cui Z, Xie H, Qin P, Weng X, Hu Z, Liang J. DeepHBV: a deep learning model to predict hepatitis B virus (HBV) integration sites. BMC Ecol Evol 2021; 21:138. [PMID: 34233610 PMCID: PMC8261932 DOI: 10.1186/s12862-021-01869-8] [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: 03/15/2021] [Accepted: 06/29/2021] [Indexed: 01/05/2023] Open
Abstract
Background The hepatitis B virus (HBV) is one of the main causes of viral hepatitis and liver cancer. HBV integration is one of the key steps in the virus-promoted malignant transformation. Results An attention-based deep learning model, DeepHBV, was developed to predict HBV integration sites. By learning local genomic features automatically, DeepHBV was trained and tested using HBV integration site data from the dsVIS database. Initially, DeepHBV showed an AUROC of 0.6363 and an AUPR of 0.5471 for the dataset. The integration of genomic features of repeat peaks and TCGA Pan-Cancer peaks significantly improved model performance, with AUROCs of 0.8378 and 0.9430 and AUPRs of 0.7535 and 0.9310, respectively. The transcription factor binding sites (TFBS) were significantly enriched near the genomic positions that were considered. The binding sites of the AR-halfsite, Arnt, Atf1, bHLHE40, bHLHE41, BMAL1, CLOCK, c-Myc, COUP-TFII, E2A, EBF1, Erra, and Foxo3 were highlighted by DeepHBV in both the dsVIS and VISDB datasets, revealing a novel integration preference for HBV. Conclusions DeepHBV is a useful tool for predicting HBV integration sites, revealing novel insights into HBV integration-related carcinogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s12862-021-01869-8.
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Affiliation(s)
- Canbiao Wu
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China
| | - Xiaofang Guo
- Department of Medical Oncology of the Eastern Hospital, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, 510700, Guangzhou, China
| | - Mengyuan Li
- Department of Gynecological Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, 510080, Guangzhou, China
| | - Jingxian Shen
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China
| | - Xiayu Fu
- Department of Thoracic Surgery, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, 510080, Guangzhou, China
| | - Qingyu Xie
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China.,School of Computer Science, South China Normal University, Guangzhou, 510631, China
| | - Zeliang Hou
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China
| | - Manman Zhai
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China.,School of Psychology, South China Normal University, Guangzhou, 510080, Guangdong, China
| | - Xiaofan Qiu
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China
| | - Zifeng Cui
- Department of Gynecological Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, 510080, Guangzhou, China
| | - Hongxian Xie
- Generulor Company Bio-X Lab, Guangzhou, 510006, Guangdong, China
| | - Pengmin Qin
- School of Psychology, South China Normal University, Guangzhou, 510080, Guangdong, China
| | - Xuchu Weng
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China.,Key Laboratory of Brain, Cognition and Education Sciences (South China Normal University), Ministry of Education, Guangzhou, 510080, Guangdong, China
| | - Zheng Hu
- Department of Gynecological Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, 510080, Guangzhou, China. .,Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
| | - Jiuxing Liang
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China. .,Key Laboratory of Brain, Cognition and Education Sciences (South China Normal University), Ministry of Education, Guangzhou, 510080, Guangdong, China.
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34
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Elpek GO. Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update. World J Clin Cases 2021; 9:4890-4917. [PMID: 34307543 PMCID: PMC8283590 DOI: 10.12998/wjcc.v9.i19.4890] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/14/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancer-related deaths worldwide. In recent years, uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets. Despite the vast amount of data on this topic, HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile. Therefore, the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase. In this context, the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior. In line with these efforts, this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in oncogenesis and tumor progression in HCC and summarize new findings. Cumulative evidence indicates that HBV DNA integration promotes genomic instability, resulting in the overexpression of genes related to cancer development, metastasis, and angiogenesis or inactivation of tumor suppressor genes. In addition, genetic variations in HBV itself, especially preS2 deletions, may play a role in malignant transformation. Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs. Similarly, viral proteins of both HBV and HCV can affect pathways that are important anticancer targets. The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated. Additional, comprehensive studies are also needed to determine these viruses' interaction with integrins, farnesoid X, and the apelin system in malignant transformation and tumor progression. Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined, further studies are warranted to decipher the relationship among inflammasomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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35
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Zhang D, Zhang K, Protzer U, Zeng C. HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site. J Clin Transl Hepatol 2021; 9:399-408. [PMID: 34221926 PMCID: PMC8237140 DOI: 10.14218/jcth.2021.00062] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV), one of the well-known DNA oncogenic viruses, is the leading cause of hepatocellular carcinoma (HCC). In infected hepatocytes, HBV DNA can be integrated into the host genome through an insertional mutagenesis process inducing tumorigenesis. Dissection of the genomic features surrounding integration sites will deepen our understanding of mechanisms underlying integration. Moreover, the quantity and biological activity of integration sites may reflect the DNA damage within affected cells or the potential survival benefits they may confer. The well-known human genomic features include repeat elements, particular regions (such as telomeres), and frequently interrupted genes (e.g., telomerase reverse transcriptase [i.e. TERT], lysine methyltransferase 2B [i.e. KMT2B], cyclin E1 [CCNE1], and cyclin A2 [CCNA2]). Consequently, distinct genomic features within diverse integrations differentiate their biological functions. Meanwhile, accumulating evidence has shown that viral proteins produced by integrants may cause cell damage even after the suppression of HBV replication. The integration-derived gene products can also serve as tumor markers, promoting the development of novel therapeutic strategies for HCC. Viral integrants can be single copy or multiple copies of different fragments with complicated rearrangement, which warrants elucidation of the whole viral integrant arrangement in future studies. All of these considerations underlie an urgent need to develop novel methodology and technology for sequence characterization and function evaluation of integration events in chronic hepatitis B-associated disease progression by monitoring both host genomic features and viral integrants. This endeavor may also serve as a promising solution for evaluating the risk of tumorigenesis and as a companion diagnostic for designing therapeutic strategies targeting integration-related disease complications.
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Affiliation(s)
- Dake Zhang
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Ke Zhang
- SCG Cell Therapy Pte. Ltd, Singapore
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Urlike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Changqing Zeng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
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36
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Kikuchi M, Kobayashi K, Nishida N, Sawai H, Sugiyama M, Mizokami M, Tokunaga K, Nakaya A. Genome-wide copy number variation analysis of hepatitis B infection in a Japanese population. Hum Genome Var 2021; 8:22. [PMID: 34103483 PMCID: PMC8187437 DOI: 10.1038/s41439-021-00154-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/24/2021] [Accepted: 04/18/2021] [Indexed: 01/06/2023] Open
Abstract
Genome-wide association studies have been performed to identify common genetic variants associated with hepatitis B (HB). However, little is known about copy number variations (CNVs) in HB. In this study, we performed a genome-wide CNV analysis between 1830 healthy controls and 1031 patients with HB infection after quality control. Using signal calling by the Axiom Analysis Suite and CNV detection by PennCNV software, we obtained a total of 4494 CNVs across all individuals. The genes with CNVs that were found only in the HB patients were associated with the immune system, such as antigen processing. A gene-level CNV association test revealed statistically significant CNVs in the contactin 6 (CNTN6) gene. Moreover, we also performed gene-level CNV association tests in disease subgroups, including hepatocellular carcinoma patients, liver cirrhosis patients, and HBV carriers, including asymptomatic carriers and patients with HBV-derived chronic hepatitis. Our findings from germline cells suggested that patient-specific CNVs may be inherent genetic risk factors for HB. The risk of contracting the hepatitis B virus may be linked to the number of copies of certain genes in an individual’s genome. A Japanese team led by Masataka Kikuchi, Osaka University, and Akihiro Nakaya, University of Tokyo, looked for repeated segments of the genome, known as copy number variants (CNVs), that differed between people with hepatitis B infections and those without. Studying around 3000 individuals of Japanese descent, the researchers identified several rare CNVs associated with immune function in hepatitis-affected individuals. They also found a common CNV in a gene called CNTN6 that the hepatitis B virus often uses to integrate itself into the genome of liver cells, a process that can lead to cancer. The findings underscore the importance of CNVs as inherited risk factors for hepatitis B and other viral infections.
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Affiliation(s)
- Masataka Kikuchi
- Department of Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Kaori Kobayashi
- Department of Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.,Medical Solutions Division, NEC Corporation, Tokyo, Japan
| | - Nao Nishida
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hiromi Sawai
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Japanese Red Cross Society, Tokyo, Japan
| | - Masaya Sugiyama
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Akihiro Nakaya
- Department of Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan. .,Laboratory of Genome Data Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
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37
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Lin SY, Zhang A, Lian J, Wang J, Chang TT, Lin YJ, Song W, Su YH. Recurrent HBV Integration Targets as Potential Drivers in Hepatocellular Carcinoma. Cells 2021; 10:cells10061294. [PMID: 34071075 PMCID: PMC8224658 DOI: 10.3390/cells10061294] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/15/2021] [Accepted: 05/20/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the major etiology of hepatocellular carcinoma (HCC), frequently with HBV integrating into the host genome. HBV integration, found in 85% of HBV-associated HCC (HBV–HCC) tissue samples, has been suggested to be oncogenic. Here, we investigated the potential of HBV–HCC driver identification via the characterization of recurrently targeted genes (RTGs). A total of 18,596 HBV integration sites from our in-house study and others were analyzed. RTGs were identified by applying three criteria: at least two HCC subjects, reported by at least two studies, and the number of reporting studies. A total of 396 RTGs were identified. Among the 28 most frequent RTGs, defined as affected in at least 10 HCC patients, 23 (82%) were associated with carcinogenesis and 5 (18%) had no known function. Available breakpoint positions from the three most frequent RTGs, TERT, MLL4/KMT2B, and PLEKHG4B, were analyzed. Mutual exclusivity of TERT promoter mutation and HBV integration into TERT was observed. We present an RTG consensus through comprehensive analysis to enable the potential identification and discovery of HCC drivers for drug development and disease management.
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Affiliation(s)
- Selena Y. Lin
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.W.); (W.S.)
| | - Adam Zhang
- The Baruch S. Blumberg Research Institute, Doylestown, PA 18902, USA; (A.Z.); (J.L.)
| | - Jessica Lian
- The Baruch S. Blumberg Research Institute, Doylestown, PA 18902, USA; (A.Z.); (J.L.)
| | - Jeremy Wang
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.W.); (W.S.)
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Medical College, Tainan 704, Taiwan;
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University Medical College, Tainan 704, Taiwan;
| | - Wei Song
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.W.); (W.S.)
| | - Ying-Hsiu Su
- The Baruch S. Blumberg Research Institute, Doylestown, PA 18902, USA; (A.Z.); (J.L.)
- Correspondence: ; Tel.: +215-489-4907
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38
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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] [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.
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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
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Xu H, Jia P, Zhao Z. DeepVISP: Deep Learning for Virus Site Integration Prediction and Motif Discovery. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2004958. [PMID: 33977077 PMCID: PMC8097320 DOI: 10.1002/advs.202004958] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Indexed: 05/08/2023]
Abstract
Approximately 15% of human cancers are estimated to be attributed to viruses. Virus sequences can be integrated into the host genome, leading to genomic instability and carcinogenesis. Here, a new deep convolutional neural network (CNN) model is developed with attention architecture, namely DeepVISP, for accurately predicting oncogenic virus integration sites (VISs) in the human genome. Using the curated benchmark integration data of three viruses, hepatitis B virus (HBV), human herpesvirus (HPV), and Epstein-Barr virus (EBV), DeepVISP achieves high accuracy and robust performance for all three viruses through automatically learning informative features and essential genomic positions only from the DNA sequences. In comparison, DeepVISP outperforms conventional machine learning methods by 8.43-34.33% measured by area under curve (AUC) value enhancement in three viruses. Moreover, DeepVISP can decode cis-regulatory factors that are potentially involved in virus integration and tumorigenesis, such as HOXB7, IKZF1, and LHX6. These findings are supported by multiple lines of evidence in literature. The clustering analysis of the informative motifs reveales that the representative k-mers in clusters could help guide virus recognition of the host genes. A user-friendly web server is developed for predicting putative oncogenic VISs in the human genome using DeepVISP.
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Affiliation(s)
- Haodong Xu
- Center for Precision HealthSchool of Biomedical InformaticsThe University of Texas Health Science Center at Houston (UTHealth)HoustonTX77030USA
| | - Peilin Jia
- Center for Precision HealthSchool of Biomedical InformaticsThe University of Texas Health Science Center at Houston (UTHealth)HoustonTX77030USA
| | - Zhongming Zhao
- Center for Precision HealthSchool of Biomedical InformaticsThe University of Texas Health Science Center at Houston (UTHealth)HoustonTX77030USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesHoustonTX77030USA
- Department of Biomedical InformaticsVanderbilt University Medical CenterNashvilleTN37203USA
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40
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HBV-Integration Studies in the Clinic: Role in the Natural History of Infection. Viruses 2021; 13:v13030368. [PMID: 33652619 PMCID: PMC7996909 DOI: 10.3390/v13030368] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/21/2021] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major global health problem causing acute and chronic liver disease that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) is essential for viral replication and the establishment of a persistent infection. Integrated HBV DNA represents another stable form of viral DNA regularly observed in the livers of infected patients. HBV DNA integration into the host genome occurs early after HBV infection. It is a common occurrence during the HBV life cycle, and it has been detected in all the phases of chronic infection. HBV DNA integration has long been considered to be the main contributor to liver tumorigenesis. The recent development of highly sensitive detection methods and research models has led to the clarification of some molecular and pathogenic aspects of HBV integration. Though HBV integration does not lead to replication-competent transcripts, it can act as a stable source of viral RNA and proteins, which may contribute in determining HBV-specific T-cell exhaustion and favoring virus persistence. The relationship between HBV DNA integration and the immune response in the liver microenvironment might be closely related to the development and progression of HBV-related diseases. While many new antiviral agents aimed at cccDNA elimination or silencing have been developed, integrated HBV DNA remains a difficult therapeutic challenge.
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Abstract
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in nearly 1 million deaths every year. Many of these patients die from severe liver diseases, including HCC. HBV may induce HCC through the induction of chronic liver inflammation, which can cause oxidative stress and DNA damage. However, many studies also indicated that HBV could induce HCC via the alteration of hepatocellular physiology that may involve genetic and epigenetic changes of the host DNA, the alteration of cellular signaling pathways, and the inhibition of DNA repair mechanisms. This alteration of cellular physiology can lead to the accumulation of DNA damages and the promotion of cell cycles and predispose hepatocytes to oncogenic transformation.
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Affiliation(s)
- Jiyoung Lee
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA.
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42
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Caruso S, O'Brien DR, Cleary SP, Roberts LR, Zucman-Rossi J. Genetics of Hepatocellular Carcinoma: Approaches to Explore Molecular Diversity. Hepatology 2021; 73 Suppl 1:14-26. [PMID: 32463918 DOI: 10.1002/hep.31394] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/11/2020] [Accepted: 05/11/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Stefano Caruso
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Université Paris 13, Functional Genomics of Solid Tumors Laboratory, Paris, France
| | - Daniel R O'Brien
- Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Sean P Cleary
- Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Université Paris 13, Functional Genomics of Solid Tumors Laboratory, Paris, France.,European Hospital Georges Pompidou, AP-HP, Paris, France
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Sze KM, Ho DW, Chiu Y, Tsui Y, Chan L, Lee JM, Chok KS, Chan AC, Tang C, Tang VW, Lo IL, Yau DT, Cheung T, Ng IO. Hepatitis B Virus-Telomerase Reverse Transcriptase Promoter Integration Harnesses Host ELF4, Resulting in Telomerase Reverse Transcriptase Gene Transcription in Hepatocellular Carcinoma. Hepatology 2021; 73:23-40. [PMID: 32170761 PMCID: PMC7898544 DOI: 10.1002/hep.31231] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/17/2020] [Accepted: 02/27/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) integrations are common in hepatocellular carcinoma (HCC). In particular, alterations of the telomerase reverse transcriptase (TERT) gene by HBV integrations are frequent; however, the molecular mechanism and functional consequence underlying TERT HBV integration are unclear. APPROACH AND RESULTS We adopted a targeted sequencing strategy to survey HBV integrations in human HBV-associated HCCs (n = 95). HBV integration at the TERT promoter was frequent (35.8%, n = 34/95) in HCC tumors and was associated with increased TERT mRNA expression and more aggressive tumor behavior. To investigate the functional importance of various integrated HBV components, we employed different luciferase reporter constructs and found that HBV enhancer I (EnhI) was the key viral component leading to TERT activation on integration at the TERT promoter. In addition, the orientation of the HBV integration at the TERT promoter further modulated the degree of TERT transcription activation in HCC cell lines and patients' HCCs. Furthermore, we performed array-based small interfering RNA library functional screening to interrogate the potential major transcription factors that physically interacted with HBV and investigated the cis-activation of host TERT gene transcription on viral integration. We identified a molecular mechanism of TERT activation through the E74 like ETS transcription factor 4 (ELF4), which normally could drive HBV gene transcription. ELF4 bound to the chimeric HBV EnhI at the TERT promoter, resulting in telomerase activation. Stable knockdown of ELF4 significantly reduced the TERT expression and sphere-forming ability in HCC cells. CONCLUSIONS Our results reveal a cis-activating mechanism harnessing host ELF4 and HBV integrated at the TERT promoter and uncover how TERT HBV-integrated HCCs may achieve TERT activation in hepatocarcinogenesis.
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Affiliation(s)
- Karen Man‐Fong Sze
- Department of PathologyThe University of Hong KongHong KongChina,State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
| | - Daniel Wai‐Hung Ho
- Department of PathologyThe University of Hong KongHong KongChina,State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
| | - Yung‐Tuen Chiu
- Department of PathologyThe University of Hong KongHong KongChina,State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
| | - Yu‐Man Tsui
- Department of PathologyThe University of Hong KongHong KongChina,State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
| | - Lo‐Kong Chan
- Department of PathologyThe University of Hong KongHong KongChina,State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
| | - Joyce Man‐Fong Lee
- Department of PathologyThe University of Hong KongHong KongChina,State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
| | - Kenneth Siu‐Ho Chok
- State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina,Department of SurgeryThe University of Hong KongHong KongChina
| | - Albert Chi‐Yan Chan
- State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina,Department of SurgeryThe University of Hong KongHong KongChina
| | | | | | | | | | - Tan‐To Cheung
- State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina,Department of SurgeryThe University of Hong KongHong KongChina
| | - Irene Oi‐Lin Ng
- Department of PathologyThe University of Hong KongHong KongChina,State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
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Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res 2020; 149:1-61. [PMID: 33579421 PMCID: PMC8796122 DOI: 10.1016/bs.acr.2020.10.001] [Citation(s) in RCA: 490] [Impact Index Per Article: 98.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC), the primary malignancy of hepatocytes, is a diagnosis with bleak outcome. According to National Cancer Institute's SEER database, the average five-year survival rate of HCC patients in the US is 19.6% but can be as low as 2.5% for advanced, metastatic disease. When diagnosed at early stages, it is treatable with locoregional treatments including surgical resection, Radio-Frequency Ablation, Trans-Arterial Chemoembolization or liver transplantation. However, HCC is usually diagnosed at advanced stages when the tumor is unresectable, making these treatments ineffective. In such instances, systemic therapy with tyrosine kinase inhibitors (TKIs) becomes the only viable option, even though it benefits only 30% of patients, provides only a modest (~3months) increase in overall survival and causes drug resistance within 6months. HCC, like many other cancers, is highly heterogeneous making a one-size fits all option problematic. The selection of liver transplantation, locoregional treatment, TKIs or immune checkpoint inhibitors as a treatment strategy depends on the disease stage and underlying condition(s). Additionally, patients with similar disease phenotype can have different molecular etiology making treatment responses different. Stratification of patients at the molecular level would facilitate development of the most effective treatment option. With the increase in efficiency and affordability of "omics"-level analysis, considerable effort has been expended in classifying HCC at the molecular, metabolic and immunologic levels. This review examines the results of these efforts and the ways they can be leveraged to develop targeted treatment options for HCC.
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Affiliation(s)
- Saranya Chidambaranathan-Reghupaty
- C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.
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Yang M, Yang G, Li F, Ou M, Li C, Chen J, Lin H, Zhang Y, Xue W, Wu Y, Xu Y, Sui W, Dai Y. HBV integrated genomic characterization revealed hepatocyte genomic alterations in HBV-related hepatocellular carcinomas. Mol Clin Oncol 2020; 13:79. [PMID: 33062269 PMCID: PMC7549396 DOI: 10.3892/mco.2020.2149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 08/28/2020] [Indexed: 12/04/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies that is closely associated with the Hepatitis B virus (HBV). HBV integration into host genomes can induce instability and the aberrant expression of human genomic DNA. To directly assess HBV integration breakpoints at whole genome level, four small sequencing libraries were constructed and the HBV integration profiles of four patients with HCC were characterized. In total, the current study identified 11,800,974, 11,216,998, 11,026,546 and 11,607,842 clean reads for patients 1-3 and 4, respectively, of which 92.82, 95.95, 97.21 and 97.29% were properly aligned to the hybrid reference genome. In addition, 220 HBV integration events were detected from the tumor tissues of four patients with HCC and an average of 55 breakpoints per sample was calculated. The results indicated that HBV integration events may be implicated in HCC physiologies and diseases. The results acquired may also provide insight into the pathogenesis of HCC, which may be valuable for future HCC therapy.
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Affiliation(s)
- Ming Yang
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Guiqi Yang
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Fengyan Li
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Minglin Ou
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Clinical Medical Research Center of The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Chunhong Li
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,College of Life Science, Guangxi Normal University, Guilin, Guangxi 541004, P.R. China
| | - Jiejing Chen
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Hua Lin
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Yue Zhang
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Wen Xue
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Yan Wu
- Clinical Medical Research Center of The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Yong Xu
- Clinical Medical Research Center of The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Weiguo Sui
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Yong Dai
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Clinical Medical Research Center of The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
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Abstract
Hepatitis B virus (HBV), which was discovered in 1965, is a threat to global public health. HBV infects human hepatocytes and leads to acute and chronic liver diseases, and there is no cure. In cells infected by HBV, viral DNA can be integrated into the cellular genome. HBV DNA integration is a complicated process during the HBV life cycle. Although HBV integration normally results in replication-incompetent transcripts, it can still act as a template for viral protein expression. Of note, it is a primary driver of hepatocellular carcinoma (HCC). Recently, with the development of detection methods and research models, the molecular biology and the pathogenicity of HBV DNA integration have been better revealed. Here, we review the advances in the research of HBV DNA integration, including molecular mechanisms, detection methods, research models, the effects on host and viral gene expression, the role of HBV integrations in the pathogenesis of HCC, and potential treatment strategies. Finally, we discuss possible future research prospects of HBV DNA integration.
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Affiliation(s)
- Kaitao Zhao
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Andrew Liu
- Laboratory of Molecular Cardiology, National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA
| | - Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
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47
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Zhang H, Dong P, Guo S, Tao C, Chen W, Zhao W, Wang J, Cheung R, Villanueva A, Fan J, Ding H, Schrodi SJ, Zhang D, Zeng C. Hypomethylation in HBV integration regions aids non-invasive surveillance to hepatocellular carcinoma by low-pass genome-wide bisulfite sequencing. BMC Med 2020; 18:200. [PMID: 32741373 PMCID: PMC7397586 DOI: 10.1186/s12916-020-01667-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 06/12/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Circulating cell-free DNA (cfDNA) methylation has been demonstrated to be a promising approach for non-invasive cancer diagnosis. However, the high cost of whole genome bisulfite sequencing (WGBS) hinders the clinical implementation of a methylation-based cfDNA early detection biomarker. We proposed a novel strategy in low-pass WGBS (~ 5 million reads) to detect methylation changes in circulating cell-free DNA (cfDNA) from patients with liver diseases and hepatocellular carcinoma (HCC). METHODS The effective small sequencing depth were determined by 5 pilot cfDNA samples with relative high-depth WGBS. CfDNA of 51 patients with hepatitis, cirrhosis, and HCC were conducted using low-pass WGBS. The strategy was validated in an independent WGBS cohort of 32 healthy individuals and 26 early-stage HCC patients. Fifteen paired tumor tissue and buffy coat samples were used to characterize the methylation of hepatitis B virus (HBV) integration regions and genome distribution of cfDNA. RESULTS A significant enrichment of cfDNA in intergenic and repeat regions, especially in previously reported HBV integration sites were observed, as a feature of cfDNA and the bias of cfDNA release. Methylation profiles nearby HBV integration sites were a better indicator for hypomethylation of tumor genome comparing to Alu and LINE (long interspersed nuclear element) repeats, and were able to facilitate the cfDNA-based HCC prediction. Hypomethylation nearby HBV integration sites (5 kb flanking) was detected in HCC patients, but not in patients with hepatitis and cirrhosis (MethylHBV5k, median:0.61 vs 0.72, P = 0.0003). Methylation levels of integration sites certain candidate regions exhibited an area under the receiver operation curve (AUC) value > 0.85 to discriminate HCC from non-HCC samples. The validation cohort achieved the prediction performance with an AUC of 0.954. CONCLUSIONS Hypomethylation around viral integration sites aids low-pass cfDNA WGBS to serve as a non-invasive approach for early HCC detection, and inspire future efforts on tumor surveillance for oncovirus with integration activity.
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Affiliation(s)
- Haikun Zhang
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Peiling Dong
- Department of Hepatology, Beijing You'an Hospital Affiliated with Capital Medical University, Beijing, 100069, China
| | - Shicheng Guo
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI, USA
| | - Chengcheng Tao
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Wei Chen
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
| | - Wenmin Zhao
- Department of Hepatology, Beijing You'an Hospital Affiliated with Capital Medical University, Beijing, 100069, China
| | - Jiakang Wang
- Biology Department, Stonybrook University, Stonybrook, NY, USA
| | - Ramsey Cheung
- Department of Gastroenterology and Hepatology, VA Palo Alto Health Care System and Stanford University, Palo Alto, CA, USA
| | - Augusto Villanueva
- Liver Cancer Research Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jian Fan
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Huiguo Ding
- Department of Hepatology, Beijing You'an Hospital Affiliated with Capital Medical University, Beijing, 100069, China
| | - Steven J Schrodi
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI, USA. .,Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, USA.
| | - Dake Zhang
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. .,Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China.
| | - Changqing Zeng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
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48
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Giannuzzi D, Aresu L. A First NGS Investigation Suggests No Association Between Viruses and Canine Cancers. Front Vet Sci 2020; 7:365. [PMID: 32766289 PMCID: PMC7380080 DOI: 10.3389/fvets.2020.00365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 05/26/2020] [Indexed: 12/16/2022] Open
Abstract
Approximately 10–15% of worldwide human cancers are attributable to viral infection. When operating as carcinogenic elements, viruses may act with various mechanisms, but the most important is represented by viral integration into the host genome, causing chromosome instability, genomic mutations, and aberrations. In canine species, few reports have described an association between viral integration and canine cancers, but more comprehensive studies are needed. The advancement of next-generation sequencing and the cost reduction have resulted in a progressive increasing of sequencing data in veterinary oncology offering an opportunity to study virome in canine cancers. In this study, we have performed viral detection and integration analyses using VirusFinder2 software tool on available whole-genome and whole-exome sequencing data of different canine cancers. Several viral sequences were detected in lymphomas, hemangiosarcomas, melanomas, and osteosarcomas, but no reliable integration sites were identified. Even if with some limitations such as the depth and type of sequencing, a restricted number of available nonhuman genomes software, and a limited knowledge on endogenous retroviruses in the canine genome, results are compelling. However, further experiments are needed, and similarly to feline species, dedicated analysis tools for the identification of viral integration sites in canine cancers are required.
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Affiliation(s)
- Diana Giannuzzi
- Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Italy
| | - Luca Aresu
- Department of Veterinary Science, University of Turin, Grugliasco, Italy
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Jia L, Gao Y, He Y, Hooper JD, Yang P. HBV induced hepatocellular carcinoma and related potential immunotherapy. Pharmacol Res 2020; 159:104992. [PMID: 32505833 DOI: 10.1016/j.phrs.2020.104992] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/16/2020] [Accepted: 05/31/2020] [Indexed: 02/06/2023]
Abstract
Chronic infection of Hepatitis B virus (HBV) has long been recognized as a major risk factor in the initiation and development of hepatocellular carcinoma (HCC), contributing to over half the cases of HCC worldwide. Transformation of the liver with HBV infection to HCC mainly results from long-term interaction between HBV and the host hepatocytes via a variety of mechanisms, including HBV DNA integration, prolonged expression of the viral HBx regulatory protein and/or aberrant preS/S envelope proteins, and epigenetic dysregulation of tumor suppressor genes. While there have been several failures in the development of drugs for HCC, the immune-tolerant microenvironment of this malignancy suggests that immunotherapeutic agents could provide benefits for these patients. This is supported by recent data showing that immunotherapy has promising activity in patients with advanced HCC. In this review, we provide an overview of HBV-induced HCC and recent immune based approaches for the treatment of HCC patients.
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Affiliation(s)
- Liyang Jia
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Yanan Gao
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Yaowu He
- Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia
| | - John D Hooper
- Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
| | - Pengyuan Yang
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, 100049 Beijing, China.
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50
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Jiang D, Deng J, Dong C, Ma X, Xiao Q, Zhou B, Yang C, Wei L, Conran C, Zheng SL, Ng IOL, Yu L, Xu J, Sham PC, Qi X, Hou J, Ji Y, Cao G, Li M. Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma. BMC Cancer 2020; 20:403. [PMID: 32393195 PMCID: PMC7216662 DOI: 10.1186/s12885-020-06842-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Recent genome-wide association studies (GWASs) have suggested several susceptibility loci of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by statistical analysis at individual single-nucleotide polymorphisms (SNPs). However, these loci only explain a small fraction of HBV-related HCC heritability. In the present study, we aimed to identify additional susceptibility loci of HBV-related HCC using advanced knowledge-based analysis. METHODS We performed knowledge-based analysis (including gene- and gene-set-based association tests) on variant-level association p-values from two existing GWASs of HBV-related HCC. Five different types of gene-sets were collected for the association analysis. A number of SNPs within the gene prioritized by the knowledge-based association tests were selected to replicate genetic associations in an independent sample of 965 cases and 923 controls. RESULTS The gene-based association analysis detected four genes significantly or suggestively associated with HBV-related HCC risk: SLC39A8, GOLGA8M, SMIM31, and WHAMMP2. The gene-set-based association analysis prioritized two promising gene sets for HCC, cell cycle G1/S transition and NOTCH1 intracellular domain regulates transcription. Within the gene sets, three promising candidate genes (CDC45, NCOR1 and KAT2A) were further prioritized for HCC. Among genes of liver-specific expression, multiple genes previously implicated in HCC were also highlighted. However, probably due to small sample size, none of the genes prioritized by the knowledge-based association analyses were successfully replicated by variant-level association test in the independent sample. CONCLUSIONS This comprehensive knowledge-based association mining study suggested several promising genes and gene-sets associated with HBV-related HCC risks, which would facilitate follow-up functional studies on the pathogenic mechanism of HCC.
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Affiliation(s)
- Deke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaen Deng
- Department of Psychiatry, the University of Hong Kong, Pokfulam, Hong Kong
| | | | - Xiaopin Ma
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Qianyi Xiao
- Center for Genomic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chou Yang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lin Wei
- Program of Computational Genomics & Medicine, NorthShore University HealthSystem, Evanston, IL, USA.,Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
| | - Carly Conran
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Pritzker School of Medicine, University of Chicago, Evanston, IL, USA
| | - S Lilly Zheng
- Program of Computational Genomics & Medicine, NorthShore University HealthSystem, Evanston, IL, USA
| | - Irene Oi-Lin Ng
- Department of Pathology, the University of Hong Kong, Pokfulam, Hong Kong.,State Key Laboratory of Liver Research, the University of Hong Kong, Pokfulam, Hong Kong
| | - Long Yu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Jianfeng Xu
- Program of Computational Genomics & Medicine, NorthShore University HealthSystem, Evanston, IL, USA
| | - Pak C Sham
- The Centre for Genomic Sciences, the University of Hong Kong, Pokfulam, Hong Kong
| | - Xiaolong Qi
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Ji
- Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China.
| | - Miaoxin Li
- Department of Psychiatry, the University of Hong Kong, Pokfulam, Hong Kong. .,The Centre for Genomic Sciences, the University of Hong Kong, Pokfulam, Hong Kong. .,State Key Laboratory for Cognitive and Brain Sciences, the University of Hong Kong, Pokfulam, Hong Kong. .,Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. .,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.
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