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1
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Singh RK, Vangala R, Torne AS, Bose D, Robertson ES. Epigenetic and epitranscriptomic regulation during oncogenic γ-herpesvirus infection. Front Microbiol 2025; 15:1484455. [PMID: 39839102 PMCID: PMC11747046 DOI: 10.3389/fmicb.2024.1484455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/18/2024] [Indexed: 01/23/2025] Open
Abstract
Oncogenic gamma herpesviruses, including Epstein-Barr Virus (EBV) and Kaposi's Sarcoma-associated Herpesvirus (KSHV), are opportunistic cancer-causing viruses and induces oncogenesis through complex mechanisms, which involves manipulation of cellular physiology as well as epigenetic and epitranscriptomic reprogramming. In this review, we describe the intricate processes by which these viruses interact with the epigenetic machinery, leading to alterations in DNA methylation, histone modifications, and the involvement of non-coding RNAs. The key viral proteins such as EBNA1 and LMP1 encoded by EBV; LANA and vGPCR encoded by KSHV; play pivotal roles in these modifications by interacting with host factors, and dysregulating signaling pathways. The resultant reprogramming can lead to activation of oncogenes, silencing of tumor suppressor genes, and evasion of the immune response, which ultimately contributes to the oncogenic potential of these viruses. Furthermore, in this review, we explore current therapeutic strategies targeting these epigenetic alterations and discuss future directions for research and treatment. Through this comprehensive examination of the epigenetic and epitranscriptomic reprogramming mechanisms employed by oncogenic gamma herpesviruses, we aim to provide valuable insights into potential avenues for novel therapeutic interventions.
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Affiliation(s)
| | | | | | | | - Erle S. Robertson
- Departments of Otorhinolaryngology-Head and Neck Surgery and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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2
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Bapteste É. The ageing virus hypothesis: Epigenetic ageing beyond the Tree of Life. Bioessays 2025; 47:e2400099. [PMID: 39400402 DOI: 10.1002/bies.202400099] [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: 04/23/2024] [Revised: 09/20/2024] [Accepted: 09/24/2024] [Indexed: 10/15/2024]
Abstract
A recent thought-provoking theory argues that complex organisms using epigenetic information for their normal development and functioning must irreversibly age as a result of epigenetic signal loss. Importantly, the scope of this theory could be considerably expanded, with scientific benefits, by analyzing epigenetic ageing beyond the borders of the Tree of Life. Viruses that use epigenetic signals for their normal functioning may also age, that is, present an increasing risk of failing to complete their individual life cycle and to disappear with time. As viruses are ancient, abundant, and infect a considerable diversity of hosts, the ageing virus hypothesis, if verified, would have important consequences for many fields of the Life sciences. Uncovering ageing viruses would integrate the most abundant and biologically central entities on Earth into theories of ageing, enhance virology, gerontology, evolutionary biology, molecular ecology, genomics, and possibly medicine through the development of new therapies manipulating viral ageing.
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Affiliation(s)
- Éric Bapteste
- Institut de Systématique, Évolution, Biodiversité (ISYEB), Sorbonne Université, CNRS, Museum National d'Histoire Naturelle, EPHE, Université Des Antilles, Paris, France
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3
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James CD, Otoa RO, Youssef AH, Fontan CT, Sannigrahi MK, Windle B, Basu D, Morgan IM. HPV16 genome structure analysis in oropharyngeal cancer PDXs identifies tumors with integrated and episomal genomes. Tumour Virus Res 2024; 18:200285. [PMID: 38936774 PMCID: PMC11261002 DOI: 10.1016/j.tvr.2024.200285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/26/2024] [Accepted: 06/11/2024] [Indexed: 06/29/2024] Open
Abstract
HPV + oropharyngeal squamous cell carcinoma (OPC) incidence recently surpassed cervical cancer and is the most common HPV-related cancer in the developed world. HPV16 is in ∼90 % of HPV + OPCs, with episomal genomes in the majority of cases. Most existing HPV16+ cancer cell lines derive from outside the oropharynx and harbor integrated HPV genomes. Thus, there is need for OPC preclinical models to evaluate standard and experimental therapeutics in the presence of episomal HPV16 oncogenic drivers. Here we characterize HPV genome structures in eight HPV16+ OPC patient-derived xenografts (PDXs), and evaluate their responses to standard chemotherapy. HPV genome state was investigated by combining Southern blot, T5 exonuclease assay, whole genome sequencing, and RNAseq data. This analysis revealed complexity and variation in integrated vs. episomal HPV forms across PDXs and demonstrated that four PDXs predominantly contain episomal HPV16. Episomal status did not ensure favorable in vivo responses to cisplatin therapy, despite the more favorable prognosis previously attributed to episomal HPV + tumors; this could be due to the small number present in the dataset. Our analysis establishes PDX models as test platforms for novel therapies designed to target maintenance of the episomal forms of HPV16 that commonly appear in OPC.
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Affiliation(s)
- Claire D James
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA
| | - Raymonde O Otoa
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA
| | - Aya H Youssef
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA
| | - Christian T Fontan
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA
| | - Malay K Sannigrahi
- Dept. Otorhinolaryngology-Head and Neck Surgery, The University of Pennsylvania, Philadelphia, PA, USA
| | - Brad Windle
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA; VCU Massey Cancer Center, Richmond, VA, 23298, USA
| | - Devraj Basu
- Dept. Otorhinolaryngology-Head and Neck Surgery, The University of Pennsylvania, Philadelphia, PA, USA.
| | - Iain M Morgan
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA; VCU Massey Cancer Center, Richmond, VA, 23298, USA.
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4
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Witt ASA, Carvalho JVRP, Serafim MSM, Arias NEC, Rodrigues RAL, Abrahão JS. The GC% landscape of the Nucleocytoviricota. Braz J Microbiol 2024; 55:3373-3387. [PMID: 39180708 PMCID: PMC11711839 DOI: 10.1007/s42770-024-01496-7] [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: 04/26/2024] [Accepted: 08/14/2024] [Indexed: 08/26/2024] Open
Abstract
Genomic studies on sequence composition employ various approaches, such as calculating the proportion of guanine and cytosine within a given sequence (GC% content), which can shed light on various aspects of the organism's biology. In this context, GC% can provide insights into virus-host relationships and evolution. Here, we present a comprehensive gene-by-gene analysis of 61 representatives belonging to the phylum Nucleocytoviricota, which comprises viruses with the largest genomes known in the virosphere. Parameters were evaluated not only based on the average GC% of a given viral species compared to the entire phylum but also considering gene position and phylogenetic history. Our results reveal that while some families exhibit similar GC% among their representatives (e.g., Marseilleviridae), others such as Poxviridae, Phycodnaviridae, and Mimiviridae have members with discrepant GC% values, likely reflecting adaptation to specific biological cycles and hosts. Interestingly, certain genes located at terminal regions or within specific genomic clusters show GC% values distinct from the average, suggesting recent acquisition or unique evolutionary pressures. Horizontal gene transfer and the presence of potential paralogs were also assessed in genes with the most discrepant GC% values, indicating multiple evolutionary histories. Taken together, to the best of our knowledge, this study represents the first global and gene-by-gene analysis of GC% distribution and profiles within genomes of Nucleocytoviricota members, highlighting their diversity and identifying potential new targets for future studies.
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Affiliation(s)
- Amanda Stéphanie Arantes Witt
- Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Mateus Sá Magalhães Serafim
- Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Nidia Esther Colquehuanca Arias
- Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Rodrigo Araújo Lima Rodrigues
- Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Jônatas Santos Abrahão
- Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
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5
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Esteller M, Dawson MA, Kadoch C, Rassool FV, Jones PA, Baylin SB. The Epigenetic Hallmarks of Cancer. Cancer Discov 2024; 14:1783-1809. [PMID: 39363741 DOI: 10.1158/2159-8290.cd-24-0296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/08/2024] [Accepted: 06/24/2024] [Indexed: 10/05/2024]
Abstract
Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, "nonmutational epigenetic reprogramming" was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and adaptive nature. Herein, we present a detailed examination of the epigenetic hallmarks affected in human cancer, elucidating the pathways and genes involved, and dissecting the disrupted landscapes for DNA methylation, histone modifications, and chromatin architecture that define the disease. Significance: Cancer is a disease characterized by constant evolution, spanning from its initial premalignant stages to the advanced invasive and disseminated stages. It is a pathology that is able to adapt and survive amidst hostile cellular microenvironments and diverse treatments implemented by medical professionals. The more fixed setup of the genetic structure cannot fully provide transformed cells with the tools to survive but the rapid and plastic nature of epigenetic changes is ready for the task. This review summarizes the epigenetic hallmarks that define the ecological success of cancer cells in our bodies.
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Affiliation(s)
- Manel Esteller
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
- Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
| | - Mark A Dawson
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Centre for Cancer Research, University of Melbourne, Melbourne, Australia
| | - Cigall Kadoch
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Howard Hughes Medical Institute, Chevy Chase, Maryland
| | - Feyruz V Rassool
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Peter A Jones
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
| | - Stephen B Baylin
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
- Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
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6
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Zhao Y, Zhang Q, Zhang B, Dai Y, Gao Y, Li C, Yu Y, Li C. Epstein-Barr Viruses: Their Immune Evasion Strategies and Implications for Autoimmune Diseases. Int J Mol Sci 2024; 25:8160. [PMID: 39125729 PMCID: PMC11311853 DOI: 10.3390/ijms25158160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Epstein-Barr virus (EBV), a member of the γ-herpesvirus family, is one of the most prevalent and persistent human viruses, infecting up to 90% of the adult population globally. EBV's life cycle includes primary infection, latency, and lytic reactivation, with the virus primarily infecting B cells and epithelial cells. This virus has evolved sophisticated strategies to evade both innate and adaptive immune responses, thereby maintaining a lifelong presence within the host. This persistence is facilitated by the expression of latent genes such as EBV nuclear antigens (EBNAs) and latent membrane proteins (LMPs), which play crucial roles in viral latency and oncogenesis. In addition to their well-known roles in several types of cancer, including nasopharyngeal carcinoma and B-cell lymphomas, recent studies have identified the pathogenic roles of EBV in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. This review highlights the intricate interactions between EBV and the host immune system, underscoring the need for further research to develop effective therapeutic and preventive strategies against EBV-associated diseases.
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Affiliation(s)
- Yuehong Zhao
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Qi Zhang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Botian Zhang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Yihao Dai
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Yifei Gao
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Chenzhong Li
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Yijing Yu
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Conglei Li
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
- Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
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Rosendo-Chalma P, Antonio-Véjar V, Ortiz Tejedor JG, Ortiz Segarra J, Vega Crespo B, Bigoni-Ordóñez GD. The Hallmarks of Cervical Cancer: Molecular Mechanisms Induced by Human Papillomavirus. BIOLOGY 2024; 13:77. [PMID: 38392296 PMCID: PMC10886769 DOI: 10.3390/biology13020077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 01/17/2024] [Accepted: 01/23/2024] [Indexed: 02/24/2024]
Abstract
Human papillomaviruses (HPVs) and, specifically, high-risk HPVs (HR-HPVs) are identified as necessary factors in the development of cancer of the lower genital tract, with CaCU standing out as the most prevalent tumor. This review summarizes ten mechanisms activated by HR-HPVs during cervical carcinogenesis, which are broadly associated with at least seven of the fourteen distinctive physiological capacities of cancer in the newly established model by Hanahan in 2022. These mechanisms involve infection by human papillomavirus, cellular tropism, genetic predisposition to uterine cervical cancer (CaCU), viral load, viral physical state, regulation of epigenetic mechanisms, loss of function of the E2 protein, deregulated expression of E6/E7 oncogenes, regulation of host cell protein function, and acquisition of the mesenchymal phenotype.
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Affiliation(s)
- Pedro Rosendo-Chalma
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer of Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (IIB-UNAM), Mexico City 14080, Mexico
- Unidad Académica de Posgrado, Universidad Católica de Cuenca, Cuenca 010101, Ecuador
| | - Verónica Antonio-Véjar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Guerrero, Mexico
| | - Jonnathan Gerardo Ortiz Tejedor
- Unidad Académica de Posgrado, Universidad Católica de Cuenca, Cuenca 010101, Ecuador
- Carrera de Bioquímica y Farmacia, Universidad Católica de Cuenca, Cuenca 010101, Ecuador
| | - Jose Ortiz Segarra
- Carrera de Medicina, Facultad de Ciencias Médicas, Universidad de Cuenca, Cuenca 010107, Ecuador
| | - Bernardo Vega Crespo
- Carrera de Medicina, Facultad de Ciencias Médicas, Universidad de Cuenca, Cuenca 010107, Ecuador
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8
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Tang CL, Li XZ, Zhou T, Deng CM, Jiang CT, Zhang YM, Liao Y, Wang TM, He YQ, Xue WQ, Jia WH, Zheng XH. EBV DNA methylation profiles and its application in distinguishing nasopharyngeal carcinoma and nasal NK/T-cell lymphoma. Clin Epigenetics 2024; 16:11. [PMID: 38212818 PMCID: PMC10785554 DOI: 10.1186/s13148-024-01624-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 01/03/2024] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND As an oncovirus, EBV is associated with multiple cancers, including solid tumors and hematological malignancies. EBV methylation plays an important role in regulating tumor occurrence. However, the EBV methylation profiles in EBV-associated tumor tissues are poorly understood. RESULTS In this study, EBV methylation capture sequencing was conducted in several different tumor tissue samples, including NPC, EBVaGC, lung LELC and parotid LELC. Besides, EBV capture sequencing and following qMSP were performed on nasopharyngeal brushing samples from NPC and nasal NKTCL patients. Our results showed that the EBV genome among different types of tumors displayed specific methylation patterns. Among the four types of tumors from epithelial origin (NPC, EBVaGC, lung LELC and parotid LELC), the most significant differences were found between EBVaGC and the others. For example, in EBVaGC, all CpG sites within 1,44,189-1,45,136 bp of the EBV genome sequence on gene RPMS1 were hyper-methylated compared to the others. Differently, significant differences of EBV CpG sites, particularly those located on gene BILF2, were observed between NPC and nasal NKTCL patients in nasopharyngeal brushing samples. Further, the methylated level of BILF2 was further detected using qMSP, and a diagnostic model distinguishing NPC and nasal NKTCL was established. The AUC of the model was 0.9801 (95% CI 0.9524-1.0000), with the sensitivity and specificity of 98.81% (95% CI 93.63-99.94%) and 76.92% (95% CI 49.74-91.82%), respectively. CONCLUSIONS Our study reveals more clues for further understanding the pathogenesis of EBV, and provides a possibility for distinguishing EBV-related tumor by detecting specific EBV CpG sites.
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Affiliation(s)
- Cao-Li Tang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China
- School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xi-Zhao Li
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Ting Zhou
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Chang-Mi Deng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Cheng-Tao Jiang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Yu-Meng Zhang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China
- School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ying Liao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Tong-Min Wang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Yong-Qiao He
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Wen-Qiong Xue
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Wei-Hua Jia
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China.
- School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Xiao-Hui Zheng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People's Republic of China.
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Perales SG, Rajasingh S, Zhou Z, Rajasingh J. Therapy of infectious diseases using epigenetic approaches. EPIGENETICS IN HUMAN DISEASE 2024:853-882. [DOI: 10.1016/b978-0-443-21863-7.00007-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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10
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Ward BJH, Prasai K, Schaal DL, Wang J, Scott RS. A distinct isoform of lymphoid enhancer binding factor 1 (LEF1) epigenetically restricts EBV reactivation to maintain viral latency. PLoS Pathog 2023; 19:e1011873. [PMID: 38113273 PMCID: PMC10763950 DOI: 10.1371/journal.ppat.1011873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 01/03/2024] [Accepted: 11/29/2023] [Indexed: 12/21/2023] Open
Abstract
As a human tumor virus, EBV is present as a latent infection in its associated malignancies where genetic and epigenetic changes have been shown to impede cellular differentiation and viral reactivation. We reported previously that levels of the Wnt signaling effector, lymphoid enhancer binding factor 1 (LEF1) increased following EBV epithelial infection and an epigenetic reprogramming event was maintained even after loss of the viral genome. Elevated LEF1 levels are also observed in nasopharyngeal carcinoma and Burkitt lymphoma. To determine the role played by LEF1 in the EBV life cycle, we used in silico analysis of EBV type 1 and 2 genomes to identify over 20 Wnt-response elements, which suggests that LEF1 may bind directly to the EBV genome and regulate the viral life cycle. Using CUT&RUN-seq, LEF1 was shown to bind the latent EBV genome at various sites encoding viral lytic products that included the immediate early transactivator BZLF1 and viral primase BSLF1 genes. The LEF1 gene encodes various long and short protein isoforms. siRNA depletion of specific LEF1 isoforms revealed that the alternative-promoter derived isoform with an N-terminal truncation (ΔN LEF1) transcriptionally repressed lytic genes associated with LEF1 binding. In addition, forced expression of the ΔN LEF1 isoform antagonized EBV reactivation. As LEF1 repression requires histone deacetylase activity through either recruitment of or direct intrinsic histone deacetylase activity, siRNA depletion of LEF1 resulted in increased histone 3 lysine 9 and lysine 27 acetylation at LEF1 binding sites and across the EBV genome. Taken together, these results indicate a novel role for LEF1 in maintaining EBV latency and restriction viral reactivation via repressive chromatin remodeling of critical lytic cycle factors.
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Affiliation(s)
- B. J. H. Ward
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
| | - Kanchanjunga Prasai
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
| | - Danielle L. Schaal
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
| | - Jian Wang
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
| | - Rona S. Scott
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
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11
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Zheng XH, Deng CM, Zhou T, Li XZ, Tang CL, Jiang CT, Liao Y, Wang TM, He YQ, Jia WH. Saliva biopsy: Detecting the difference of EBV DNA methylation in the diagnosis of nasopharyngeal carcinoma. Int J Cancer 2023; 153:882-892. [PMID: 37170851 DOI: 10.1002/ijc.34561] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 04/04/2023] [Accepted: 04/14/2023] [Indexed: 05/13/2023]
Abstract
Saliva sampling is a non-invasive method, and could be performed by donors themselves. However, there are few studies reporting biomarkers in saliva in the diagnosis of NPC. A total of 987 salivary samples were used in this study. First, EBV DNA methylation was profiled by capture sequencing in the discovery cohort (n = 36). Second, a q-PCR based method was developed and five representative EBV DNA CpG sites (11 029 bp, 45 849 bp, 57 945 bp, 66 226 bp and 128 102 bp) were selected and quantified to obtain the methylated density in the validation cohort1 (n = 801). Third, a validation cohort2 (n = 108) was used to further verify the differences of EBV methylation in saliva. A significant increase of EBV methylation was found in NPC patients compared with controls. The methylated score of EBV genome obtained by capture sequencing could distinguish NPC from controls (sensitivity 90%, specificity 100%). Further, the methylated density of EBV DNA CpG sites revealed by q-PCR showed a good diagnostic performance. The sensitivity and specificity of detecting a single CpG site (11 029 bp) could reach 75.4% and 99.7% in the validation cohort1, and 78.2% and 100% in the validation cohort2. Besides, the methylated density of the CpG site was found to decrease below the COV in NPC patients after therapy, and increase above the COV after recurrence. Our study provides an appealing alternative for the non-invasive detection of NPC without clinical setting. It paves the way for conducting a home-based large-scale screening in the future.
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Affiliation(s)
- Xiao-Hui Zheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Chang-Mi Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Ting Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xi-Zhao Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Cao-Li Tang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Cheng-Tao Jiang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Ying Liao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Tong-Min Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Yong-Qiao He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Wei-Hua Jia
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
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12
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Lai TY, Ko YC, Chen YL, Lin SF. The Way to Malignant Transformation: Can Epigenetic Alterations Be Used to Diagnose Early-Stage Head and Neck Cancer? Biomedicines 2023; 11:1717. [PMID: 37371812 PMCID: PMC10296077 DOI: 10.3390/biomedicines11061717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/05/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Identifying and treating tumors early is the key to secondary prevention in cancer control. At present, prevention of oral cancer is still challenging because the molecular drivers responsible for malignant transformation of the 11 clinically defined oral potentially malignant disorders are still unknown. In this review, we focused on studies that elucidate the epigenetic alterations demarcating malignant and nonmalignant epigenomes and prioritized findings from clinical samples. Head and neck included, the genomes of many cancer types are largely hypomethylated and accompanied by focal hypermethylation on certain specific regions. We revisited prior studies that demonstrated that sufficient uptake of folate, the primary dietary methyl donor, is associated with oral cancer reduction. As epigenetically driven phenotypic plasticity, a newly recognized hallmark of cancer, has been linked to tumor initiation, cell fate determination, and drug resistance, we discussed prior findings that might be associated with this hallmark, including gene clusters (11q13.3, 19q13.43, 20q11.2, 22q11-13) with great potential for oral cancer biomarkers, and successful examples in screening early-stage nasopharyngeal carcinoma. Although one-size-fits-all approaches have been shown to be ineffective in most cancer therapies, the rapid development of epigenome sequencing methods raises the possibility that this nonmutagenic approach may be an exception. Only time will tell.
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Affiliation(s)
- Ting-Yu Lai
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan;
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
| | - Ying-Chieh Ko
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
| | - Yu-Lian Chen
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
| | - Su-Fang Lin
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
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13
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Wang C, Liu X, Liang J, Narita Y, Ding W, Li D, Zhang L, Wang H, Leong MML, Hou I, Gerdt C, Jiang C, Zhong Q, Tang Z, Forney C, Kottyan L, Weirauch MT, Gewurz BE, Zeng MS, Jiang S, Teng M, Zhao B. A DNA tumor virus globally reprograms host 3D genome architecture to achieve immortal growth. Nat Commun 2023; 14:1598. [PMID: 36949074 PMCID: PMC10033825 DOI: 10.1038/s41467-023-37347-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 03/13/2023] [Indexed: 03/24/2023] Open
Abstract
Epstein-Barr virus (EBV) immortalization of resting B lymphocytes (RBLs) to lymphoblastoid cell lines (LCLs) models human DNA tumor virus oncogenesis. RBL and LCL chromatin interaction maps are compared to identify the spatial and temporal genome architectural changes during EBV B cell transformation. EBV induces global genome reorganization where contact domains frequently merge or subdivide during transformation. Repressed B compartments in RBLs frequently switch to active A compartments in LCLs. LCLs gain 40% new contact domain boundaries. Newly gained LCL boundaries have strong CTCF binding at their borders while in RBLs, the same sites have much less CTCF binding. Some LCL CTCF sites also have EBV nuclear antigen (EBNA) leader protein EBNALP binding. LCLs have more local interactions than RBLs at LCL dependency factors and super-enhancer targets. RNA Pol II HiChIP and FISH of RBL and LCL further validate the Hi-C results. EBNA3A inactivation globally alters LCL genome interactions. EBNA3A inactivation reduces CTCF and RAD21 DNA binding. EBNA3C inactivation rewires the looping at the CDKN2A/B and AICDA loci. Disruption of a CTCF site at AICDA locus increases AICDA expression. These data suggest that EBV controls lymphocyte growth by globally reorganizing host genome architecture to facilitate the expression of key oncogenes.
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Affiliation(s)
- Chong Wang
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Xiang Liu
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Jun Liang
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Yohei Narita
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Weiyue Ding
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Difei Li
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Luyao Zhang
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Hongbo Wang
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Merrin Man Long Leong
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Isabella Hou
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Catherine Gerdt
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Chang Jiang
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
- Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Qian Zhong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Zhonghui Tang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510060, China
| | - Carmy Forney
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Leah Kottyan
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Matthew T Weirauch
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Benjamin E Gewurz
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Sizun Jiang
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02115, USA.
| | - Mingxiang Teng
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.
| | - Bo Zhao
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA.
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14
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Lupo J, Truffot A, Andreani J, Habib M, Epaulard O, Morand P, Germi R. Virological Markers in Epstein–Barr Virus-Associated Diseases. Viruses 2023; 15:v15030656. [PMID: 36992365 PMCID: PMC10051789 DOI: 10.3390/v15030656] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/21/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Epstein–Barr virus (EBV) is an oncogenic virus infecting more than 95% of the world’s population. After primary infection—responsible for infectious mononucleosis in young adults—the virus persists lifelong in the infected host, especially in memory B cells. Viral persistence is usually without clinical consequences, although it can lead to EBV-associated cancers such as lymphoma or carcinoma. Recent reports also suggest a link between EBV infection and multiple sclerosis. In the absence of vaccines, research efforts have focused on virological markers applicable in clinical practice for the management of patients with EBV-associated diseases. Nasopharyngeal carcinoma is an EBV-associated malignancy for which serological and molecular markers are widely used in clinical practice. Measuring blood EBV DNA load is additionally, useful for preventing lymphoproliferative disorders in transplant patients, with this marker also being explored in various other EBV-associated lymphomas. New technologies based on next-generation sequencing offer the opportunity to explore other biomarkers such as the EBV DNA methylome, strain diversity, or viral miRNA. Here, we review the clinical utility of different virological markers in EBV-associated diseases. Indeed, evaluating existing or new markers in EBV-associated malignancies or immune-mediated inflammatory diseases triggered by EBV infection continues to be a challenge.
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Affiliation(s)
- Julien Lupo
- Institut de Biologie Structurale, Université Grenoble Alpes, UMR 5075 CEA/CNRS/UGA, 71 Avenue des Martyrs, 38000 Grenoble, France
- Laboratoire de Virologie, CHU Grenoble Alpes, CS 10217, CEDEX 09, 38043 Grenoble, France
- Correspondence:
| | - Aurélie Truffot
- Institut de Biologie Structurale, Université Grenoble Alpes, UMR 5075 CEA/CNRS/UGA, 71 Avenue des Martyrs, 38000 Grenoble, France
- Laboratoire de Virologie, CHU Grenoble Alpes, CS 10217, CEDEX 09, 38043 Grenoble, France
| | - Julien Andreani
- Institut de Biologie Structurale, Université Grenoble Alpes, UMR 5075 CEA/CNRS/UGA, 71 Avenue des Martyrs, 38000 Grenoble, France
- Laboratoire de Virologie, CHU Grenoble Alpes, CS 10217, CEDEX 09, 38043 Grenoble, France
| | - Mohammed Habib
- Institut de Biologie Structurale, Université Grenoble Alpes, UMR 5075 CEA/CNRS/UGA, 71 Avenue des Martyrs, 38000 Grenoble, France
| | - Olivier Epaulard
- Institut de Biologie Structurale, Université Grenoble Alpes, UMR 5075 CEA/CNRS/UGA, 71 Avenue des Martyrs, 38000 Grenoble, France
- Service de Maladies Infectieuses, CHU Grenoble Alpes, CS 10217, CEDEX 09, 38043 Grenoble, France
| | - Patrice Morand
- Institut de Biologie Structurale, Université Grenoble Alpes, UMR 5075 CEA/CNRS/UGA, 71 Avenue des Martyrs, 38000 Grenoble, France
- Laboratoire de Virologie, CHU Grenoble Alpes, CS 10217, CEDEX 09, 38043 Grenoble, France
| | - Raphaële Germi
- Institut de Biologie Structurale, Université Grenoble Alpes, UMR 5075 CEA/CNRS/UGA, 71 Avenue des Martyrs, 38000 Grenoble, France
- Laboratoire de Virologie, CHU Grenoble Alpes, CS 10217, CEDEX 09, 38043 Grenoble, France
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15
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Prétet JL, Dalstein V, Touzé A, Beby-Defaux A, Soussan P, Jacquin É, Birembaut P, Clavel C, Mougin C, Rousseau A, Lacau Saint Guily J. High levels of HPV16-L1 antibody but not HPV16 DNA load or integration predict oropharyngeal patient outcome: The Papillophar study. Clin Exp Med 2023; 23:87-96. [PMID: 35199231 DOI: 10.1007/s10238-022-00796-2] [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: 09/30/2021] [Accepted: 01/18/2022] [Indexed: 11/30/2022]
Abstract
The incidence of oropharyngeal cancers (OPC) is increasing in the world. Among OPC, those induced by human papillomaviruses have a better prognosis than non-HPV-associated OPC. The objective of this study was to highlight the relevance of HPV16 load, HPV16 DNA integration and HPV16-L1 serology on progression-free survival and overall survival of OPC patients. The PAPILLOPHAR cohort consists of 362 patients with oropharyngeal squamous cell carcinomas prospectively followed up for 5 years after treatment. Tumor biopsies and sera were collected at inclusion to investigate tumor HPV DNA/RNA characteristics and HPV16 L1 serology, respectively. Twenty-seven percent of tumor biopsies were HPV DNA- and RNA-positive and HPV16 represented 93% of HPV-positive cases. Among them, neither HPV16 viral load nor HPV16 DNA integration was associated with overall survival (OS) or progression-free survival (PFS). In contrast, high anti-HPV16 L1 antibody titers were significantly associated with a better OS and PFS. This study reveals that HPV16 load and integration are not relevant prognosis biomarkers in OPC patients.Clinical Relevance: High levels of HPV16 L1 antibodies may be useful to predict OPC patient outcome following treatment.ClinicalTrials.gov Identifier: NCT00918710, May 2017.
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Affiliation(s)
- Jean-Luc Prétet
- Laboratoire de Biologie Cellulaire Et Moléculaire, PC-Bio, EA3181, UBFC, Université de Franche-Comté, CNR Papillomavirus, Centre Hospitalier Régional Universitaire, CHRU Besancon, Boulevard A Fleming, 25030, Besançon Cedex, France.
| | - Véronique Dalstein
- Inserm UMR-S 1250 P3Cell, Université de Reims Champagne-Ardenne, SFR CAP-Santé, 51092, Reims, France.,Laboratoire de Biopathologie, CHU Maison Blanche, Reims, France
| | - Antoine Touzé
- UMR INRAE ISP Équipe Biologie Des Infections À Polyomavirus, Faculté Des Sciences, Pharmaceutiques 31 avenue Monge, 37200, Tours, France
| | - Agnès Beby-Defaux
- Service de Virologie, CHU de Poitiers, Faculté de Médecine Et de Pharmacie de Poitiers, EA 4331 LITEC, Université de Poitiers, Poitiers, France
| | - Patrick Soussan
- Laboratoire de Virologie, Hôpital Tenon, CRSA Inserm U 938 Sorbonne University, Paris, France
| | - Élise Jacquin
- Laboratoire de Biologie Cellulaire Et Moléculaire, PC-Bio, EA3181, UBFC, Université de Franche-Comté, CNR Papillomavirus, Centre Hospitalier Régional Universitaire, CHRU Besancon, Boulevard A Fleming, 25030, Besançon Cedex, France.,INSERM UMR-S 1193, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Philippe Birembaut
- Inserm UMR-S 1250 P3Cell, Université de Reims Champagne-Ardenne, SFR CAP-Santé, 51092, Reims, France.,Laboratoire de Biopathologie, CHU Maison Blanche, Reims, France
| | - Christine Clavel
- Inserm UMR-S 1250 P3Cell, Université de Reims Champagne-Ardenne, SFR CAP-Santé, 51092, Reims, France.,Laboratoire de Biopathologie, CHU Maison Blanche, Reims, France
| | - Christiane Mougin
- Laboratoire de Biologie Cellulaire Et Moléculaire, PC-Bio, EA3181, UBFC, Université de Franche-Comté, CNR Papillomavirus, Centre Hospitalier Régional Universitaire, CHRU Besancon, Boulevard A Fleming, 25030, Besançon Cedex, France.,INSERM UMR1098, Univ. Bourgogne Franche-Comté, 25000, Besançon Cedex, France
| | - Alexandra Rousseau
- Research Platform Paris-East (URCEST-CRC-CRB), Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France
| | - Jean Lacau Saint Guily
- Department of Otolaryngology, HNS, Tenon Hospital, APHP and Sorbonne University, Paris, France.,Department of OL-HNS, Rothschild Foundation Hospital and Sorbonne University, Paris, France
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16
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Watson MM, van der Giezen M, Søreide K. Gut Microbiome Influence on Human Epigenetics, Health, and Disease. HANDBOOK OF EPIGENETICS 2023:669-686. [DOI: 10.1016/b978-0-323-91909-8.00012-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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17
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Hillyar CR, Kanabar SS, Pufal KR, Lawson AW, Saw Hee JL, Rallis KS, Nibber A, Sideris M. A systematic review and meta-analysis of the diagnostic effectiveness of human papillomavirus methylation biomarkers for detection of cervical cancer. Epigenomics 2022; 14:1055-1072. [PMID: 36169190 DOI: 10.2217/epi-2022-0160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: The aim of this systematic review and meta-analysis was to assess the evidence for the diagnostic effectiveness of human papillomavirus (HPV) methylation biomarkers for detection of cervical cancer. Methods: PubMed, Embase and Web of Science were searched. Nine articles focusing on HPV methylation for detection of precancerous and cancerous cervical lesions were included. The QUADAS-2 tool was used for quality assessment. The receiver operating characteristic (ROC) was the main diagnostic performance parameter extracted. Results: Of the nine articles included in this study, seven were of moderate quality and two were of high quality. A meta-analysis of the ROC for 27 HPV methylation biomarkers revealed an overall pooled ROC of 0.770 (95% CI: 0.720-0.819; I2: 98.4%; Q: 1537.4; p < 0.01). Four methylation biomarkers had strong diagnostic ability (ROC > 0.900), 17 were moderate (ROC: 0.7000-0.8999) and six were poor (ROC < 0.700). Conclusion: HPV methylation biomarkers hold significant promise as independent screening tests for the detection of cervical precancerous and cancerous lesions.
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Affiliation(s)
- Christopher Rt Hillyar
- Green Templeton College, University of Oxford, Oxford, OX2 6HG, UK.,Surgery, Women's & Oncology Division, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK
| | - Shivani S Kanabar
- University of Birmingham Medical School, College of Medical & Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Kamil R Pufal
- University of Birmingham Medical School, College of Medical & Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Alexander W Lawson
- University of Birmingham Medical School, College of Medical & Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Joshua Li Saw Hee
- University of Birmingham Medical School, College of Medical & Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Kathrine S Rallis
- Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, E1 2AD, UK.,Cancer Research UK City of London Centre, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQZ, UK
| | - Anjan Nibber
- Green Templeton College, University of Oxford, Oxford, OX2 6HG, UK.,Surgery, Women's & Oncology Division, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK
| | - Michail Sideris
- Cancer Research UK Barts Centre, Queen Mary University of London, London, EC1M 5PZ, UK.,Department of Gynaecological Oncology, Barts Health NHS Trust, London, E1 1BB, UK
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18
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Borde C, Quignon F, Amiel C, Gozlan J, Marechal V, Brissot E. Methyl-qPCR: a new method to investigate Epstein-Barr virus infection in post-transplant lymphoproliferative diseases. Clin Epigenetics 2022; 14:33. [PMID: 35246247 PMCID: PMC8895795 DOI: 10.1186/s13148-022-01255-1] [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: 12/15/2021] [Accepted: 02/22/2022] [Indexed: 11/16/2022] Open
Abstract
Epstein–Barr virus DNA viral load is used as a surrogate marker to start Rituximab in transplant recipients at risk of developing PTLD. However, an elevated EBV DNAemia does not discriminate lymphoproliferation and replication. We designed a new molecular assay (methyl-qPCR) to distinguish methylated versus unmethylated viral genomes. In blood, viral genomes were highly methylated in EBV primary infections, PTLD and 4/5 transplant recipients with high viral load. The only patient with under-methylated EBV genomes did not respond to rituximab. Methyl-qPCR is a convenient method to discriminate between latent and lytic EBV genomes and could be useful in treatment decisions.
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Affiliation(s)
- Chloé Borde
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, 75012, Paris, France
| | | | - Corinne Amiel
- AP-HP, Service de Virologie, Hôpital Tenon, 75020, Paris, France
| | - Joël Gozlan
- Sorbonne Université, Service de Virologie, AP-HP, Hôpital Saint-Antoine, 75012, Paris, France
| | - Vincent Marechal
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, 75012, Paris, France
| | - Eolia Brissot
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), 75012, Paris, France. .,AP-HP, Hôpital Saint-Antoine, Service d'Hématologie Clinique Et Thérapie Cellulaire, 75012, Paris, France.
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19
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Molecular Basis of Epstein-Barr Virus Latency Establishment and Lytic Reactivation. Viruses 2021; 13:v13122344. [PMID: 34960613 PMCID: PMC8706188 DOI: 10.3390/v13122344] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 12/27/2022] Open
Abstract
Epstein–Barr virus (EBV) is a causative agent of infectious mononucleosis and several types of cancer. Like other herpesviruses, it establishes an asymptomatic, life-long latent infection, with occasional reactivation and shedding of progeny viruses. During latency, EBV expresses a small number of viral genes, and exists as an episome in the host–cell nucleus. Expression patterns of latency genes are dependent on the cell type, time after infection, and milieu of the cell (e.g., germinal center or peripheral blood). Upon lytic induction, expression of the viral immediate-early genes, BZLF1 and BRLF1, are induced, followed by early gene expression, viral DNA replication, late gene expression, and maturation and egress of progeny virions. Furthermore, EBV reactivation involves more than just progeny production. The EBV life cycle is regulated by signal transduction, transcription factors, promoter sequences, epigenetics, and the 3D structure of the genome. In this article, the molecular basis of EBV latency establishment and reactivation is summarized.
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20
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Bauer M, Jasinski-Bergner S, Mandelboim O, Wickenhauser C, Seliger B. Epstein-Barr Virus-Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies. Cancers (Basel) 2021; 13:cancers13205189. [PMID: 34680337 PMCID: PMC8533749 DOI: 10.3390/cancers13205189] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The Epstein–Barr virus, also termed human herpes virus 4, is a human pathogenic double-stranded DNA virus. It is highly prevalent and has been linked to the development of 1–2% of cancers worldwide. EBV-associated malignancies encompass various structural and epigenetic alterations. In addition, EBV-encoded gene products and microRNAs interfere with innate and adaptive immunity and modulate the tumor microenvironment. This review provides an overview of the characteristic features of EBV with a focus on the intrinsic and extrinsic immune evasion strategies, which contribute to EBV-associated malignancies. Abstract The detailed mechanisms of Epstein–Barr virus (EBV) infection in the initiation and progression of EBV-associated malignancies are not yet completely understood. During the last years, new insights into the mechanisms of malignant transformation of EBV-infected cells including somatic mutations and epigenetic modifications, their impact on the microenvironment and resulting unique immune signatures related to immune system functional status and immune escape strategies have been reported. In this context, there exists increasing evidence that EBV-infected tumor cells can influence the tumor microenvironment to their own benefit by establishing an immune-suppressive surrounding. The identified mechanisms include EBV gene integration and latent expression of EBV-infection-triggered cytokines by tumor and/or bystander cells, e.g., cancer-associated fibroblasts with effects on the composition and spatial distribution of the immune cell subpopulations next to the infected cells, stroma constituents and extracellular vesicles. This review summarizes (i) the typical stages of the viral life cycle and EBV-associated transformation, (ii) strategies to detect EBV genome and activity and to differentiate various latency types, (iii) the role of the tumor microenvironment in EBV-associated malignancies, (iv) the different immune escape mechanisms and (v) their clinical relevance. This gained information will enhance the development of therapies against EBV-mediated diseases to improve patient outcome.
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Affiliation(s)
- Marcus Bauer
- Department of Pathology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany; (M.B.); (C.W.)
| | - Simon Jasinski-Bergner
- Department of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany;
| | - Ofer Mandelboim
- Department of Immunology, Faculty of Medicine, The Hebrew University of Jerusalem, En Kerem, P.O. Box 12271, Jerusalem 91120, Israel;
| | - Claudia Wickenhauser
- Department of Pathology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany; (M.B.); (C.W.)
| | - Barbara Seliger
- Department of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany;
- Fraunhofer Institute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, Germany
- Correspondence: ; Tel.: +49-(345)-557-1357
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21
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Chaiwongkot A, Phanuphak N, Pankam T, Bhattarakosol P. Human papillomavirus 16 L1 gene methylation as a potential biomarker for predicting anal intraepithelial neoplasia in men who have sex with men (MSM). PLoS One 2021; 16:e0256852. [PMID: 34469465 PMCID: PMC8409669 DOI: 10.1371/journal.pone.0256852] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 08/17/2021] [Indexed: 12/18/2022] Open
Abstract
The human papillomavirus (HPV) 16 early promoter and L1 gene methylation were quantitatively measured using pyrosequencing assay in anal cells collected from men who have sex with men (MSM) to determine potential biomarkers for HPV-related anal cancer. The methylation patterns of HPV16 genes, including the early promoter (CpG 31, 37, 43, 52, and 58) and L1 genes (CpG 5600, 5606, 5609, 5615, 7136, and 7145), were analyzed in 178 anal samples. The samples were diagnosed as normal, anal intraepithelial neoplasia (AIN) 1, AIN2, and AIN3. Low methylation levels of the early promoter (< 10%) and L1 genes (< 20%) were found in all detected normal anal cells. In comparison, medium to high methylation (≥ 20–60%) in the early promoter was found in 1.5% (1/67) and 5% (2/40) of AIN1 and AIN2-3 samples, respectively. Interestingly, slightly increased L1 gene methylation levels (≥ 20–60%), especially at the HPV16 5’L1 regions CpGs 5600 and 5609, were demonstrated in AIN2-3 specimen. Moreover, a negative correlation between high HPV16 L1 gene methylation at CpGs 5600, 5609, 5615, and 7145 and a percentual CD4 count was found in AIN3 HIV positive cases. When comparing the methylation status of AIN2-3 to that of normal/AIN1 lesions, the results indicated the potential of using HPV16 L1 gene methylation as a biomarker for HPV-related cancer screening.
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Affiliation(s)
- Arkom Chaiwongkot
- Faculty of Medicine, Applied Medical Virology Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Medicine, Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
- * E-mail:
| | | | | | - Parvapan Bhattarakosol
- Faculty of Medicine, Applied Medical Virology Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Medicine, Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
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22
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MicroRNA and Other Non-Coding RNAs in Epstein-Barr Virus-Associated Cancers. Cancers (Basel) 2021; 13:cancers13153909. [PMID: 34359809 PMCID: PMC8345394 DOI: 10.3390/cancers13153909] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/27/2021] [Accepted: 08/01/2021] [Indexed: 12/12/2022] Open
Abstract
EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs.
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23
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Arslan F, Franci G, Maria Nastri B, Pagliano P. Hepatitis B virus-induced hepatocarcinogenesis: A virological and oncological perspective. J Viral Hepat 2021; 28:1104-1109. [PMID: 34003561 DOI: 10.1111/jvh.13551] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/24/2021] [Accepted: 05/03/2021] [Indexed: 12/11/2022]
Abstract
Hepatitis B virus (HBV) is a partially double-stranded DNA virus associated with hepatocellular carcinoma (HCC). The viral integration into the hepatocyte genome, the viral protein-induced oncogenesis, the increased hepatocyte turnover and the chronic inflammatory response towards HBV are all hypothesized mechanisms for the development of HCC. The fact that HBV infection and HCC prevalence show different correlations in various regions of the world indicates that there may be virus-independent phenomena for cancer development in these regions. From this point of view, it is important to review our knowledge and to examine the relationship between HBV and HCC in the light of current data. In this article, we investigate the relationship between HBV and HCC by presenting epidemiological and microbiological data, accompanied by the principles of viral oncogenesis.
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Affiliation(s)
- Ferhat Arslan
- Department of Infectious Diseases and Clinical Microbiology, Istanbul Medeniyet University, Istanbul, Turkey
| | - Gianluigi Franci
- Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy
| | - Bianca Maria Nastri
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Pasquale Pagliano
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana", Unit of Infectious Diseases, University of Salerno, Baronissi, Italy
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24
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Sun YH, Gao J, Liu XD, Tang HW, Cao SL, Zhang JK, Wen PH, Wang ZH, Li J, Guo WZ, Zhang SJ. Interaction analysis of gene variants related to one-carbon metabolism with chronic hepatitis B infection in Chinese patients. J Gene Med 2021; 23:e3347. [PMID: 33894044 DOI: 10.1002/jgm.3347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/09/2021] [Accepted: 04/21/2021] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The risk of chronic hepatitis B (CHB) infection is influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by polymorphic variants in one-carbon metabolism genes. In the present study, we investigated the relationship between polymorphisms belonging to the one-carbon metabolic pathway and CHB infection. METHODS A case-control study using 230 CHB patients and 234 unrelated healthy controls was carried out to assess the genetic association of 24 single nucleotide polymorphisins (SNPs) determined by mass spectrometry. RESULTS Three SNPs, comprising rs10717122 and rs2229717 in serine hydroxymethyltransferase1/2 (SHMT2) and rs585800 in betaine-homocysteine S-methyltransferase (BHMT), were associated with the risk of CHB. Patients with DEL allele, DEL.DEL and DEL.T genotypes of rs10717122 had a 1.40-, 2.00- and 1.83-fold increased risk for CHB, respectively. Cases inheriting TA genotype of rs585800 had a 2.19-fold risk for CHB infection. The T allele of rs2229717 was less represented in the CHB cases (odds ratio = 0.66, 95% confidence interval = 0.48-0.92). The T allele of rs2229717 was less in patients with a low hepatitis B virus-DNA level compared to the control group (odds ratio = 0.49, 95% confidence interval = 0.25-0.97) and TT genotype of rs2229717 had a significant correlation with hepatitis B surface antigen level (p = 0.0195). Further gene-gene interaction analysis showed that subjects carrying the rs10717122 DEL.DEL/DEL.T and rs585800 TT/TA genotypes had a 2.74-fold increased risk of CHB. CONCLUSIONS The results of the present study suggest that rs10717122, rs585800 and rs2229717 and gene-gene interactions of rs10717122 and rs585800 affect the outcome of CHB infection, at the same time as indicating their usefulness as a predictive and diagnostic biomarker of CHB infection.
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Affiliation(s)
- Yao-Hui Sun
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
| | - Jie Gao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
| | - Xu-Dong Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
| | - Hong-Wei Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
| | - Sheng-Li Cao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
| | - Jia-Kai Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
| | - Pei-Hao Wen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
| | - Zhi-Hui Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
| | - Jie Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
| | - Wen-Zhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
| | - Shui-Jun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Henan, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Henan, China
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25
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Castro de Moura M, Davalos V, Planas-Serra L, Alvarez-Errico D, Arribas C, Ruiz M, Aguilera-Albesa S, Troya J, Valencia-Ramos J, Vélez-Santamaria V, Rodríguez-Palmero A, Villar-Garcia J, Horcajada JP, Albu S, Casasnovas C, Rull A, Reverte L, Dietl B, Dalmau D, Arranz MJ, Llucià-Carol L, Planas AM, Pérez-Tur J, Fernandez-Cadenas I, Villares P, Tenorio J, Colobran R, Martin-Nalda A, Soler-Palacin P, Vidal F, Pujol A, Esteller M. Epigenome-wide association study of COVID-19 severity with respiratory failure. EBioMedicine 2021; 66:103339. [PMID: 33867313 PMCID: PMC8047083 DOI: 10.1016/j.ebiom.2021.103339] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 03/16/2021] [Accepted: 03/26/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. METHODS Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. FINDINGS The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. INTERPRETATION We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. FUNDING The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.
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Affiliation(s)
- Manuel Castro de Moura
- Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Barcelona, Catalonia, Spain
| | - Veronica Davalos
- Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Barcelona, Catalonia, Spain
| | - Laura Planas-Serra
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Damiana Alvarez-Errico
- Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Barcelona, Catalonia, Spain
| | - Carles Arribas
- Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Barcelona, Catalonia, Spain
| | - Montserrat Ruiz
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | | | - Jesús Troya
- Infanta Leonor University Hospital, Madrid, Spain
| | | | - Valentina Vélez-Santamaria
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Agustí Rodríguez-Palmero
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; University Hospital Germans Trias i Pujol, Badalona, Barcelona, Catalonia, Spain
| | - Judit Villar-Garcia
- Hospital del Mar - IMIM Biomedical Research Institute, Barcelona, Catalonia, Spain
| | - Juan P Horcajada
- Hospital del Mar - IMIM Biomedical Research Institute, Barcelona, Catalonia, Spain
| | - Sergiu Albu
- Institut Guttmann Foundation, Badalona, Barcelona, Catalonia, Spain
| | - Carlos Casasnovas
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Anna Rull
- Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
| | - Laia Reverte
- Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
| | - Beatriz Dietl
- Servei de malalties infeccioses Hospital Universitari MutuaTerrassa, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - David Dalmau
- MutuaTerrassa Research and Innovation Foundation, HIV/AIDS Unit Hospital Universitari MutuaTerrassa, University of Barcelona, Barcelona, Catalonia, Spain
| | - Maria J Arranz
- Fundaciò Docència i Recerca Mutua Terrassa i Hospital Universitari Mutua Terrassa, Barcelona, Catalonia, Spain
| | - Laia Llucià-Carol
- Stroke Pharmacogenomics and Genetics Group, Sant Pau Institute of Research, Sant Pau Hospital, Barcelona, Catalonia, Spain
| | - Anna M Planas
- Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Area of Neurosciences, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Jordi Pérez-Tur
- Institut de Biomedicina de València-CSIC, CIBERNED, Unitat Mixta de Neurologia i Genètica, IIS La Fe, Vallencia, Spain
| | - Israel Fernandez-Cadenas
- Stroke Pharmacogenomics and Genetics Group, Sant Pau Institute of Research, Sant Pau Hospital, Barcelona, Catalonia, Spain
| | - Paula Villares
- Internal Medicine Department, Hospital HM Sanchinarro, HM Hospitales, Madrid, Spain
| | - Jair Tenorio
- INGEMM-Instituto de Genética Médica y Molecular, Hospital Universitario La Paz, Madrid, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
| | - Roger Colobran
- Immunology Division, Genetics Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, UAB, Barcelona, Catalonia, Spain
| | - Andrea Martin-Nalda
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain
| | - Pere Soler-Palacin
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain
| | - Francesc Vidal
- Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
| | - Aurora Pujol
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
| | - Manel Esteller
- Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Catalonia, Spain.
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Inagaki T, Sato Y, Ito J, Takaki M, Okuno Y, Yaguchi M, Masud HMAA, Watanabe T, Sato K, Iwami S, Murata T, Kimura H. Direct Evidence of Abortive Lytic Infection-Mediated Establishment of Epstein-Barr Virus Latency During B-Cell Infection. Front Microbiol 2021; 11:575255. [PMID: 33613459 PMCID: PMC7888302 DOI: 10.3389/fmicb.2020.575255] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 12/15/2020] [Indexed: 12/25/2022] Open
Abstract
Viral infection induces dynamic changes in transcriptional profiles. Virus-induced and antiviral responses are intertwined during the infection. Epstein-Barr virus (EBV) is a human gammaherpesvirus that provides a model of herpesvirus latency. To measure the transcriptome changes during the establishment of EBV latency, we infected EBV-negative Akata cells with EBV-EGFP and performed transcriptome sequencing (RNA-seq) at 0, 2, 4, 7, 10, and 14 days after infection. We found transient downregulation of mitotic division-related genes, reflecting reprogramming of cell growth by EBV, and a burst of viral lytic gene expression in the early phase of infection. Experimental and mathematical investigations demonstrate that infectious virions were not produced in the pre-latent phase, suggesting the presence of an abortive lytic infection. Fate mapping using recombinant EBV provided direct evidence that the abortive lytic infection in the pre-latent phase converges to latent infection during EBV infection of B-cells, shedding light on novel roles of viral lytic gene(s) in establishing latency. Furthermore, we find that the BZLF1 protein, which is a key regulator of reactivation, was dispensable for abortive lytic infection in the pre-latent phase, suggesting the divergent regulation of viral gene expressions from a productive lytic infection.
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Affiliation(s)
- Tomoki Inagaki
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshitaka Sato
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Kawaguchi, Japan
| | - Jumpei Ito
- Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Mitsuaki Takaki
- Mathematical Biology Laboratory, Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan
| | - Yusuke Okuno
- Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan
| | - Masahiro Yaguchi
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - H. M. Abdullah Al Masud
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Microbiology, Faculty of Biological Sciences, University of Chittagong, Chattogram, Bangladesh
| | - Takahiro Watanabe
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kei Sato
- Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Shingo Iwami
- Mathematical Biology Laboratory, Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Japan
- MIRAI, Japan Science and Technology Agency, Kawaguchi, Japan
| | - Takayuki Murata
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Virology and Parasitology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Hiroshi Kimura
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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27
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Ikeda T, Gion Y, Nishimura Y, Nishimura MF, Yoshino T, Sato Y. Epstein-Barr Virus-Positive Mucocutaneous Ulcer: A Unique and Curious Disease Entity. Int J Mol Sci 2021; 22:ijms22031053. [PMID: 33494358 PMCID: PMC7865427 DOI: 10.3390/ijms22031053] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Epstein–Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in 2010. EBVMCU is a unifocal mucosal or cutaneous ulcer that often occurs after local trauma in patients with immunosuppression; the patients generally have a good prognosis. It is histologically characterized by proliferating EBV-positive atypical B cells accompanied by ulcers. On the basis of conventional pathologic criteria, EBVMCU may be misdiagnosed as EBV-positive diffuse large B-cell lymphoma or other lymphomas. However, its prognosis differs from that of EBV-associated lymphomas, in that patients with EBVMCU frequently show spontaneous regression or complete remission without chemotherapy. Therefore, EBVMCU is now recognized as a low-grade malignancy or a pseudo-malignant lesion. Avoiding unnecessary chemotherapy by distinguishing EBVMCU from other EBV-associated lymphomas will reduce the burden and unnecessary harm on patients. On the basis of these facts, EBVMCU was first described as a new clinicopathological entity by the World Health Organization in 2017. In this review, we discuss the clinicopathological characteristics of previously reported EBVMCU cases, while focusing on up-to-date clinical, pathological, and genetic aspects.
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Affiliation(s)
- Tomoka Ikeda
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (T.I.); (M.F.N.); (T.Y.)
| | - Yuka Gion
- Division of Pathophysiology, Okayama University Graduate School of Health Sciences, Okayama 700-8558, Japan;
| | - Yoshito Nishimura
- Department of General Medicine, Okayama University Hospital, Okayama 700-8558, Japan;
| | - Midori Filiz Nishimura
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (T.I.); (M.F.N.); (T.Y.)
| | - Tadashi Yoshino
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (T.I.); (M.F.N.); (T.Y.)
| | - Yasuharu Sato
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (T.I.); (M.F.N.); (T.Y.)
- Division of Pathophysiology, Okayama University Graduate School of Health Sciences, Okayama 700-8558, Japan;
- Correspondence: ; Tel.: +81-86-235-7150; Fax: +81-86-235-7156
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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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Ignatova E, Seriak D, Fedyanin M, Tryakin A, Pokataev I, Menshikova S, Vakhabova Y, Smirnova K, Tjulandin S, Ajani JA. Epstein-Barr virus-associated gastric cancer: disease that requires special approach. Gastric Cancer 2020; 23:951-960. [PMID: 32514646 DOI: 10.1007/s10120-020-01095-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
Epstein-Barr virus-associated gastric cancer [EBV-associated GC, EBV( +) GC] is a distinct molecular subtype of gastrointestinal (GI) cancers. It accounts for up to 10% of all molecular subtypes of gastric cancer (GC). It has unique genetic and epigenetic features, which determine its definitive phenotype with male and younger age predominance, proximal stomach localization, and diffuse adenocarcinoma histology. EBV( +) GC also has a unique epigenetic profile and mutational status with frequent mutations of PIK3CA, ARID1A and BCOR, and PD-L1 and PD-L2 amplifications, as well. The aim of this review is to highlight clinical significance of EBV( +) GC and prognostic role of EBV infection, and to determine potentially appropriate drug therapy for this disease.
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Affiliation(s)
- Ekaterina Ignatova
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation.
| | - Daria Seriak
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation
| | - Mikhail Fedyanin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Alexey Tryakin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Ilya Pokataev
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Sofia Menshikova
- Department of Anticancer Drug Treatment, AO K31 City, Moscow, Russian Federation
| | - Yuliya Vakhabova
- Chemotherapy Department of Tumors Drug Treatment, Moscow Scientific Research Oncological Institution N.a. P.A. Herzen, Branch of Federal State Budgetary Institution "National Medical Research Center of Radiology" of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
| | - Ksenia Smirnova
- Laboratory of Viral Carcinogenesis, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
| | - Sergey Tjulandin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
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Rosendo-Chalma P, Antonio-Vejar V, Bigoni-Ordóñez GD, Patiño-Morales CC, Cano-García A, García-Carrancá A. CDH1 and SNAI1 are regulated by E7 from human papillomavirus types 16 and 18. Int J Oncol 2020; 57:301-313. [PMID: 32319591 DOI: 10.3892/ijo.2020.5039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 10/24/2019] [Indexed: 11/05/2022] Open
Abstract
A common characteristic of cancer types associated with viruses is the dysregulated expression of the CDH1 gene, which encodes E‑cadherin, in general by activation of DNA methyltransferases (Dnmts). In cervical cancer, E7 protein from high risk human papillomaviruses (HPVs) has been demonstrated to interact with Dnmt1 and histone deacetylase type 1 (HDAC1). The present study proposed that E7 may regulate the expression of CDH1 through two pathways: i) Epigenetic, including DNA methylation; and ii) Epigenetic‑independent, including the induction of negative regulators of CDH1 expression, such as Snail family transcriptional repressor Snai1 and Snai2. To test this hypothesis, HPV16‑ and HPV18‑positive cell lines were used to determine the methylation pattern of the CDH1 promoter and its expression in association with its negative regulators. Different methylation frequencies were identified in the CDH1 promoter in HeLa (88.24%) compared with SiHa (17.65%) and Ca Ski (0%) cell lines. Significant differences in the expression of SNAI1 were observed between these cell lines, and an inverse association was identified between the expression levels of SNAI1 and CDH1. In addition, suppressing E7 not only increased the expression of CDH1, but notably decreased the expression of SNAI1 and modified the methylation pattern of the CDH1 promoter. These results suggested that the expression of CDH1 was dependent on the expression of SNAI1 and was inversely associated with the expression of E7. The present results indicated that E7 from HPV16/18 regulated the expression of CDH1 by the two following pathways in which Snai1 is involved: i) Hypermethylation of the CDH1 promoter region and increasing expression of SNAI1, as observed in HeLa; and ii) Hypomethylation of the CDH1 promoter region and expression of SNAI1, as observed in SiHa. Therefore, the suppression of CDH1 and expression of SNAI1 may be considered to be biomarkers of metastasis in uterine cervical cancer.
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Affiliation(s)
- Pedro Rosendo-Chalma
- Programa de Doctorado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas (IIB), Universidad Nacional Autónoma de México (UNAM), Mexico City 10450, Mexico
| | - Verónica Antonio-Vejar
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer of Instituto de Investigaciones Biomédicas‑Universidad Nacional Autónoma de México (IIB‑UNAM) and División de Investigación Básica of Instituto Nacional de Cancerología‑Secretaría de Salud (INCan‑SSA), Mexico City 14080, Mexico
| | - Gabriele Davide Bigoni-Ordóñez
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer of Instituto de Investigaciones Biomédicas‑Universidad Nacional Autónoma de México (IIB‑UNAM) and División de Investigación Básica of Instituto Nacional de Cancerología‑Secretaría de Salud (INCan‑SSA), Mexico City 14080, Mexico
| | - Carlos César Patiño-Morales
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer of Instituto de Investigaciones Biomédicas‑Universidad Nacional Autónoma de México (IIB‑UNAM) and División de Investigación Básica of Instituto Nacional de Cancerología‑Secretaría de Salud (INCan‑SSA), Mexico City 14080, Mexico
| | - Amparo Cano-García
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC‑UAM), Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ), Madrid 28029, Spain
| | - Alejandro García-Carrancá
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer of Instituto de Investigaciones Biomédicas‑Universidad Nacional Autónoma de México (IIB‑UNAM) and División de Investigación Básica of Instituto Nacional de Cancerología‑Secretaría de Salud (INCan‑SSA), Mexico City 14080, Mexico
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31
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Fertey J, Hagmann J, Ruscheweyh HJ, Munk C, Kjaer S, Huson D, Haedicke-Jarboui J, Stubenrauch F, Iftner T. Methylation of CpG 5962 in L1 of the human papillomavirus 16 genome as a potential predictive marker for viral persistence: A prospective large cohort study using cervical swab samples. Cancer Med 2019; 9:1058-1068. [PMID: 31856411 PMCID: PMC6997067 DOI: 10.1002/cam4.2771] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 11/22/2019] [Accepted: 11/26/2019] [Indexed: 01/06/2023] Open
Abstract
Several studies have demonstrated that the viral genome can be methylated by the host cell during progression from persistent infection to cervical cancer. The aim of this study was to investigate whether methylation at a specific site could predict the development of viral persistence and whether viral load shows a correlation with specific methylation patterns. HPV16‐positive samples from women aged 20–29 years (n = 99) with a follow‐up time of 13 years, were included from a Danish cohort comprising 11 088 women. Viral load was measured by real‐time PCR and methylation status was determined for 39 CpG sites in the upstream regulatory region (URR), E6/E7, and L1 region of HPV16 by next‐generation sequencing. Participants were divided into two groups according to whether they were persistently (≥ 24 months) or transiently HPV16 infected. The general methylation status was significantly different between women with a persistent and women with a transient infection outcome (P = .025). One site located in L1 (nt. 5962) was statistically significantly (P = .00048) different in the methylation status after correction using the Holm‐Sidak method (alpha = 0.05). Correlation analyses of samples from HPV16 persistently infected women suggest that methylation is higher although viral load is lower. This study indicates that methylation at position 5962 of the HPV16 genome within the L1 gene might be a predictive marker for the development of a persistent HPV16 infection.
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Affiliation(s)
- Jasmin Fertey
- Medical Virology, Institute of Medical Virology, University Hospital of Tuebingen, Tuebingen, Germany
| | - Jörg Hagmann
- Department of Molecular Biology, Max Planck Institute for Developmental Biology, Tuebingen, Germany
| | | | - Christian Munk
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Susanne Kjaer
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Daniel Huson
- Centre for Bioinformatics, Tuebingen University, Tuebingen, Germany
| | - Juliane Haedicke-Jarboui
- Medical Virology, Institute of Medical Virology, University Hospital of Tuebingen, Tuebingen, Germany
| | - Frank Stubenrauch
- Medical Virology, Institute of Medical Virology, University Hospital of Tuebingen, Tuebingen, Germany
| | - Thomas Iftner
- Medical Virology, Institute of Medical Virology, University Hospital of Tuebingen, Tuebingen, Germany
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Yang J, Zhang X, Blumenthal RM, Cheng X. Detection of DNA Modifications by Sequence-Specific Transcription Factors. J Mol Biol 2019:S0022-2836(19)30568-6. [PMID: 31626807 DOI: 10.1016/j.jmb.2019.09.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 12/16/2022]
Abstract
The establishment, detection, and alteration or elimination of epigenetic DNA modifications are essential to controlling gene expression ranging from bacteria to mammals. The DNA methylations occurring at cytosine and adenine are carried out by SAM-dependent methyltransferases. Successive oxidations of 5-methylcytosine (5mC) by Tet dioxygenases generate 5-hydroxymethyl (5hmC), 5-formyl (5fC), and 5-carboxyl (5caC) derivatives; thus, DNA elements with multiple methylation sites can have a wide range of modification states. In contrast, oxidation of N6-methyladenine by homologs of Escherichia coli AlkB removes the methyl group directly. Both Tet and AlkB enzymes are 2-oxoglutarate- and Fe(II)-dependent dioxygenases. DNA-binding proteins decode the modification status of specific genomic regions. This article centers on two families of sequence-specific transcription factors: bZIP (basic leucine-zipper) proteins, exemplified by the AP-1 and CEBPβ recognition of 5mC; and bHLH (basic helix-loop-helix) proteins, exemplified by MAX and TCF4 recognition of 5caC. We discuss the impact of template strand DNA modification on the activities of DNA and RNA polymerases, and the varied tendencies of modifications to alter base pairing and their interactions with DNA repair enzymes.
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Affiliation(s)
- Jie Yang
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xing Zhang
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Robert M Blumenthal
- Department of Medical Microbiology and Immunology, and Program in Bioinformatics, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
| | - Xiaodong Cheng
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Kottaridi C, Leventakou D, Pouliakis A, Pergialiotis V, Chrelias G, Patsouri E, Zacharatou A, Panopoulou E, Damaskou V, Sioulas V, Chrelias C, Kalantaridou S, Panayiotides IG. Searching HPV genome for methylation sites involved in molecular progression to cervical precancer. J Cancer 2019; 10:4588-4595. [PMID: 31528222 PMCID: PMC6746133 DOI: 10.7150/jca.30081] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 05/08/2019] [Indexed: 02/07/2023] Open
Abstract
Background: Human Papilloma Virus has been considered as the main cause for cervical cancer. In this study we investigated epigenetic changes and especially methylation of specific sites of HPV genome. The main goal was to correlate methylation status with histological grade as well as to determine its accuracy in predicting the disease severity by establishing optimum methylation cutoffs. Methods: In total, sections from 145 cases genotyped as HPV16 were obtained from formalin- fixed, paraffin-embedded tissue of cervical biopsies, conization or hysterectomy specimens. Highly accurate pyrosequencing of bisulfite converted DNA, was used to quantify the methylation percentages of UTR promoter, enhancer and 5' UTR, E6 CpGs 494, 502, 506 and E7 CpGs 765, 780, 790. The samples were separated in different groupings based on the histological outcome. Statistical analysis was performed by SAS 9.4 for Windows and methylation cutoffs were identified by MATLAB programming language. Results: The most important methylation sites were at the enhancer and especially UTR 7535 and 7553 sites. Specifically for CIN3+ (i.e. HSIL or SCC) discrimination, a balanced sensitivity vs. specificity (68.1%, 66.2% respectively) with positive predictive value (PPV) and negative predictive value (NPV) (66.2%, 68.2% respectively) was achieved for UTR 7535 methylation of 6.1% cutoff with overall accuracy 67.1%, while for UTR 7553 a sensitivity 60.9%, specificity 69.0%, PPV=65.6%, NPV=64.5% and overall accuracy=65.0% at threshold 10.1% was observed. Conclusion: Viral HPV16 genome was found methylated in NF-1 binding sites of UTR in cases with high grade disease. Methylation percentages of E6 and E7 CpG sites were elevated at the cancer group.
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Affiliation(s)
- Christine Kottaridi
- 2 nd Department of Pathology, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Danai Leventakou
- 2 nd Department of Pathology, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Abraham Pouliakis
- 2 nd Department of Pathology, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Vasileios Pergialiotis
- 3 rd Department of Gynaecology and Obstetrics, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - George Chrelias
- 3 rd Department of Gynaecology and Obstetrics, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Eugenia Patsouri
- 2 nd Department of Pathology, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Andriani Zacharatou
- 2 nd Department of Pathology, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Eleni Panopoulou
- 2 nd Department of Pathology, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Vasileia Damaskou
- 2 nd Department of Pathology, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Vasileios Sioulas
- 3 rd Department of Gynaecology and Obstetrics, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Charalambos Chrelias
- 3 rd Department of Gynaecology and Obstetrics, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Sofia Kalantaridou
- 3 rd Department of Gynaecology and Obstetrics, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
| | - Ioannis G Panayiotides
- 2 nd Department of Pathology, University General Hospital "ATTIKON", School of Medicine, National and Kapodistrian University of Athens, Athens 12464, Greece
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Liu J, Chen S, Zou Z, Tan D, Liu X, Wang X. Pathological Pattern of Intrahepatic HBV in HCC is Phenocopied by PDX-Derived Mice: a Novel Model for Antiviral Treatment. Transl Oncol 2019; 12:1138-1146. [PMID: 31202090 PMCID: PMC6581976 DOI: 10.1016/j.tranon.2019.05.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 05/08/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is one of the most prominent risk factors for hepatocellular carcinoma (HCC) development and virus-mediated cases represents more than 80% of HCC in East Asia, where it is endemic. Currently, the HBV status of pathological HCC is not fully clarified, especially by comparison to nontumorous tissues. Lack of clinicopathological animal models of HCC impedes clinical application of antiviral treatment in the field. MATERIALS AND METHODS A cohort sample of 14 HCC and corresponding stroma tissues were analyzed for pathological patterns of HBV antigens using immunohistochemistry; 10 fresh primary tumor tissues were inoculated into NOD/SCID mice and risk factors for patient-derived xenograft (PDX) model were identified by the univariate F test. Consistency of HBV features and cellular biomarkers between patient tissues and tumor grafts were examined. RESULTS In HCC, HBV surface antigen (HBsAg) was mainly absent. Only 9.9% of samples showed HBsAg positivity in the tumor tissue that was limited to benign hepatocytes. In contrast, HBV core antigen (HBcAg) exhibited positive staining in all HCC tissues, located mainly in the cytoplasm of tumor cells. Of 14 HCC cases, three were diagnosed as occult infection of HBV based on HBcAg expression. The successful rate for the PDX model was 20% (2/10). Tumor lesions on hepatic lobes of V and VI, severe liver dysfunction and higher CA125 showed p-values of 0.01, 0.035, and 0.01, respectively. HBsAg absence in original tumors of #6 and 8 patients were faithfully reproduced by engraftments. Mixed distribution of HBcAg in cellular compartments of original tumor cells was also observed in mice. ki67 was dramatically increased in tumor grafts. CONCLUSION We delineated pathological HBV profiles of HCC specimens and perilesional areas, which provided evidence for virus-based therapy in the future. PDX mice may phenocopy virological and cellular features of patient tissues, which is novel in the virus-related hepatocarcinogenesis field.
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Affiliation(s)
- Jiao Liu
- Department of Endoscope, the General Hospital of Shenyang Military Region, Shenyang 110000, PR China.
| | - Siyuan Chen
- Department of Gastroenterology, the Second Affiliated Hospital of Army Medical University, Chongqing 400007, PR China.
| | - Zhe Zou
- Department of Gastroenterology, the Second Affiliated Hospital of Army Medical University, Chongqing 400007, PR China.
| | - Dehong Tan
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Army Medical University, Chongqing 400007, PR China.
| | - Xiangde Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Army Medical University, Chongqing 400007, PR China.
| | - Xing Wang
- Department of Gastroenterology, the Second Affiliated Hospital of Army Medical University, Chongqing 400007, PR China.
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Methylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases. Nat Commun 2019; 10:3256. [PMID: 31332191 PMCID: PMC6646310 DOI: 10.1038/s41467-019-11226-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 07/02/2019] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) is associated with a number of diseases, including malignancies. Currently, it is not known whether patients with different EBV-associated diseases have different methylation profiles of circulating EBV DNA. Through whole-genome methylation analysis of plasma samples from patients with nasopharyngeal carcinoma (NPC), EBV-associated lymphoma and infectious mononucleosis, we demonstrate that EBV DNA methylation profiles exhibit a disease-associated pattern. This observation implies a significant potential for the development of methylation analysis of plasma EBV DNA for NPC diagnostics. We further analyse the plasma EBV DNA methylome of NPC and non-NPC subjects from a prospective screening cohort. Plasma EBV DNA fragments demonstrate differential methylation patterns between NPC and non-NPC subjects. Combining such differential methylation patterns with the fractional concentration (count) and size of plasma EBV DNA, population screening of NPC is performed with an improved positive predictive value of 35.1%, compared to a count- and size-based only protocol. Epstein-Barr virus (EBV) is associated with different malignant diseases and circulating EBV DNA is a biomarker for nasopharyngeal carcinoma (NPC). Here, the authors report that plasma EBV DNA methylation profiles show disease-associated patterns and can help to distinguish NPC and non-NPC subjects.
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36
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Abstract
Biomarker discovery and validation are necessary for improving the prediction of clinical outcomes and patient monitoring. Despite considerable interest in biomarker discovery and development, improvements in the range and quality of biomarkers are still needed. The main challenge is how to integrate preclinical data to obtain a reliable biomarker that can be measured with acceptable costs in routine clinical practice. Epigenetic alterations are already being incorporated as valuable candidates in the biomarker field. Furthermore, their reversible nature offers a promising opportunity to ameliorate disease symptoms by using epigenetic-based therapy. Thus, beyond helping to understand disease biology, clinical epigenetics is being incorporated into patient management in oncology, as well as being explored for clinical applicability for other human pathologies such as neurological and infectious diseases and immune system disorders.
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Schaeffner M, Mrozek-Gorska P, Buschle A, Woellmer A, Tagawa T, Cernilogar FM, Schotta G, Krietenstein N, Lieleg C, Korber P, Hammerschmidt W. BZLF1 interacts with chromatin remodelers promoting escape from latent infections with EBV. Life Sci Alliance 2019; 2:e201800108. [PMID: 30926617 PMCID: PMC6441497 DOI: 10.26508/lsa.201800108] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 03/17/2019] [Accepted: 03/18/2019] [Indexed: 12/16/2022] Open
Abstract
A hallmark of EBV infections is its latent phase, when all viral lytic genes are repressed. Repression results from a high nucleosome occupancy and epigenetic silencing by cellular factors such as the Polycomb repressive complex 2 (PRC2) and DNA methyltransferases that, respectively, introduce repressive histone marks and DNA methylation. The viral transcription factor BZLF1 acts as a molecular switch to induce transition from the latent to the lytic or productive phase of EBV's life cycle. It is unknown how BZLF1 can bind to the epigenetically silenced viral DNA and whether it directly reactivates the viral genome through chromatin remodeling. We addressed these fundamental questions and found that BZLF1 binds to nucleosomal DNA motifs both in vivo and in vitro. BZLF1 co-precipitates with cellular chromatin remodeler ATPases, and the knock-down of one of them, INO80, impaired lytic reactivation and virus synthesis. In Assay for Transposase-Accessible Chromatin-seq experiments, non-accessible chromatin opens up locally when BZLF1 binds to its cognate sequence motifs in viral DNA. We conclude that BZLF1 reactivates the EBV genome by directly binding to silenced chromatin and recruiting cellular chromatin-remodeling enzymes, which implement a permissive state for lytic viral transcription. BZLF1 shares this mode of action with a limited number of cellular pioneer factors, which are instrumental in transcriptional activation, differentiation, and reprogramming in all eukaryotic cells.
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Affiliation(s)
- Marisa Schaeffner
- Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | - Paulina Mrozek-Gorska
- Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | - Alexander Buschle
- Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | - Anne Woellmer
- Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | - Takanobu Tagawa
- Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | - Filippo M Cernilogar
- Biomedical Center, Molecular Biology, Ludwig-Maximilians-Universität Munich, Planegg, Germany
| | - Gunnar Schotta
- Biomedical Center, Molecular Biology, Ludwig-Maximilians-Universität Munich, Planegg, Germany
- Center for Integrated Protein Science Munich, Munich, Germany
| | - Nils Krietenstein
- Biomedical Center, Molecular Biology, Ludwig-Maximilians-Universität Munich, Planegg, Germany
| | - Corinna Lieleg
- Biomedical Center, Molecular Biology, Ludwig-Maximilians-Universität Munich, Planegg, Germany
| | - Philipp Korber
- Biomedical Center, Molecular Biology, Ludwig-Maximilians-Universität Munich, Planegg, Germany
| | - Wolfgang Hammerschmidt
- Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
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Vysotskaya IV, Letyagin V, Shabanov M, Kirsanov V, Kim E, Levkina N. Current Issues in Carcinogenesis. CLINICAL ONCOHEMATOLOGY 2019; 12:101-106. [DOI: 10.21320/2500-2139-2019-12-1-101-106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
The review presents current data on the major pathogenetic mechanisms underlying uncontrolled growth and dissemination of tumor and its resistance to conventional treatment. Cell genetic instability associated with accumulation of mutations in genes controlling cell growth and differentiation is a key factor in tumor proliferation. Due understanding and detailed analysis of carcinogenesis processes provide the basis for creation of new anticancer drugs which in turn enables optimization and individualization of cancer treatment.
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Affiliation(s)
| | | | | | | | - E.A. Kim
- IM Sechenov First Moscow State Medical University
| | - N.V. Levkina
- IM Sechenov First Moscow State Medical University
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Abstract
Since their discovery as the etiologic agents of cervical cancer in the mid-1970s, human papillomaviruses (HPVs) have been linked with a growing number of epithelial-derived tumors, including head and neck squamous cell carcinomas. HPV demonstrates a particular predilection for causing tumors of the oropharynx, with the majority of cases involving infection with high-oncogenic risk HPV-16. People living with HIV are at increased risk of infection with HPV- and HPV-related oral complications even with adequate control of their HIV infection with antiretroviral therapy. In this chapter, we discuss the molecular mechanisms that underlie HPV-mediated oncogenesis in the oropharynx. We also describe the progress that has been made in understanding the epidemiology of oral HPV infection and the determinants of oral HPV-related pathology. Finally, we examine what can be done to treat and prevent oral HPV infection, benign lesions, and cancer, particularly in the context of the HIV-positive patient.
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Silva GÁF, Nunes RAL, Morale MG, Boccardo E, Aguayo F, Termini L. Oxidative stress: therapeutic approaches for cervical cancer treatment. Clinics (Sao Paulo) 2018; 73:e548s. [PMID: 30540121 PMCID: PMC6257060 DOI: 10.6061/clinics/2018/e548s] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 09/24/2018] [Indexed: 12/20/2022] Open
Abstract
Oxidative stress results from an imbalance between the generation and elimination of oxidant species. This condition may result in DNA, RNA and protein damage, leading to the accumulation of genetic alterations that can favor malignant transformation. Persistent infection with high-risk human papillomavirus types is associated with inflammatory responses and reactive oxygen species production. In this context, oxidative stress, chronic inflammation and high-risk human papillomavirus can act in a synergistic manner. To counteract the harmful effects of oxidant species, protective molecules, known as antioxidant defenses, are produced by cells to maintain redox homeostasis. In recent years, the use of natural antioxidants as therapeutic strategies for cancer treatment has attracted the attention of the scientific community. This review discusses specific molecules and mechanisms that can act against or together with oxidative stress, presenting alternatives for cervical cancer prevention and treatment.
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Affiliation(s)
- Gabriela Ávila Fernandes Silva
- Instituto do Cancer do Estado de Sao Paulo ICESP, Centro de Investigacao Translacional em Oncologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Departamento de Radiologia e Oncologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, BR
| | - Rafaella Almeida Lima Nunes
- Instituto do Cancer do Estado de Sao Paulo ICESP, Centro de Investigacao Translacional em Oncologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Departamento de Radiologia e Oncologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, BR
| | - Mirian Galliote Morale
- Instituto do Cancer do Estado de Sao Paulo ICESP, Centro de Investigacao Translacional em Oncologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Departamento de Radiologia e Oncologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, BR
| | - Enrique Boccardo
- Laboratorio de Oncovirologia, Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Francisco Aguayo
- Centro Avanzado de Enfermedades Cronicas (ACCDiS), Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Oncologia Basico Clinica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Lara Termini
- Instituto do Cancer do Estado de Sao Paulo ICESP, Centro de Investigacao Translacional em Oncologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
- *Corresponding author. E-mail:
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Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells. mSphere 2018; 3:3/6/e00478-18. [PMID: 30487153 PMCID: PMC6262262 DOI: 10.1128/msphere.00478-18] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Epigenetic modifications play a pivotal role in the expression of the genes of Epstein-Barr virus (EBV). We found that de novo EBV infection of primary B cells caused moderate induction of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 (K27) methyltransferase. To investigate the role of EZH2, we knocked out the EZH2 gene in EBV-negative Akata cells by the CRISPR/Cas9 system and infected the cells with EBV, followed by selection of EBV-positive cells. During the latent state, growth of EZH2-knockout (KO) cells was significantly slower after infection compared to wild-type controls, despite similar levels of viral gene expression between cell lines. After induction of the lytic cycle by anti-IgG, KO of EZH2 caused notable induction of expression of both latent and lytic viral genes, as well as increases in both viral DNA replication and progeny production. These results demonstrate that EZH2 is crucial for the intricate epigenetic regulation of not only lytic but also latent gene expression in Akata cells.IMPORTANCE The life cycle of EBV is regulated by epigenetic modifications, such as CpG methylation and histone modifications. Here, we found that the expression of EZH2, which encodes a histone H3K27 methyltransferase, was induced by EBV infection; therefore, we generated EZH2-KO cells to investigate the role of EZH2 in EBV-infected Akata B cells. Disruption of EZH2 resulted in increased expression of EBV genes during the lytic phase and, therefore, efficient viral replication and progeny production. Our results shed light on the mechanisms underlying reactivation from an epigenetic point of view and further suggest a role for EZH2 as a form of innate immunity that restricts viral replication in infected cells.
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Ren R, Horton JR, Zhang X, Blumenthal RM, Cheng X. Detecting and interpreting DNA methylation marks. Curr Opin Struct Biol 2018; 53:88-99. [PMID: 30031306 DOI: 10.1016/j.sbi.2018.06.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 06/19/2018] [Indexed: 12/22/2022]
Abstract
The generation, alteration, recognition, and erasure of epigenetic modifications of DNA are fundamental to controlling gene expression in mammals. These covalent DNA modifications include cytosine methylation by AdoMet-dependent methyltransferases and 5-methylcytosine oxidation by Fe(II)-dependent and α-ketoglutarate-dependent dioxygenases. Sequence-specific transcription factors are responsible for interpreting the modification status of specific regions of chromatin. This review focuses on recent developments in characterizing the functional and structural links between the modification status of two DNA bases: 5-methylcytosine and 5-methyluracil (thymine).
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Affiliation(s)
- Ren Ren
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - John R Horton
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xing Zhang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Robert M Blumenthal
- Department of Medical Microbiology and Immunology, and Program in Bioinformatics, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
| | - Xiaodong Cheng
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Oyervides-Muñoz MA, Pérez-Maya AA, Rodríguez-Gutiérrez HF, Gómez-Macias GS, Fajardo-Ramírez OR, Treviño V, Barrera-Saldaña HA, Garza-Rodríguez ML. Understanding the HPV integration and its progression to cervical cancer. INFECTION GENETICS AND EVOLUTION 2018. [PMID: 29518579 DOI: 10.1016/j.meegid.2018.03.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Li D, Fu W, Swaminathan S. Continuous DNA replication is required for late gene transcription and maintenance of replication compartments in gammaherpesviruses. PLoS Pathog 2018; 14:e1007070. [PMID: 29813138 PMCID: PMC5993329 DOI: 10.1371/journal.ppat.1007070] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 06/08/2018] [Accepted: 05/02/2018] [Indexed: 12/11/2022] Open
Abstract
Late gene transcription in herpesviruses is dependent on viral DNA replication in cis but the mechanistic basis for this linkage remains unknown. DNA replication results in demethylated DNA, topological changes, removal of proteins and recruitment of proteins to promoters. One or more of these effects of DNA replication may facilitate late gene transcription. Using 5-azacytidine to promote demethylation of DNA, we demonstrate that late gene transcription cannot be rescued by DNA demethylation. Late gene transcription precedes significant increases in DNA copy number, indicating that increased template numbers also do not contribute to the linkage between replication and late gene transcription. By using serial, timed blockade of DNA replication and measurement of late gene mRNA accumulation, we demonstrate that late gene transcription requires ongoing DNA replication. Consistent with these findings, blocking DNA replication led to dissolution of DNA replication complexes which also contain RNA polymerase II and BGLF4, an EBV protein required for transcription of several late genes. These data indicate that ongoing DNA replication maintains integrity of a replication-transcription complex which is required for recruitment and retention of factors necessary for late gene transcription. Herpesviruses exhibit both latent and lytic replication cycles. Gammaherpesviruses such as Kaposi’s sarcoma-associated herpesvirus and Epstein Barr virus undergo lytic replication when they reactivate from latency. During this process, when infectious virions are produced, an orderly cascade of gene expression occurs. Late lytic genes, which primarily encode structural components of the virion, are only transcribed after replication of the DNA genome has occurred. Unlike early lytic genes, late gene transcription is tightly linked to viral DNA replication; if viral DNA replication is blocked, late gene mRNA accumulation is severely inhibited. The mechanism by which late gene transcription is linked to DNA replication has remained elusive. In this paper we show that a process of continuous DNA replication is required. If one blocks DNA replication, further transcription also ceases, indicating that concurrent DNA replication is required to maintain late transcription. We also show that when DNA replication is blocked, the nuclear complexes in which herpesviruses are replicating dissociate. These replication complexes also serve as factories of viral transcription. When the complexes disperse, proteins required for transcription dissociate from the DNA replication machinery. These data indicate that ongoing DNA replication is necessary to maintain the physical and functional integrity of these structures. Our study provides new insight into this linkage that ensures coordination between viral replication and late gene expression.
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Affiliation(s)
- Dajiang Li
- Division of Infectious Diseases, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Wenmin Fu
- Division of Infectious Diseases, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Sankar Swaminathan
- Division of Infectious Diseases, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
- Department of Medicine, George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah, United States of America
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PM20D1 is a quantitative trait locus associated with Alzheimer's disease. Nat Med 2018; 24:598-603. [PMID: 29736028 DOI: 10.1038/s41591-018-0013-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 02/12/2018] [Indexed: 11/09/2022]
Abstract
The chances to develop Alzheimer's disease (AD) result from a combination of genetic and non-genetic risk factors 1 , the latter likely being mediated by epigenetic mechanisms 2 . In the past, genome-wide association studies (GWAS) have identified an important number of risk loci associated with AD pathology 3 , but a causal relationship remains difficult to establish. In contrast, locus-specific or epigenome-wide association studies (EWAS) have revealed site-specific epigenetic alterations, which provide mechanistic insights for a particular risk gene but often lack the statistical power of GWAS 4 . Here, combining both approaches, we report a previously unidentified association of the peptidase M20-domain-containing protein 1 (PM20D1) with AD. We find that PM20D1 is a methylation and expression quantitative trait locus coupled to an AD-risk associated haplotype, which displays enhancer-like characteristics and contacts the PM20D1 promoter via a haplotype-dependent, CCCTC-binding-factor-mediated chromatin loop. Furthermore, PM20D1 is increased following AD-related neurotoxic insults at symptomatic stages in the APP/PS1 mouse model of AD and in human patients with AD who are carriers of the non-risk haplotype. In line, genetically increasing or decreasing the expression of PM20D1 reduces and aggravates AD-related pathologies, respectively. These findings suggest that in a particular genetic background, PM20D1 contributes to neuroprotection against AD.
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Guidry JT, Birdwell CE, Scott RS. Epstein-Barr virus in the pathogenesis of oral cancers. Oral Dis 2018; 24:497-508. [PMID: 28190296 PMCID: PMC5554094 DOI: 10.1111/odi.12656] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 01/30/2017] [Accepted: 01/31/2017] [Indexed: 12/28/2022]
Abstract
Epstein-Barr virus (EBV) is a ubiquitous gamma-herpesvirus that establishes a lifelong persistent infection in the oral cavity and is intermittently shed in the saliva. EBV exhibits a biphasic life cycle, supported by its dual tropism for B lymphocytes and epithelial cells, which allows the virus to be transmitted within oral lymphoid tissues. While infection is often benign, EBV is associated with a number of lymphomas and carcinomas that arise in the oral cavity and at other anatomical sites. Incomplete association of EBV in cancer has questioned if EBV is merely a passenger or a driver of the tumorigenic process. However, the ability of EBV to immortalize B cells and its prevalence in a subset of cancers has implicated EBV as a carcinogenic cofactor in cellular contexts where the viral life cycle is altered. In many cases, EBV likely acts as an agent of tumor progression rather than tumor initiation, conferring malignant phenotypes observed in EBV-positive cancers. Given that the oral cavity serves as the main site of EBV residence and transmission, here we review the prevalence of EBV in oral malignancies and the mechanisms by which EBV acts as an agent of tumor progression.
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Affiliation(s)
- Joseph T. Guidry
- Department of Microbiology and Immunology, Center for Tumor and Molecular Virology, and Feist-Weiller Cancer Center. Louisiana State University Health Sciences Center-Shreveport. Shreveport, LA 71103
| | - Christine E. Birdwell
- Department of Microbiology and Immunology, Center for Tumor and Molecular Virology, and Feist-Weiller Cancer Center. Louisiana State University Health Sciences Center-Shreveport. Shreveport, LA 71103
| | - Rona S. Scott
- Department of Microbiology and Immunology, Center for Tumor and Molecular Virology, and Feist-Weiller Cancer Center. Louisiana State University Health Sciences Center-Shreveport. Shreveport, LA 71103
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Amaro-Filho SM, Pereira Chaves CB, Felix SP, Basto DL, de Almeida LM, Moreira MAM. HPV DNA methylation at the early promoter and E1/E2 integrity: A comparison between HPV16, HPV18 and HPV45 in cervical cancer. PAPILLOMAVIRUS RESEARCH 2018; 5:172-179. [PMID: 29649654 PMCID: PMC6046686 DOI: 10.1016/j.pvr.2018.04.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 04/06/2018] [Accepted: 04/06/2018] [Indexed: 11/26/2022]
Abstract
Objectives To compare and describe type-specific characteristics of HPV16, HPV18 and HPV45 in cervical cancer with respect to 3′LCR methylation and disruption of E1/E2. Methods The methylation level of 137 cervical cancer samples (70 with HPV16, 37 with HPV18, and 30 with HPV45) of Brazilian patients was analyzed by pyrosequencing. PCR amplifications were performed to characterize E1 and E2 disruption as an episomal surrogate. Results The 3′LCR of HPV16 showed a higher methylation at all CpG sites (7%, 9%, 11%, 10% and 10%) than homologous HPV18 regions (4%, 5%. 6%, 9% and 5%) and HPV45 regions (7%, 7% and 5%). Presence of intact E1/E2 was associated with higher HPV16 and HPV18 methylation levels at all CpG sites (p < 0.05). Disruption of E1/E2 was more frequently found in HPV45 (97%) and HPV18 (84%) than in HPV16 DNA (30%). HPV16 disruption was more frequently found in E1 (48%) unlike HPV18, where it was found in E2 (61%). Concomitant disruption of E1/E2 was most frequent in HPV45 (72%). Conclusions The findings showed a higher methylation associated with intact E1/E2 for HPV16 and HPV18. The closely phylogenetic related HPV18 and HPV45 share a similar methylation level and the frequency of viral genome disruption.
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Affiliation(s)
- Sérgio Menezes Amaro-Filho
- Genetics Program, Instituto Nacional de Câncer (INCA), Andre Cavalcanti 37, Rio de Janeiro, RJ 20231-050, Brazil.
| | | | - Shayany Pinto Felix
- Genetics Program, Instituto Nacional de Câncer (INCA), Andre Cavalcanti 37, Rio de Janeiro, RJ 20231-050, Brazil.
| | - Diogo Lisbôa Basto
- Genetics Program, Instituto Nacional de Câncer (INCA), Andre Cavalcanti 37, Rio de Janeiro, RJ 20231-050, Brazil.
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Almohammed R, Osborn K, Ramasubramanyan S, Perez-Fernandez IBN, Godfrey A, Mancini EJ, Sinclair AJ. Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta. J Gen Virol 2018; 99:805-817. [PMID: 29580369 PMCID: PMC6096924 DOI: 10.1099/jgv.0.001056] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The human gamma herpes virus Epstein–Barr virus (EBV) exploits multiple routes to evade the cellular immune response. During the EBV lytic replication cycle, viral proteins are expressed that provide excellent targets for recognition by cytotoxic T cells. This is countered by the viral BNLF2a gene. In B cells during latency, where BNLF2a is not expressed, we show that its regulatory region is embedded in repressive chromatin. The expression of BNLF2a mirrors the expression of a viral lytic cycle transcriptional regulator, Zta (BZLF1, EB1, ZEBRA), in B cells and we propose that Zta plays a role in up-regulating BNLF2a. In cells undergoing EBV lytic replication, we identified two distinct regions of interaction of Zta with the chromatin-associated BNLF2a promoter. We identify five potential Zta-response elements (ZREs) in the promoter that are highly conserved between virus isolates. Zta binds to these elements in vitro and activates the expression of the BNLF2a promoter in both epithelial and B cells. We also found redundancy amongst the ZREs. The EBV genome undergoes a biphasic DNA methylation cycle during its infection cycle. One of the ZREs contains an integral CpG motif. We show that this can be DNA methylated during EBV latency and that both Zta binding and promoter activation are enhanced by its methylation. In summary, we find that the BNLF2a promoter is directly targeted by Zta and that DNA methylation within the proximal ZRE aids activation. The implications for regulation of this key viral gene during the reactivation of EBV from latency are discussed.
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Affiliation(s)
- Rajaei Almohammed
- School of Life Sciences, University of Sussex, Brighton, East Sussex, UK.,Present address: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
| | - Kay Osborn
- School of Life Sciences, University of Sussex, Brighton, East Sussex, UK
| | - Sharada Ramasubramanyan
- School of Life Sciences, University of Sussex, Brighton, East Sussex, UK.,Present address: RS Mehta Jain Department of Biochemistry and Cell Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India
| | | | - Anja Godfrey
- School of Life Sciences, University of Sussex, Brighton, East Sussex, UK
| | - Erika J Mancini
- School of Life Sciences, University of Sussex, Brighton, East Sussex, UK
| | - Alison J Sinclair
- School of Life Sciences, University of Sussex, Brighton, East Sussex, UK
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Liu L, Ying C, Zhao Z, Sui L, Zhang X, Qian C, Wang Q, Chen L, Guo Q, Wu J. Identification of reliable biomarkers of human papillomavirus 16 methylation in cervical lesions based on integration status using high-resolution melting analysis. Clin Epigenetics 2018; 10:10. [PMID: 29410710 PMCID: PMC5781301 DOI: 10.1186/s13148-018-0445-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 01/11/2018] [Indexed: 01/13/2023] Open
Abstract
Background The dynamic methylation of human papillomavirus (HPV) 16 DNA is thought to be associated with the progression of cervical lesions. Previous studies that did not consider the physical status of HPV 16 may have incorrectly mapped HPV 16 methylomes. In order to identify reliable biomarkers for squamous cervical cancer (SCC), we comprehensively evaluated the methylation of HPV 16 depending on the integration incidence of each sample. Methods Based on the integration status of 115 HPV 16-infected patients (50 SCC, 30 high-grade squamous intraepithelial lesion [HSIL], and 35 low-grade squamous intraepithelial lesion [LSIL]) and HPV 16-infected Caski cell lines by PCR detection of integrated papillomavirus sequences, we designed a series of primers that would not be influenced by breakpoints for a high-resolution melting (HRM) PCR method to detect the genome methylation. Results A few regions with recurrent interruptions were identified in E1, E2/E4, L1, and L2 despite scattering of breakpoints throughout all eight genes of HPV 16. Frequent integration sites often occurred concomitantly with methylated CpG sites. The HRM PCR method showed 100% agreement with pyrosequencing when 3% was set as the cutoff value. A panel of CpG sites such as nt5606, nt5609, nt5615, and nt5378 can be combined in reweighing calculations to distinguish SCC from HSIL and LSIL patients which have high sensitivity and specificity (88% and 92.31%, respectively). Conclusions Our research shows that combination of CpG sites nt5606, nt5609, nt5615, and nt5378 can be used as potential diagnosis biomarkers for SCC, and the HRM PCR method is suitable for clinical methylation analysis. Electronic supplementary material The online version of this article (10.1186/s13148-018-0445-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lu Liu
- 1Department of Clinical Laboratory, The Obstetrics and Gynecology Hospital of Fudan University, Fangxie Road No. 419, Huangpu District, Shanghai, 200001 China
| | - Chunmei Ying
- 1Department of Clinical Laboratory, The Obstetrics and Gynecology Hospital of Fudan University, Fangxie Road No. 419, Huangpu District, Shanghai, 200001 China
| | - Zhen Zhao
- 2Department of Clinical Laboratory, Minhang District Central Hospital, Shanghai, China
| | - Long Sui
- 3Medical Center of Diagnosis and Treatment for Cervical Diseases, The Obstetrics and Gynecology Hospital of Fudan University, Fangxie Road No. 419, Huangpu District, Shanghai, 200001 China
| | - Xinyan Zhang
- 4The Research Institute of Obstetrics and Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Chunyan Qian
- 5Yuhang Branch, Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Qing Wang
- 3Medical Center of Diagnosis and Treatment for Cervical Diseases, The Obstetrics and Gynecology Hospital of Fudan University, Fangxie Road No. 419, Huangpu District, Shanghai, 200001 China
| | - Limei Chen
- 3Medical Center of Diagnosis and Treatment for Cervical Diseases, The Obstetrics and Gynecology Hospital of Fudan University, Fangxie Road No. 419, Huangpu District, Shanghai, 200001 China
| | - Qisang Guo
- 3Medical Center of Diagnosis and Treatment for Cervical Diseases, The Obstetrics and Gynecology Hospital of Fudan University, Fangxie Road No. 419, Huangpu District, Shanghai, 200001 China
| | - Jiangnan Wu
- 6Department of Clinical Statistics, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
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Zhou Z, Rajasingh S, Barani B, Samanta S, Dawn B, Wang R, Rajasingh J. Therapy of Infectious Diseases Using Epigenetic Approaches. EPIGENETICS IN HUMAN DISEASE 2018:689-715. [DOI: 10.1016/b978-0-12-812215-0.00022-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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