|
1
|
Lin H, Han Y, Sang Y, Wu Y, Tian M, Chen X, Lin X, Lin X. OTUD1 enhances gastric cancer aggressiveness by deubiquitinating EBV-encoded protein BALF1 to stabilize the apoptosis inhibitor Bcl-2. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167132. [PMID: 38565386 DOI: 10.1016/j.bbadis.2024.167132] [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: 12/28/2023] [Revised: 02/29/2024] [Accepted: 03/20/2024] [Indexed: 04/04/2024]
Abstract
The Epstein-Barr virus (EBV) is implicated in several cancers, including EBV-associated gastric cancer (EBVaGC). This study focuses on EBV-encoded BALF1 (BamH1 A fragment leftward reading frame 1), a key apoptosis regulator in EBV-related cancers, whose specific impact on EBVaGC was previously unknown. Our findings indicate that BALF1 overexpression in gastric cancer cells significantly enhances their proliferation, migration, and resistance to chemotherapy-induced apoptosis, confirming BALF1's oncogenic potential. A novel discovery is that BALF1 undergoes degradation via the ubiquitin-proteasome pathway. Through analysis of 69 deubiquitinating enzymes (DUBs), ovarian tumor protease (OTU) domain-containing protein 1 (OTUD1) emerged as a vital regulator for maintaining BALF1 protein stability. Furthermore, BALF1 was found to play a role in regulating the stability of the B-cell lymphoma-2 (Bcl-2) protein, increasing its levels through deubiquitination. This mechanism reveals BALF1's multifaceted oncogenic role in gastric cancer, as it contributes both directly and indirectly to cancer progression, particularly by stabilizing Bcl-2, known for its anti-apoptotic characteristics. These insights significantly deepen our understanding of EBV's involvement in the pathogenesis of gastric cancer. The elucidation of OTUD1's role in BALF1 regulation and its influence on Bcl-2 stabilization provide new avenues for therapeutic intervention in EBVaGC, bridging the gap between viral oncogenesis and cellular protein regulation and offering a more holistic view of gastric cancer development under the influence of EBV.
Collapse
Affiliation(s)
- Hanbin Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China
| | - Yuting Han
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China
| | - Yuchao Sang
- Anxi County Hospital, Quanzhou 362400, China
| | - Yuecheng Wu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China
| | - Mengyue Tian
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China
| | - Xintan Chen
- Anxi County Hospital, Quanzhou 362400, China
| | - Xu Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou 350122, China.
| | - Xinjian Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China; Anxi County Hospital, Quanzhou 362400, China.
| |
Collapse
|
|
2
|
Sun Y, Shi D, Sun J, Zhang Y, Liu W, Luo B. Regulation mechanism of EBV-encoded EBER1 and LMP2A on YAP1 and the impact of YAP1 on the EBV infection status in EBV-associated gastric carcinoma. Virus Res 2024; 343:199352. [PMID: 38462175 PMCID: PMC10982081 DOI: 10.1016/j.virusres.2024.199352] [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: 01/25/2024] [Revised: 03/07/2024] [Accepted: 03/07/2024] [Indexed: 03/12/2024]
Abstract
This study aims to explore the role and regulatory mechanism of Yes-associated protein 1 (YAP1) in the development of Epstein-Barr virus-associated gastric cancer (EBVaGC). Here we showed that EBV can upregulate the expression and activity of YAP1 protein through its encoded latent products EBV-encoded small RNA 1 (EBER1) and latent membrane protein 2A (LMP2A), enhancing the malignant characteristics of EBVaGC cells. In addition, we also showed that overexpression of YAP1 induced the expression of EBV encoding latent and lytic phase genes and proteins in the epithelial cell line AGS-EBV infected with EBV, and increased the copy number of the EBV genome, while loss of YAP1 expression reduced the aforementioned indicators. Moreover, we found that YAP1 enhanced EBV lytic reactivation induced by two known activators, 12-O-tetradecanoylhorbol-13-acetate (TPA) and sodium butyrate (NaB). These results indicated a bidirectional regulatory mechanism between EBV and YAP1 proteins, providing new experimental evidence for further understanding the regulation of EBV infection patterns and carcinogenic mechanisms in gastric cancer.
Collapse
Affiliation(s)
- Yujie Sun
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Duo Shi
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Jiting Sun
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Yan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China; Department of Clinical Laboratory, Zibo Central Hospital, ZiBo 255036, China
| | - Wen Liu
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China.
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China.
| |
Collapse
|
|
3
|
Iizasa H, Kartika AV, Fekadu S, Okada S, Onomura D, Wadi AFAA, Khatun MM, Moe TM, Nishikawa J, Yoshiyama H. Development of Epstein-Barr virus-associated gastric cancer: Infection, inflammation, and oncogenesis. World J Gastroenterol 2022; 28:6249-6257. [PMID: 36504553 PMCID: PMC9730441 DOI: 10.3748/wjg.v28.i44.6249] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/24/2022] [Accepted: 11/09/2022] [Indexed: 11/25/2022] Open
Abstract
Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) cells originate from a single-cell clone infected with EBV. However, more than 95% of patients with gastric cancer have a history of Helicobacter pylori (H. pylori) infection, and H. pylori is a major causative agent of gastric cancer. Therefore, it has long been argued that H. pylori infection may affect the development of EBVaGC, a subtype of gastric cancer. Atrophic gastrointestinal inflammation, a symptom of H. pylori infection, is observed in the gastric mucosa of EBVaGC. Therefore, it remains unclear whether H. pylori infection is a cofactor for gastric carcinogenesis caused by EBV infection or whether H. pylori and EBV infections act independently on gastric cancer formation. It has been reported that EBV infection assists in the onco-genesis of gastric cancer caused by H. pylori infection. In contrast, several studies have reported that H. pylori infection accelerates tumorigenesis initiated by EBV infection. By reviewing both clinical epidemiological and experimental data, we reorganized the role of H. pylori and EBV infections in gastric cancer formation.
Collapse
Affiliation(s)
- Hisashi Iizasa
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| | - Andy Visi Kartika
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
- Faculty of Medicine, Muslim University of Indonesia, Makassar 90231, Indonesia
| | - Sintayehu Fekadu
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
- Department of Medical Microbiology and Parasitology, Hawassa University, College of Medicine and Health Science, Hawassa 1560, Ethiopia
| | - Shunpei Okada
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| | - Daichi Onomura
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| | | | - Mosammat Mahmuda Khatun
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| | - Thin Myat Moe
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| | - Jun Nishikawa
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| |
Collapse
|
|
4
|
MC180295 Inhibited Epstein–Barr Virus-Associated Gastric Carcinoma Cell Growth by Suppressing DNA Repair and the Cell Cycle. Int J Mol Sci 2022; 23:ijms231810597. [PMID: 36142506 PMCID: PMC9500863 DOI: 10.3390/ijms231810597] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 08/29/2022] [Accepted: 09/08/2022] [Indexed: 11/16/2022] Open
Abstract
DNA methylation of both viral and host DNA is one of the major mechanisms involved in the development of Epstein–Barr virus-associated gastric carcinoma (EBVaGC); thus, epigenetic treatment using demethylating agents would seem to be promising. We have verified the effect of MC180295, which was discovered by screening for demethylating agents. MC180295 inhibited cell growth of the EBVaGC cell lines YCCEL1 and SNU719 in a dose-dependent manner. In a cell cycle analysis, growth arrest and apoptosis were observed in both YCCEL1 and SNU719 cells treated with MC180295. MKN28 cells infected with EBV were sensitive to MC180295 and showed more significant inhibition of cell growth compared to controls without EBV infection. Serial analysis of gene expression analysis showed the expression of genes belonging to the role of BRCA1 in DNA damage response and cell cycle control chromosomal replication to be significantly reduced after MC180295 treatment. We confirmed with quantitative PCR that the expression levels of BRCA2, FANCM, RAD51, TOP2A, and CDC45 were significantly decreased by MC180295. LMP1 and BZLF1 are EBV genes with expression that is epigenetically regulated, and MC180295 could up-regulate their expression. In conclusion, MC180295 inhibited the growth of EBVaGC cells by suppressing DNA repair and the cell cycle.
Collapse
|
|
5
|
Epstein-Barr Virus miR-BART1-3p Regulates the miR-17-92 Cluster by Targeting E2F3. Int J Mol Sci 2021; 22:ijms222010936. [PMID: 34681596 PMCID: PMC8539899 DOI: 10.3390/ijms222010936] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 12/21/2022] Open
Abstract
Epstein-Barr virus (EBV) is associated with several tumors and generates BamHI A rightward transcript (BART) microRNAs (miRNAs) from BART transcript introns. These BART miRNAs are expressed at higher levels in EBV-associated epithelial malignancies than in EBV-infected B lymphomas. To test the effects of EBV miRNA on the cell cycle and cell growth, we transfected miR-BART1-3p, a highly expressed EBV-associated miRNA, into gastric carcinoma cells. We found that miR-BART1-3p induced G0/G1 arrest and suppressed cell growth in gastric carcinoma cells. As our microarray analyses showed that E2F3, a cell cycle regulator, was inhibited by EBV infection, we hypothesized that miR-BART1-3p regulates E2F3. Luciferase assays revealed that miR-BART1-3p directly targeted the 3′-UTR of E2F3 mRNA. Both E2F3 mRNA and encoded protein levels were reduced following miR-BART1-3p transfection. In contrast, E2F3 expression in AGS-EBV cells transfected with a miR-BART1-3p inhibitor was enhanced. As E2F3 has been shown to regulate the expression of highly conserved miR-17-92 clusters in vertebrates, we examined whether this expression is affected by miR-BART1-3p, which can downregulate E2F3. The expression of E2F3, miR-17-92a-1 cluster host gene (MIR17HG), and miR-17-92 cluster miRNAs was significantly reduced in EBV-associated gastric carcinoma (EBVaGC) patients compared with EBV-negative gastric carcinoma (EBVnGC) patients. Further, miR-BART1-3p as well as the siRNA specific to E2F3 inhibited the expression of the miR-17-92 cluster, while inhibition of miR-BART1-3p enhanced the expression of the miR-17-92 cluster in cultured GC cells. Our results suggest a possible role of miR-BART1-3p in cell cycle regulation and in regulation of the miR-17-92 cluster through E2F3 suppression.
Collapse
|
|
6
|
Chen K, Wang M, Zhang R, Li J. Detection of Epstein-Barr virus encoded RNA in fixed cells and tissues using CRISPR/Cas-mediated RCasFISH. Anal Biochem 2021; 625:114211. [PMID: 33915117 DOI: 10.1016/j.ab.2021.114211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 03/15/2021] [Accepted: 04/13/2021] [Indexed: 12/12/2022]
Abstract
Identification of Epstein-Barr virus (EBV)-infected cells is critical for the diagnosis and clinical management of EBV-associated diseases. EBV-encoded RNA (EBER) located in the nucleus is a reliable marker due to its high levels of expression and inherent stability in tissue specimens. EBER in situ hybridization has long been the gold standard for detecting tumor-associated latent EBV infection and is valuable in determining the primary site and radiation fields of EBV-related malignancies. However, reliable detection is somewhat restricted by diffused signal and time-consuming procedure of this method, especially when proteins and RNA needed to be labeled simultaneously. Here, we optimized and validated our CRISPR-dCas9 mediated in situ RNA imaging tool-RCasFISH that enabled us to detect EBER rapidly and was compatible with IHC methods in fixed cells and tissue sections. Our approach could provide an attractive alternative for the molecular diagnosis of latent EBV infection.
Collapse
Affiliation(s)
- Kun Chen
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, 100730, PR China; Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, 100730, PR China
| | - Meng Wang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, 100730, PR China; Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, 100730, PR China
| | - Rui Zhang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, 100730, PR China; Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, 100730, PR China.
| | - Jinming Li
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, 100730, PR China; Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, 100730, PR China.
| |
Collapse
|
|
7
|
Re VD, Brisotto G, Repetto O, De Zorzi M, Caggiari L, Zanussi S, Alessandrini L, Canzonieri V, Miolo G, Puglisi F, Belluco C, Steffan A, Cannizzaro R. Overview of Epstein-Barr-Virus-Associated Gastric Cancer Correlated with Prognostic Classification and Development of Therapeutic Options. Int J Mol Sci 2020; 21:E9400. [PMID: 33321820 PMCID: PMC7764600 DOI: 10.3390/ijms21249400] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer (GC) is a deadly disease with poor prognosis that is characterized by heterogeneity. New classifications based on histologic features, genotypes, and molecular phenotypes, for example, the Cancer Genome Atlas subtypes and those by the Asian Cancer Research Group, help understand the carcinogenic differences in GC and have led to the identification of an Epstein-Barr virus (EBV)-related GC subtype (EBVaGC), providing new indications for tailored treatment and prognostic factors. This article provides a review of the features of EBVaGC and an update on the latest insights from EBV-related research with a particular focus on the strict interaction between EBV infection and the gastric tumor environment, including the host immune response. This information may help increase our knowledge of EBVaGC pathogenesis and the mechanisms that sustain the immune response of patients since this mechanism has been demonstrated to offer a survival advantage in a proportion of patients with GC.
Collapse
Affiliation(s)
- Valli De Re
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Giulia Brisotto
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Ombretta Repetto
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Mariangela De Zorzi
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Laura Caggiari
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Stefania Zanussi
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Lara Alessandrini
- Pathology, Department of Medicine DIMED, University of Padova, 61-35121 Padova, Italy;
| | - Vincenzo Canzonieri
- Surgical and Health Sciences, Department of Medical, University of Trieste Medical School, 34100 Trieste, Italy;
- Pathology, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
| | - Gianmaria Miolo
- Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy; (G.M.); (F.P.)
| | - Fabio Puglisi
- Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy; (G.M.); (F.P.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Claudio Belluco
- Surgical Oncology, Department of Surgery, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy;
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Renato Cannizzaro
- Gastroenterology, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy;
| |
Collapse
|
|
8
|
Epstein-Barr virus-associated gastric cancer: A distinct subtype. Cancer Lett 2020; 495:191-199. [PMID: 32979463 DOI: 10.1016/j.canlet.2020.09.019] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/28/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022]
Abstract
Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a common malignant tumor associated with EBV infection. The molecular classification of gastric carcinoma indicates that EBVaGC is a distinct subtype in terms of oncogenesis and molecular features. Viral proteins, Bam-HI-A rightward transcripts (BART) miRNAs, and Bam-HI A rightward frame 1 (BARF1) promote oncogenesis after EBV infection via the induction of methylation, regulation of host gene expression, and malignant transformation. Together with abnormal mutations and amplification of the host genome as driving factors, interactions between the EBV genome and host genome accelerate carcinogenesis. The molecular profile of EBVaGC is that of EBV driving DNA hypermethylation, frequent phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, and the overexpression of Janus kinase 2 (JAK2), programmed death ligand-1 (PD-L1), and PD-L2. Clinically, the frequency of lymph node metastasis is lower, and the prognosis is better for EBVaGC than EBV-negative gastric cancer (EBVnGC). Pathologically, EBVaGC is a gastric adenocarcinoma with lymphoid stroma. This review interprets how the EBV genome is involved in the oncogenesis of gastric cancer and describes the molecular and clinicopathological features of EBVaGC.
Collapse
|
|
9
|
Bu W, Joyce MG, Nguyen H, Banh DV, Aguilar F, Tariq Z, Yap ML, Tsujimura Y, Gillespie RA, Tsybovsky Y, Andrews SF, Narpala SR, McDermott AB, Rossmann MG, Yasutomi Y, Nabel GJ, Kanekiyo M, Cohen JI. Immunization with Components of the Viral Fusion Apparatus Elicits Antibodies That Neutralize Epstein-Barr Virus in B Cells and Epithelial Cells. Immunity 2019; 50:1305-1316.e6. [PMID: 30979688 PMCID: PMC6660903 DOI: 10.1016/j.immuni.2019.03.010] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/16/2019] [Accepted: 03/12/2019] [Indexed: 12/22/2022]
Abstract
Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with epithelial-cell cancers and B cell lymphomas. An effective EBV vaccine is not available. We found that antibodies to the EBV glycoprotein gH/gL complex were the principal components in human plasma that neutralized infection of epithelial cells and that antibodies to gH/gL and gp42 contributed to B cell neutralization. Immunization of mice and nonhuman primates with nanoparticle vaccines that displayed components of the viral-fusion machinery EBV gH/gL or gH/gL/gp42 elicited antibodies that potently neutralized both epithelial-cell and B cell infection. Immune serum from nonhuman primates inhibited EBV-glycoprotein-mediated fusion of epithelial cells and B cells and targeted an epitope critical for virus-cell fusion. Therefore, unlike the leading EBV gp350 vaccine candidate, which only protects B cells from infection, these EBV nanoparticle vaccines elicit antibodies that inhibit the virus-fusion apparatus and provide cell-type-independent protection from virus infection.
Collapse
Affiliation(s)
- Wei Bu
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - M Gordon Joyce
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA
| | - Hanh Nguyen
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dalton V Banh
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Fiona Aguilar
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Zeshan Tariq
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Moh Lan Yap
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA; Present address: Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, 31900 Kampar, Perak, Malaysia
| | - Yusuke Tsujimura
- Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, Ibaraki 305-0843, Japan
| | - Rebecca A Gillespie
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yaroslav Tsybovsky
- Electron Microscopy Laboratory, Advanced Research Technology Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
| | - Sarah F Andrews
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sandeep R Narpala
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Adrian B McDermott
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Michael G Rossmann
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Yasuhiro Yasutomi
- Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, Ibaraki 305-0843, Japan
| | - Gary J Nabel
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Masaru Kanekiyo
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jeffrey I Cohen
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
| |
Collapse
|
|
10
|
Choi SJ, Ryu E, Lee S, Huh S, Shin YS, Kang BW, Kim JG, Cho H, Kang H. Adenosine Induces EBV Lytic Reactivation through ADORA1 in EBV-Associated Gastric Carcinoma. Int J Mol Sci 2019; 20:ijms20061286. [PMID: 30875759 PMCID: PMC6471230 DOI: 10.3390/ijms20061286] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 02/28/2019] [Accepted: 03/03/2019] [Indexed: 02/07/2023] Open
Abstract
Cordyceps species are known to contain numerous bioactive compounds, including cordycepin. Extracts of Cordyceps militaris (CME) are used in diverse medicinal purposes because of their bioactive components. Cordycepin, one of the active components of CME, exhibits anti-proliferative, pro-apoptotic, and anti-inflammatory effects. Cordycepin structurally differs from adenosine in that its ribose lacks an oxygen atom at the 3′ position. We previously reported that cordycepin suppresses Epstein–Barr virus (EBV) gene expression and lytic replication in EBV-associated gastric carcinoma (EBVaGC). However, other studies reported that cordycepin induces EBV gene expression and lytic reactivation. Thus, it was reasonable to clarify the bioactive effects of CME bioactive compounds on the EBV life cycle. We first confirmed that CME preferentially induces EBV gene expression and lytic reactivation; second, we determined that adenosine in CME induces EBV gene expression and lytic reactivation; third, we discovered that the adenosine A1 receptor (ADORA1) is required for adenosine to initiate signaling for upregulating BZLF1, which encodes for a key EBV regulator (Zta) of the EBV lytic cycle; finally, we showed that BZLF1 upregulation by adenosine leads to delayed tumor development in the EBVaGC xenograft mouse model. Taken together, these results suggest that adenosine is an EBV lytic cycle inducer that inhibits EBVaGC development.
Collapse
Affiliation(s)
- Su Jin Choi
- College of Pharmacy and Cancer Research Institute and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
| | - Eunhyun Ryu
- College of Pharmacy and Cancer Research Institute and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
| | - Seulki Lee
- College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul 01369, Korea.
| | - Sora Huh
- College of Pharmacy and Cancer Research Institute and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
| | - Yu Su Shin
- Department of Medical Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong 27709, Korea.
| | - Byung Woog Kang
- Department of Oncology/Hematology and Cancer Research Institute and School of Medicine, Kyungpook National University Hospital and Kyungpook National University, Daegu 41404, Korea.
| | - Jong Gwang Kim
- Department of Oncology/Hematology and Cancer Research Institute and School of Medicine, Kyungpook National University Hospital and Kyungpook National University, Daegu 41404, Korea.
| | - Hyosun Cho
- College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul 01369, Korea.
| | - Hyojeung Kang
- College of Pharmacy and Cancer Research Institute and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
| |
Collapse
|
|
11
|
Infection of Epstein⁻Barr Virus in Type III Latency Modulates Biogenesis of Exosomes and the Expression Profile of Exosomal miRNAs in the Burkitt Lymphoma Mutu Cell Lines. Cancers (Basel) 2018; 10:cancers10070237. [PMID: 30029522 PMCID: PMC6071279 DOI: 10.3390/cancers10070237] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 12/15/2022] Open
Abstract
Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is associated with various malignancies in B lymphocytes and epithelial cells. EBV encodes 49 microRNAs in two separated regions, termed the BART and BHRF1 loci. Although accumulating evidence demonstrates that EBV infection regulates the profile of microRNAs in the cells, little is known about the microRNAs in exosomes released from infected cells. Here, we characterized the expression profile of intracellular and exosomal microRNAs in EBV-negative, and two related EBV-infected Burkitt lymphoma cell lines having type I and type III latency by next-generation sequencing. We found that the biogenesis of exosomes is upregulated in type III latently infected cells compared with EBV-negative and type I latently infected cells. We also observed that viral and several specific host microRNAs were predominantly incorporated in the exosomes released from the cells in type III latency. We confirmed that multiple viral microRNAs were transferred to the epithelial cells cocultured with EBV-infected B cells. Our findings indicate that EBV infection, in particular in type III latency, modulates the biogenesis of exosomes and the profile of exosomal microRNAs, potentially contributing to phenotypic changes in cells receiving these exosomes.
Collapse
|
|
12
|
Nanbo A, Ohashi M, Yoshiyama H, Ohba Y. The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission. Front Microbiol 2018; 9:984. [PMID: 29867885 PMCID: PMC5962739 DOI: 10.3389/fmicb.2018.00984] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 04/26/2018] [Indexed: 01/01/2023] Open
Abstract
Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is closely linked to various lymphoid and epithelial malignancies. Previous studies demonstrated that the efficiency of EBV infection in epithelial cells is significantly enhanced by coculturing them with latently infected B cells relative to cell-free infection, suggesting that cell-to-cell contact-mediated viral transmission is the dominant mode of infection by EBV in epithelial cells. However, a detailed mechanism underlying this process has not been fully understood. In the present study, we assessed the role of transforming growth factor β (TGF-β), which is known to induce EBV's lytic cycle by upregulation of EBV's latent-lytic switch BZLF1 gene. We have found that 5 days of cocultivation facilitated cell-to-cell contact-mediated EBV transmission. Replication of EBV was induced in cocultured B cells both with and without a direct cell contact in a time-dependent manner. Treatment of a blocking antibody for TGF-β suppressed both induction of the lytic cycle in cocultured B cells and subsequent viral transmission. Cocultivation with epithelial cells facilitated expression of TGF-β receptors in B cells and increased their susceptibility to TGF-β. Finally, we confirmed the spontaneous secretion of TGF-β from epithelial cells, which was not affected by cell-contact. In contrast, the extracellular microvesicles, exosomes derived from cocultured cells partly contributed to cell-to-cell contact-mediated viral transmission. Taken together, our findings support a role for TGF-β derived from epithelial cells in efficient viral transmission, which fosters induction of the viral lytic cycle in the donor B cells.
Collapse
Affiliation(s)
- Asuka Nanbo
- Department of Cell Physiology, Faculty and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Makoto Ohashi
- Department of Oncology, University of Wisconsin, Madison, WI, United States
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo, Japan
| | - Yusuke Ohba
- Department of Cell Physiology, Faculty and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| |
Collapse
|
|
13
|
Tsai MH, Lin X, Shumilov A, Bernhardt K, Feederle R, Poirey R, Kopp-Schneider A, Pereira B, Almeida R, Delecluse HJ. The biological properties of different Epstein-Barr virus strains explain their association with various types of cancers. Oncotarget 2018; 8:10238-10254. [PMID: 28052012 PMCID: PMC5354655 DOI: 10.18632/oncotarget.14380] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 12/15/2016] [Indexed: 12/27/2022] Open
Abstract
The Epstein-Barr virus (EBV) is etiologically associated with the development of multiple types of tumors, but it is unclear whether this diversity is due to infection with different EBV strains. We report a comparative characterization of SNU719, GP202, and YCCEL1, three EBV strains that were isolated from gastric carcinomas, M81, a virus isolated in a nasopharyngeal carcinoma and several well-characterized laboratory type A strains. We found that B95-8, Akata and GP202 induced cell growth more efficiently than YCCEL1, SNU719 and M81 and this correlated positively with the expression levels of the viral BHRF1 miRNAs. In infected B cells, all strains except Akata and B95-8 induced lytic replication, a risk factor for carcinoma development, although less efficiently than M81. The panel of viruses induced tumors in immunocompromised mice with variable speed and efficacy that did not strictly mirror their in vitro characteristics, suggesting that additional parameters play an important role. We found that YCCEL1 and M81 infected primary epithelial cells, gastric carcinoma cells and gastric spheroids more efficiently than Akata or B95-8. Reciprocally, Akata and B95-8 had a stronger tropism for B cells than YCCEL1 or M81. These data suggest that different EBV strains will induce the development of lymphoid tumors with variable efficacy in immunocompromised patients and that there is a parallel between the cell tropism of the viral strains and the lineage of the tumors they induce. Thus, EBV strains can be endowed with properties that will influence their transforming abilities and the type of tumor they induce.
Collapse
Affiliation(s)
- Ming-Han Tsai
- German Cancer Research Centre (DKFZ), Unit F100, 69120 Heidelberg, Germany.,Inserm unit U1074, DKFZ, 69120 Heidelberg, Germany
| | - Xiaochen Lin
- German Cancer Research Centre (DKFZ), Unit F100, 69120 Heidelberg, Germany.,Inserm unit U1074, DKFZ, 69120 Heidelberg, Germany
| | - Anatoliy Shumilov
- German Cancer Research Centre (DKFZ), Unit F100, 69120 Heidelberg, Germany.,Inserm unit U1074, DKFZ, 69120 Heidelberg, Germany
| | - Katharina Bernhardt
- German Cancer Research Centre (DKFZ), Unit F100, 69120 Heidelberg, Germany.,Inserm unit U1074, DKFZ, 69120 Heidelberg, Germany
| | - Regina Feederle
- German Cancer Research Centre (DKFZ), Unit F100, 69120 Heidelberg, Germany.,Inserm unit U1074, DKFZ, 69120 Heidelberg, Germany.,Institute for Diabetes and Obesitas, Monoclonal Antibody Core Facility, German Research Center for Environmental Health, Helmholtz Zentrum München, 81377 Munich, Germany
| | - Remy Poirey
- German Cancer Research Centre (DKFZ), Unit F100, 69120 Heidelberg, Germany.,Inserm unit U1074, DKFZ, 69120 Heidelberg, Germany
| | | | - Bruno Pereira
- Differentiation and Cancer Group, IPATIMUP, Rua Dr Roberto Frias s/n, 4200 - 465 Porto, Portugal
| | - Raquel Almeida
- Differentiation and Cancer Group, IPATIMUP, Rua Dr Roberto Frias s/n, 4200 - 465 Porto, Portugal
| | - Henri-Jacques Delecluse
- German Cancer Research Centre (DKFZ), Unit F100, 69120 Heidelberg, Germany.,Inserm unit U1074, DKFZ, 69120 Heidelberg, Germany
| |
Collapse
|
|
14
|
Singh S, Jha HC. Status of Epstein-Barr Virus Coinfection with Helicobacter pylori in Gastric Cancer. JOURNAL OF ONCOLOGY 2017; 2017:3456264. [PMID: 28421114 PMCID: PMC5379099 DOI: 10.1155/2017/3456264] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 02/14/2017] [Indexed: 12/14/2022]
Abstract
Epstein-Barr virus is a ubiquitous human herpesvirus whose primary infection causes mononucleosis, Burkett's lymphoma, nasopharyngeal carcinoma, autoimmune diseases, and gastric cancer (GC). The persistent infection causes malignancies in lymph and epithelial cells. Helicobacter pylori causes gastritis in human with chronic inflammation. This chronic inflammation is thought to be the cause of genomic instability. About 45%-word population have a probability of having both pathogens, namely, H. pylori and EBV. Approximately 180 per hundred thousand population is developing GC along with many gastric abnormalities. This makes GC the third leading cause of cancer-related death worldwide. Although lots of research are carried out individually for EBV and H. pylori, still there are very few reports available on coinfection of both pathogens. Recent studies suggested that EBV and H. pylori coinfection increases the occurrence of GC as well as the early age of GC detection comparing to individual infection. The aim of this review is to present status on coinfection of both pathogens and their association with GC.
Collapse
Affiliation(s)
- Shyam Singh
- Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, India
| | - Hem Chandra Jha
- Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, India
| |
Collapse
|
|
15
|
Matsusaka K, Kaneda A. DNA and Histone Methylation in Gastric Cancer. CANCER DRUG DISCOVERY AND DEVELOPMENT 2017:377-390. [DOI: 10.1007/978-3-319-59786-7_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
16
|
Nanbo A, Kachi K, Yoshiyama H, Ohba Y. Epstein–Barr virus exploits host endocytic machinery for cell-to-cell viral transmission rather than a virological synapse. J Gen Virol 2016; 97:2989-3006. [DOI: 10.1099/jgv.0.000605] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Asuka Nanbo
- Department of Cell Physiology, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo, Japan
| | - Kunihiro Kachi
- Graduate School of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo, Japan
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane, Japan
| | - Yusuke Ohba
- Department of Cell Physiology, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo, Japan
| |
Collapse
|
|
17
|
Makielski KR, Lee D, Lorenz LD, Nawandar DM, Chiu YF, Kenney SC, Lambert PF. Human papillomavirus promotes Epstein-Barr virus maintenance and lytic reactivation in immortalized oral keratinocytes. Virology 2016; 495:52-62. [PMID: 27179345 DOI: 10.1016/j.virol.2016.05.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 05/05/2016] [Accepted: 05/06/2016] [Indexed: 11/18/2022]
Abstract
Epstein-Barr virus and human papillomaviruses are human tumor viruses that infect and replicate in upper aerodigestive tract epithelia and cause head and neck cancers. The productive phases of both viruses are tied to stratified epithelia highlighting the possibility that these viruses may affect each other's life cycles. Our lab has established an in vitro model system to test the effects of EBV and HPV co-infection in stratified squamous oral epithelial cells. Our results indicate that HPV increases maintenance of the EBV genome in the co-infected cells and promotes lytic reactivation of EBV in upper layers of stratified epithelium. Expression of the HPV oncogenes E6 and E7 were found to be necessary and sufficient to account for HPV-mediated lytic reactivation of EBV. Our findings indicate that HPV increases the capacity of epithelial cells to support the EBV life cycle, which could in turn increase EBV-mediated pathogenesis in the oral cavity.
Collapse
Affiliation(s)
- Kathleen R Makielski
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, United States
| | - Denis Lee
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, United States
| | - Laurel D Lorenz
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, United States
| | - Dhananjay M Nawandar
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, United States
| | - Ya-Fang Chiu
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, United States; Morgridge Institute for Research, University of Wisconsin-Madison, 330 N. Orchard Street, Madison, WI 53715, United States
| | - Shannon C Kenney
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, United States
| | - Paul F Lambert
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, United States.
| |
Collapse
|
|
18
|
Jha HC, Banerjee S, Robertson ES. The Role of Gammaherpesviruses in Cancer Pathogenesis. Pathogens 2016; 5:pathogens5010018. [PMID: 26861404 PMCID: PMC4810139 DOI: 10.3390/pathogens5010018] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 01/27/2016] [Indexed: 12/15/2022] Open
Abstract
Worldwide, one fifth of cancers in the population are associated with viral infections. Among them, gammaherpesvirus, specifically HHV4 (EBV) and HHV8 (KSHV), are two oncogenic viral agents associated with a large number of human malignancies. In this review, we summarize the current understanding of the molecular mechanisms related to EBV and KSHV infection and their ability to induce cellular transformation. We describe their strategies for manipulating major cellular systems through the utilization of cell cycle, apoptosis, immune modulation, epigenetic modification, and altered signal transduction pathways, including NF-kB, Notch, Wnt, MAPK, TLR, etc. We also discuss the important EBV latent antigens, namely EBNA1, EBNA2, EBNA3’s and LMP’s, which are important for targeting these major cellular pathways. KSHV infection progresses through the engagement of the activities of the major latent proteins LANA, v-FLIP and v-Cyclin, and the lytic replication and transcription activator (RTA). This review is a current, comprehensive approach that describes an in-depth understanding of gammaherpes viral encoded gene manipulation of the host system through targeting important biological processes in viral-associated cancers.
Collapse
Affiliation(s)
- Hem Chandra Jha
- Department of Microbiology and Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 201E Johnson Pavilion, 3610, Hamilton Walk, Philadelphia, PA 19104, USA.
| | - Shuvomoy Banerjee
- Department of Microbiology and Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 201E Johnson Pavilion, 3610, Hamilton Walk, Philadelphia, PA 19104, USA.
| | - Erle S Robertson
- Department of Microbiology and Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 201E Johnson Pavilion, 3610, Hamilton Walk, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
19
|
Stamatiou DP, Derdas SP, Zoras OL, Spandidos DA. Herpes and polyoma family viruses in thyroid cancer. Oncol Lett 2016; 11:1635-1644. [PMID: 26998055 PMCID: PMC4774504 DOI: 10.3892/ol.2016.4144] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 01/26/2016] [Indexed: 02/06/2023] Open
Abstract
Thyroid cancer is considered the most common malignancy that affects the endocrine system. Generally, thyroid cancer derives from follicular epithelial cells, and thyroid cancer is divided into well-differentiated papillary (80% of cases) and follicular (15% of cases) carcinoma. Follicular thyroid cancer is further divided into the conventional and oncocytic (Hürthle cell) type, poorly differentiated carcinoma and anaplastic carcinoma. Both poorly differentiated and anaplastic carcinoma can arise either de novo, or secondarily from papillary and follicular thyroid cancer. The incidence of thyroid cancer has significantly increased for both males and females of all ages, particularly for females between 55–64 years of age, from 1999 through 2008. The increased rates refer to tumors of all stages, though they were mostly noted in localized disease. Recently, viruses have been implicated in the direct regulation of epithelial-mesenchymal transition (EMT) and the development of metastases. More specifically, Epstein-Barr virus (EBV) proteins may potentially lead to the development of metastasis through the regulation of the metastasis suppressor, Nm23, and the control of Twist expression. The significant enhancement of the metastatic potential, through the induction of angiogenesis and changes to the tumor microenvironment, subsequent to viral infection, has been documented, while EMT also contributes to cancer cell permissiveness to viruses. A number of viruses have been identified to be associated with carcinogenesis, and these include lymphotropic herpesviruses, namely EBV and Kaposi's sarcoma-associated herpesvirus [KSHV, also known as human herpesvirus type 8 (HHV8)]; two hepatitis viruses, hepatitis B virus (HBV) and hepatitis C virus (HCV); human papillomaviruses (HPVs); human T cell lymphoma virus (HTLV); and a new polyomavirus, Merkel cell polyomavirus identified in 2008. In this review, we examined the association between thyroid cancer and two oncogenic virus families, the herpes and polyoma family viruses, and we discuss their potential role as causative agents in thyroid carcinogenesis.
Collapse
Affiliation(s)
- Dimitris P Stamatiou
- Department of Surgical Oncology, University Hospital, University of Crete, Heraklion 71003, Greece; Laboratory of Clinical Virology, University of Crete, Medical School, Heraklion 71409, Greece
| | - Stavros P Derdas
- Laboratory of Clinical Virology, University of Crete, Medical School, Heraklion 71409, Greece
| | - Odysseas L Zoras
- Department of Surgical Oncology, University Hospital, University of Crete, Heraklion 71003, Greece
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, University of Crete, Medical School, Heraklion 71409, Greece
| |
Collapse
|
|
20
|
Xiao K, Yu Z, Li X, Li X, Tang K, Tu C, Qi P, Liao Q, Chen P, Zeng Z, Li G, Xiong W. Genome-wide Analysis of Epstein-Barr Virus (EBV) Integration and Strain in C666-1 and Raji Cells. J Cancer 2016; 7:214-24. [PMID: 26819646 PMCID: PMC4716855 DOI: 10.7150/jca.13150] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Accepted: 10/18/2015] [Indexed: 02/06/2023] Open
Abstract
EBV is a key risk factor for many malignancy diseases such as nasopharyngeal carcinoma (NPC) and Burkitt lymphoma (BL). EBV integration has been reported, but its scale and impact to cancer development is remains unclear. C666-1 (NPC cell line) and Raji (BL cell line) are commonly studied EBV-positive cancer cells. A rare few EBV integration sites in Raji were found in previous research by traditional methods. To deeply survey EBV integration, we sequenced C666-1 and Raji whole genomes by the next generation sequencing (NGS) technology and a total of 909 breakpoints were detected in the two cell lines. Moreover, we observed that the number of integration sites was positive correlated with the total amount of chromosome structural variations (SVs) and copy number structural variations (CNVs), and most breakpoints located inside or nearby genome structural variations regions. It suggested that host genome instability provided an opportunity for EBV integration on one hand and the integration aggravated host genome instability on the other hand. Then, we respectively assembled the C666-1 and Raji EBV strains which would be useful resources for EBV-relative studies. Thus, we report the most comprehensive characterization of EBV integration in NPC cell and BL cell, and EBV shows the wide range and random integration to increase the tumorigenesis. The NGS provides an incomparable level of resolution on EBV integration and a convenient approach to obtain viral strain compared to any research technology before.
Collapse
Affiliation(s)
- Kai Xiao
- 1. Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.; 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China.; 3. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Zhengyuan Yu
- 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China
| | - Xiayu Li
- 3. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Xiaoling Li
- 1. Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.; 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China.; 3. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Ke Tang
- 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China
| | - Chaofeng Tu
- 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China
| | - Peng Qi
- 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China
| | - Qianjin Liao
- 1. Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.; 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China
| | - Pan Chen
- 1. Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.; 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China
| | - Zhaoyang Zeng
- 1. Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.; 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China.; 3. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Guiyuan Li
- 1. Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.; 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China.; 3. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Wei Xiong
- 1. Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.; 2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China.; 3. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| |
Collapse
|
|
21
|
Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD-Mediated caspase-3-Dependent Apoptosis. J Virol 2015; 90:1359-68. [PMID: 26581978 DOI: 10.1128/jvi.02794-15] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 11/08/2015] [Indexed: 01/22/2023] Open
Abstract
UNLABELLED Epstein-Barr virus (EBV) is a human gammaherpesvirus associated with a variety of tumor types. EBV can establish latency or undergo lytic replication in host cells. In general, EBV remains latent in tumors and expresses a limited repertoire of latent proteins to avoid host immune surveillance. When the lytic cycle is triggered by some as-yet-unknown form of stimulation, lytic gene expression and progeny virus production commence. Thus far, the exact mechanism of EBV latency maintenance and the in vivo triggering signal for lytic induction have yet to be elucidated. Previously, we have shown that the EBV microRNA miR-BART20-5p directly targets the immediate early genes BRLF1 and BZLF1 as well as Bcl-2-associated death promoter (BAD) in EBV-associated gastric carcinoma. In this study, we found that both mRNA and protein levels of BRLF1 and BZLF1 were suppressed in cells following BAD knockdown and increased after BAD overexpression. Progeny virus production was also downregulated by specific knockdown of BAD. Our results demonstrated that caspase-3-dependent apoptosis is a prerequisite for BAD-mediated EBV lytic cycle induction. Therefore, our data suggest that miR-BART20-5p plays an important role in latency maintenance and tumor persistence of EBV-associated gastric carcinoma by inhibiting BAD-mediated caspase-3-dependent apoptosis, which would trigger immediate early gene expression. IMPORTANCE EBV has an ability to remain latent in host cells, including EBV-associated tumor cells hiding from immune surveillance. However, the exact molecular mechanisms of EBV latency maintenance remain poorly understood. Here, we demonstrated that miR-BART20-5p inhibited the expression of EBV immediate early genes indirectly, by suppressing BAD-induced caspase-3-dependent apoptosis, in addition to directly, as we previously reported. Our study suggests that EBV-associated tumor cells might endure apoptotic stress to some extent and remain latent with the aid of miR-BART20-5p. Blocking the expression or function of BART20-5p may expedite EBV-associated tumor cell death via immune attack and apoptosis.
Collapse
|
|
22
|
Wang HB, Zhang H, Zhang JP, Li Y, Zhao B, Feng GK, Du Y, Xiong D, Zhong Q, Liu WL, Du H, Li MZ, Huang WL, Tsao SW, Hutt-Fletcher L, Zeng YX, Kieff E, Zeng MS. Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells. Nat Commun 2015; 6:6240. [PMID: 25670642 PMCID: PMC4339892 DOI: 10.1038/ncomms7240] [Citation(s) in RCA: 130] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 01/08/2015] [Indexed: 02/07/2023] Open
Abstract
Epstein-Barr virus (EBV) is implicated as an aetiological factor in B lymphomas and nasopharyngeal carcinoma. The mechanisms of cell-free EBV infection of nasopharyngeal epithelial cells remain elusive. EBV glycoprotein B (gB) is the critical fusion protein for infection of both B and epithelial cells, and determines EBV susceptibility of non-B cells. Here we show that neuropilin 1 (NRP1) directly interacts with EBV gB(23-431). Either knockdown of NRP1 or pretreatment of EBV with soluble NRP1 suppresses EBV infection. Upregulation of NRP1 by overexpression or EGF treatment enhances EBV infection. However, NRP2, the homologue of NRP1, impairs EBV infection. EBV enters nasopharyngeal epithelial cells through NRP1-facilitated internalization and fusion, and through macropinocytosis and lipid raft-dependent endocytosis. NRP1 partially mediates EBV-activated EGFR/RAS/ERK signalling, and NRP1-dependent receptor tyrosine kinase (RTK) signalling promotes EBV infection. Taken together, NRP1 is identified as an EBV entry factor that cooperatively activates RTK signalling, which subsequently promotes EBV infection in nasopharyngeal epithelial cells.
Collapse
Affiliation(s)
- Hong-Bo Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Hua Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Jing-Ping Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Yan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Bo Zhao
- Department of Medicine and Microbiology and Molecular Genetics, Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Guo-Kai Feng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Yong Du
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Dan Xiong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Qian Zhong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Wan-Li Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Huamao Du
- College of Biotechnology, Southwest University, Chongqing 400715, People's Republic of China
| | - Man-Zhi Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Wen-Lin Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Sai Wah Tsao
- Department of Anatomy and Center for Cancer Research, University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Lindsey Hutt-Fletcher
- Department of Microbiology and Immunology, Louisiana State University, Health Science Center, Shreveport, Louisiana 71130, USA
| | - Yi-Xin Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| | - Elliott Kieff
- Department of Medicine and Microbiology and Molecular Genetics, Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People's Republic of China
| |
Collapse
|
|
23
|
Nishikawa J, Yoshiyama H, Iizasa H, Kanehiro Y, Nakamura M, Nishimura J, Saito M, Okamoto T, Sakai K, Suehiro Y, Yamasaki T, Oga A, Yanai H, Sakaida I. Epstein-barr virus in gastric carcinoma. Cancers (Basel) 2014; 6:2259-74. [PMID: 25386788 PMCID: PMC4276965 DOI: 10.3390/cancers6042259] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 09/27/2014] [Accepted: 10/28/2014] [Indexed: 12/28/2022] Open
Abstract
The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma, all tumor cells harbor the clonal EBV genome. Gastric carcinoma associated with EBV has distinct clinicopathological features, occurs predominately in men and in younger-aged individuals, and presents a generally diffuse histological type. Most cases of EBV-associated gastric carcinoma exhibit a histology rich in lymphocyte infiltration. The immunological reactiveness in the host may represent a relatively preferable prognosis in EBV-positive cases. This fact highlights the important role of EBV in the development of EBV-associated gastric carcinoma. We have clearly proved direct infection of human gastric epithelialcells by EBV. The infection was achieved by using a recombinant EBV. Promotion of growth by EBV infection was observed in the cells. Considerable data suggest that EBV may directly contribute to the development of EBV-associated GC. This tumor-promoting effect seems to involve multiple mechanisms, because EBV affects several host proteins and pathways that normally promote apoptosis and regulate cell proliferation.
Collapse
Affiliation(s)
- Jun Nishikawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo City, Shimane 693-8501, Japan.
| | - Hisashi Iizasa
- Department of Microbiology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo City, Shimane 693-8501, Japan.
| | - Yuichi Kanehiro
- Department of Microbiology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo City, Shimane 693-8501, Japan.
| | - Munetaka Nakamura
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Junichi Nishimura
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Mari Saito
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Takeshi Okamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Kouhei Sakai
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Yutaka Suehiro
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Takahiro Yamasaki
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Atsunori Oga
- Department of Pathology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Hideo Yanai
- Department of Clinical Research, National Hospital Organization Kanmon Medical Center, 1-1 Sotoura, Chofu, Shimonoseki, Yamaguchi 752-8510, Japan.
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| |
Collapse
|
|
24
|
Kim H, Choi H, Lee SK. Epstein-Barr virus miR-BART20-5p regulates cell proliferation and apoptosis by targeting BAD. Cancer Lett 2014; 356:733-42. [PMID: 25449437 DOI: 10.1016/j.canlet.2014.10.023] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 10/22/2014] [Accepted: 10/22/2014] [Indexed: 12/11/2022]
Abstract
Although Epstein-Barr virus (EBV) BamHI A rightward transcript (BART) microRNAs (miRNAs) are ubiquitously expressed in EBV-associated tumors, the role of most BART miRNAs is unclear. In this study, we showed that Bcl-2-associated death promoter (BAD) expression was significantly lower in EBV-infected AGS-EBV cells than in EBV-negative AGS cells and investigated whether BART miRNAs target BAD. Using bioinformatics analysis, five BART miRNAs showing seed match with the 3' untranslated region (3'-UTR) of BAD were selected. Of these, only miR-BART20-5p reduced BAD expression when individually transfected into AGS cells. A luciferase assay revealed that miR-BART20-5p directly targets BAD. The expression of BAD mRNA and protein was decreased by miR-BART20-5p and increased by an inhibitor of miR-BART20-5p. PE-Annexin V staining and cell proliferation assays showed that miR-BART20-5p reduced apoptosis and enhanced cell growth. Furthermore, miR-BART20-5p increased chemoresistance to 5-fluorouracil and docetaxel. Our data suggest that miR-BART20-5p contributes to tumorigenesis of EBV-associated gastric carcinoma by directly targeting the 3'-UTR of BAD.
Collapse
Affiliation(s)
- Hyoji Kim
- Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, South Korea
| | - Hoyun Choi
- Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, South Korea
| | - Suk Kyeong Lee
- Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, South Korea.
| |
Collapse
|
|
25
|
Tsang CM, Deng W, Yip YL, Zeng MS, Lo KW, Tsao SW. Epstein-Barr virus infection and persistence in nasopharyngeal epithelial cells. CHINESE JOURNAL OF CANCER 2014; 33:549-55. [PMID: 25223910 PMCID: PMC4244318 DOI: 10.5732/cjc.014.10169] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epstein-Barr virus (EBV) infection is closely associated with undifferentiated nasopharyngeal carcinoma (NPC), strongly implicating a role for EBV in NPC pathogenesis; conversely, EBV infection is rarely detected in normal nasopharyngeal epithelial tissues. In general, EBV does not show a strong tropism for infecting human epithelial cells, and EBV infection in oropharyngeal epithelial cells is believed to be lytic in nature. To establish life-long infection in humans, EBV has evolved efficient strategies to infect B cells and hijack their cellular machinery for latent infection. Lytic EBV infection in oropharyngeal epithelial cells, though an infrequent event, is believed to be a major source of infectious EBV particles for salivary transmission. The biological events associated with nasopharyngeal epithelial cells are only beginning to be understood with the advancement of EBV infection methods and the availability of nasopharyngeal epithelial cell models for EBV infection studies. EBV infection in human epithelial cells is a highly inefficient process compared to that in B cells, which express the complement receptor type 2 (CR2) to mediate EBV infection. Although receptor(s) on the epithelial cell surface for EBV infection remain(s) to be identified, EBV infection in epithelial cells could be achieved via the interaction of glycoproteins on the viral envelope with surface integrins on epithelial cells, which might trigger membrane fusion to internalize EBV in cells. Normal nasopharyngeal epithelial cells are not permissive for latent EBV infection, and EBV infection in normal nasopharyngeal epithelial cells usually results in growth arrest. However, genetic alterations in premalignant nasopharyngeal epithelial cells, including p16 deletion and cyclin D1 overexpression, could override the growth inhibitory effect of EBV infection to support stable and latent EBV infection in nasopharyngeal epithelial cells. The EBV episome in NPC is clonal in nature, suggesting that NPC develops from a single EBV-infected nasopharyngeal epithelial cell, and the establishment of persistent and latent EBV infection in premalignant nasopharyngeal epithelium may represent an early and critical event for NPC development.
Collapse
Affiliation(s)
- Chi Man Tsang
- Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | | | | | | | | | | |
Collapse
|
|
26
|
Murata T, Sato Y, Kimura H. Modes of infection and oncogenesis by the Epstein-Barr virus. Rev Med Virol 2014; 24:242-53. [PMID: 24578255 DOI: 10.1002/rmv.1786] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 01/19/2014] [Accepted: 01/23/2014] [Indexed: 12/15/2022]
Abstract
The EBV is a human γ-herpesvirus associated with various neoplasms. It is responsible for causing cancers of B, T, and NK cells as well as cells of epithelial origin. Such diversity in target cells and the complicated steps of oncogenesis are perplexing when we speculate about the mechanisms of action of EBV-positive cancers. Here, we first note three common features that contribute to the development and maintenance of EBV-positive cancers: effects of EBV oncogenes, immunosuppression and evasion/exploitation of the immune system, and genetic and epigenetic predisposition/alteration of the host genome. Then, we demonstrate the mechanisms of oncogenesis and the means by which each EBV-positive cancer develops, with particular focus on the mode of EBV infection. The EBV has two alternative life cycles: lytic and latent. The latter is categorized into four programs (latency types 0-III) in which latent viral genes are expressed differentially depending on the tissue of origin and state of cells. The production of viral latent genes tends to decrease with an increase in time, and, in an approximate manner, the expression levels of viral genes are inversely correlated with the degree of abnormalities in the host genome. Occasional execution of the viral lytic cycle also contributes to oncogenesis. Understanding this life cycle of the EBV and its relevance in oncogenesis may provide valuable clues to the development of effective therapies for the associated cancers.
Collapse
Affiliation(s)
- Takayuki Murata
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Virology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | | | | |
Collapse
|
|
27
|
Abstract
Epstein-Barr virus (EBV) is a member of gamma-herpesvirus, which can cause various types of tumor. Coexisting with the host for a long period of time, it has evolved unique and sophisticated strategy for survival by taking complicated, tactical modes of infection. Such modes include latent and lytic infections, and latent state is further categorized into four types. Differences and transitions in such lifestyles are significantly associated not only with virus amplification, but also with pathology and advancement of the disorders. I here review oncogenesis and pathogenesis of EBV-related disorders, especially focusing on our recent results on the modes of EBV infection.
Collapse
|
|
28
|
Companioni O, Bonet C, Muñoz X, Weiderpass E, Panico S, Tumino R, Palli D, Agnoli C, Vineis P, Boutron-Ruault MC, Racine A, Clavel-Chapelon F, Travis RC, Khaw KT, Riboli E, Murphy N, Vergnaud AC, Trichopoulou A, Benetou V, Trichopoulos D, Lund E, Johansen D, Lindkvist B, Johansson M, Sund M, Ardanaz E, Sánchez-Cantalejo E, Huerta JM, Dorronsoro M, Ramón Quirós J, Tjonneland A, Mortensen LM, Overvad K, Chang-Claude J, Rizzato C, Boeing H, Bueno-de-Mesquita HB, Bueno de Mesquita HB, Siersema P, Peeters PHM, Numans ME, Carneiro F, Licaj I, Freisling H, Sala N, González CA. Polymorphisms of Helicobacter pylori signaling pathway genes and gastric cancer risk in the European Prospective Investigation into Cancer-Eurgast cohort. Int J Cancer 2014; 134:92-101. [PMID: 23824692 DOI: 10.1002/ijc.28357] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 04/16/2013] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccharide and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while NFKB1 activates the transcription of pro-inflammatory cytokines to elicit an immune response. Single nucleotide polymorphisms (SNPs) in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1,284 matched controls from the European Prospective Investigation into Cancer cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log-additive model, we found a significant association between SNPs in CD14, NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant (p = 0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC (p = 0.0003) and CD14 with cardia GC (p = 0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results, we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC.
Collapse
Affiliation(s)
- Osmel Companioni
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, Barcelona, 08908, Spain
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Exosomes derived from Epstein-Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells. J Virol 2013; 87:10334-47. [PMID: 23864627 DOI: 10.1128/jvi.01310-13] [Citation(s) in RCA: 273] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Epstein-Barr virus (EBV), a human gammaherpesvirus, establishes a lifelong latent infection in B lymphocytes and epithelial cells following primary infection. Several lines of evidence suggest that exosomes derived from EBV-infected cells are internalized and transfer viral factors, including EBV-encoded latent membrane protein and microRNAs, to the recipient cells. However, the detailed mechanism by which exosomes are internalized and their physiological impact on the recipient cells are still poorly understood. In this study, we visualized the internalization of fluorescently labeled exosomes derived from EBV-uninfected and EBV-infected B cells of type I and type III latency into EBV-negative epithelial cells. In this way, we demonstrated that exosomes derived from all three cell types were internalized into the target cells in a similar fashion. Internalization of exosomes was significantly suppressed by treatment with an inhibitor of dynamin and also by the knockdown of caveolin-1. Labeled exosomes were colocalized with caveolae and subsequently trafficked through endocytic pathways. Moreover, we observed that exosomes derived from type III latency cells upregulated proliferation and expression of intercellular adhesion molecule 1 (ICAM-1) in the recipient cells more significantly than did those derived from EBV-negative and type I latency cells. We also identified the EBV latent membrane protein 1 (LMP1) gene as responsible for induction of ICAM-1 expression. Taken together, our data indicate that exosomes released from EBV-infected B cells are internalized via caveola-dependent endocytosis, which, in turn, contributes to phenotypic changes in the recipient cells through transferring one or more viral factors.
Collapse
|
|
30
|
Iizasa H, Nanbo A, Nishikawa J, Jinushi M, Yoshiyama H. Epstein-Barr Virus (EBV)-associated gastric carcinoma. Viruses 2013; 4:3420-39. [PMID: 23342366 PMCID: PMC3528272 DOI: 10.3390/v4123420] [Citation(s) in RCA: 141] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The ubiquitous Epstein-Barr virus (EBV) is associated with several human tumors, which include lymphoid and epithelial malignancies. It is known that EBV persistently infects the memory B cell pool of healthy individuals by activating growth and survival signaling pathways that can contribute to B cell lymphomagenesis. Although the monoclonal proliferation of EBV-infected cells can be observed in epithelial tumors, such as nasopharyngeal carcinoma and EBV-associated gastric carcinoma, the precise role of EBV in the carcinogenic progress is not fully understood. This review features characteristics and current understanding of EBV-associated gastric carcinoma. EBV-associated gastric carcinoma comprises almost 10% of all gastric carcinoma cases and expresses restricted EBV latent genes (Latency I). Firstly, definition, epidemiology, and clinical features are discussed. Then, the route of infection and carcinogenic role of viral genes are presented. Of particular interest, the association with frequent genomic CpG methylation and role of miRNA for carcinogenesis are topically discussed. Finally, the possibility of therapies targeting EBV-associated gastric carcinoma is proposed.
Collapse
Affiliation(s)
- Hisashi Iizasa
- Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan;
| | - Asuka Nanbo
- Graduate School of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo 060-0812, Japan;
| | - Jun Nishikawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan;
| | - Masahisa Jinushi
- Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan; (J.M.); (H.Y.)
| | - Hironori Yoshiyama
- Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan; (J.M.); (H.Y.)
- Author to whom correspondence should be addressed; ; Tel.: +81-11-706-6073; Fax: +81-11-706-6071
| |
Collapse
|
|
31
|
Different distributions of Epstein-Barr virus early and late gene transcripts within viral replication compartments. J Virol 2013; 87:6693-9. [PMID: 23552415 DOI: 10.1128/jvi.00219-13] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Productive replication of the Epstein-Barr virus (EBV) occurs in discrete sites in nuclei, called replication compartments, where viral genome DNA synthesis and transcription take place. The replication compartments include subnuclear domains, designated BMRF1 cores, which are highly enriched in the BMRF1 protein. During viral lytic replication, newly synthesized viral DNA genomes are organized around and then stored inside BMRF1 cores. Here, we examined spatial distribution of viral early and late gene mRNAs within replication compartments using confocal laser scanning microscopy and three-dimensional surface reconstruction imaging. EBV early mRNAs were mainly located outside the BMRF1 cores, while viral late mRNAs were identified inside, corresponding well with the fact that late gene transcription is dependent on viral DNA replication. From these results, we speculate that sites for viral early and late gene transcription are separated with reference to BMRF1 cores.
Collapse
|
|
32
|
Kim DN, Seo MK, Choi H, Kim SY, Shin HJ, Yoon AR, Tao Q, Rha SY, Lee SK. Characterization of naturally Epstein-Barr virus-infected gastric carcinoma cell line YCCEL1. J Gen Virol 2012; 94:497-506. [PMID: 23175241 DOI: 10.1099/vir.0.045237-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Epstein-Barr virus (EBV) is a herpesvirus associated with lymphomas and carcinomas. While EBV-associated epithelial cell lines are good model systems to investigate the role of EBV in carcinoma, only a few cell lines are available as they are hard to acquire. A greater variety of naturally EBV-infected cell lines which are derived from tumour patients are needed to represent various features of EBVaGC. We characterized cell line YCCEL1, established from a Korean EBVaGC patient, to ascertain whether it can be used to study the roles of EBV in EBVaGC. The expression of EBV genes and cell surface markers was examined by in situ hybridization, RT-PCR, Western blot analysis, immunofluorescence assay and Northern blot analysis. EBV episomal status was analysed by Southern blotting and real-time PCR. This cell line expressed EBV nuclear antigen 1 (EBNA1) and latent membrane protein 2A (LMP2A), but not EBNA2, LMP2B nor LMP1. The majority of the lytic proteins were not detected in YCCEL1 cells either before or after treatment with 12-O-tetradecanoylphorbol-13-acetate. YCCEL1 cells expressed BART microRNAs (miRNAs) at high level but did not express BHRF1 miRNAs. YCCEL1 cells expressed cytokeratin, but not CD21 and CD19, suggesting CD21-independent EBV infection. The latent EBV gene and EBV miRNA expression pattern of YCCEL1 cells closely resembled that of general EBVaGC cases. Our results support the value of YCCEL1 cells as a good model system to study the role of EBV in gastric carcinogenesis.
Collapse
Affiliation(s)
- Do Nyun Kim
- Department of Medical Lifescience, Research Institute of Immunobiology, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | - Min Koo Seo
- Department of Medical Lifescience, Research Institute of Immunobiology, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | - Hoyun Choi
- Department of Medical Lifescience, Research Institute of Immunobiology, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | - Su Yeon Kim
- Department of Medical Lifescience, Research Institute of Immunobiology, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | - Hee Jong Shin
- Department of Medical Lifescience, Research Institute of Immunobiology, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | - A-Ran Yoon
- Department of Medical Lifescience, Research Institute of Immunobiology, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | - Qian Tao
- Department of Clinical Oncology, Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong, PR China
| | - Sun Young Rha
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Suk Kyeong Lee
- Department of Medical Lifescience, Research Institute of Immunobiology, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea
| |
Collapse
|
|
33
|
Roles of cell signaling pathways in cell-to-cell contact-mediated Epstein-Barr virus transmission. J Virol 2012; 86:9285-96. [PMID: 22718812 DOI: 10.1128/jvi.00712-12] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Epstein-Barr virus (EBV), a human gamma herpesvirus, establishes a life-long latent infection in B lymphocytes and epithelial cells following primary infection. Several lines of evidence indicate that the efficiency of EBV infection in epithelial cells is accelerated up to 10(4)-fold by coculturing with EBV-infected Burkitt's lymphoma (BL) cells compared to infection with cell-free virions, indicating that EBV infection into epithelial cells is mainly mediated via cell-to-cell contact. However, the molecular mechanisms involved in this pathway are poorly understood. Here, we establish a novel assay to assess cell-to-cell contact-mediated EBV transmission by coculturing an EBV-infected BL cell line with an EBV-negative epithelial cell line under stimulation for lytic cycle induction. By using this assay, we confirmed that EBV was transmitted from BL cells to epithelial cells via cell-to-cell contact but not via cell-to-cell fusion. The inhibitor treatments of extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-κB pathways blocked EBV transmission in addition to lytic induction. The blockage of the phosphoinositide 3-kinase (PI3K) pathway impaired EBV transmission coupled with the inhibition of lytic induction. Knockdown of the RelA/p65 subunit of NF-κB reduced viral transmission. Moreover, these signaling pathways were activated in cocultured BL cells and in epithelial cells. Finally, we observed that viral replication was induced in cocultured BL cells. Taken together, our data suggest that cell-to-cell contact induces multiple cell signaling pathways in BL cells and epithelial cells, contributing to the induction of the viral lytic cycle in BL cells and the enhancement of viral transmission to epithelial cells.
Collapse
|
|
34
|
Takada K. Role of EBER and BARF1 in nasopharyngeal carcinoma (NPC) tumorigenesis. Semin Cancer Biol 2011; 22:162-5. [PMID: 22210180 DOI: 10.1016/j.semcancer.2011.12.007] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Revised: 12/15/2011] [Accepted: 12/15/2011] [Indexed: 12/25/2022]
Abstract
Epstein-Barr virus (EBV)-encoded small RNA (EBER) is the most abundant EBV viral transcript and is used as a target molecule to detect EBV-infected cells in tissues by in situ hybridization. EBER is expected to form double-stranded RNA-like structures. The results of the present study show that EBER contributes to oncogenesis by modulating innate immunity in patients with NPC and Burkett's lymphoma. BARF1 is a homolog of the human proto-oncogene c-fms and is expressed as a latent gene in NPC. Reconstitution of NPC-type EBV infection using NPC-derived cell lines shows that BARF1 contributes to the tumorigenicity of NPC cells.
Collapse
Affiliation(s)
- Kenzo Takada
- Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan.
| |
Collapse
|
|
35
|
Noda C, Murata T, Kanda T, Yoshiyama H, Sugimoto A, Kawashima D, Saito S, Isomura H, Tsurumi T. Identification and characterization of CCAAT enhancer-binding protein (C/EBP) as a transcriptional activator for Epstein-Barr virus oncogene latent membrane protein 1. J Biol Chem 2011; 286:42524-42533. [PMID: 22013073 DOI: 10.1074/jbc.m111.271734] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Epstein-Barr virus LMP1, a major oncoprotein expressed in latent infection, is critical for primary B cell transformation, functioning as a TNFR family member by aggregation in the plasma membrane resulting in constitutive activation of cellular signals, such as NF-κB, MAPK, JAK/STAT, and AKT. Although transcription of LMP1 in latent type III cells is generally under the control of the viral coactivator EBNA2, little is known about EBNA2-independent LMP1 expression in type II latency. We thus screened a cDNA library for factors that can activate the LMP1 promoter in an EBNA2-independent manner, using a reporter assay system. So far, we have screened >20,000 clones, and here identified C/EBPε as a new transcriptional activator. Exogenous expression of C/EBPα, -β, or -ε efficiently augmented LMP1 mRNA and protein levels in EBV-positive cell lines, whereas other members of the C/EBP family exhibited modest or little activity. It has been demonstrated that LMP1 gene transcription depends on two promoter regions: proximal (ED-L1) and distal (TR-L1). Interestingly, although we first used the proximal promoter for screening, we found that C/EBP increased transcription from both promoters in latent EBV-positive cells. Mutagenesis in reporter assays and EMSA identified only one functional C/EBP binding site, through which activation of both proximal and distal promoters is mediated. Introduction of point mutations into the identified C/EBP site in EBV-BAC caused reduced LMP1 transcription from both LMP1 promoters in epithelial cells. In conclusion, C/EBP is a newly identified transcriptional activator of the LMP1 gene, independent of the EBNA2 coactivator.
Collapse
Affiliation(s)
- Chieko Noda
- Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681; Department of Oncology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603
| | - Takayuki Murata
- Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681
| | - Teru Kanda
- Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681
| | - Hironori Yoshiyama
- Research Center for Infection-associated Cancer, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan
| | - Atsuko Sugimoto
- Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681
| | - Daisuke Kawashima
- Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681
| | - Shinichi Saito
- Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681
| | - Hiroki Isomura
- Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681
| | - Tatsuya Tsurumi
- Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681; Department of Oncology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603.
| |
Collapse
|
|
36
|
Fukayama M, Ushiku T. Epstein-Barr virus-associated gastric carcinoma. Pathol Res Pract 2011; 207:529-37. [PMID: 21944426 DOI: 10.1016/j.prp.2011.07.004] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Accepted: 07/29/2011] [Indexed: 12/13/2022]
Abstract
Epstein-Barr virus (EBV) has been accepted as an infective agent causing gastric carcinoma (GC). EBV-associated GC, comprising nearly 10% of all cases of GC, is the monoclonal growth of EBV-infected epithelial cells, which express only several EBV-latent genes (Latency I program). Histopathologically, there are two subtypes, lymphoepithelioma-like carcinoma and the ordinary type of GC. Other features include the lace pattern of carcinoma cells in the intramucosal stage and the dense infiltration of lymphocytes and macrophages at the invasive site of the submucosa. The primary molecular abnormality in EBV-associated GC is global and non-random CpG island methylation in the promoter region of many cancer-related genes. Experimental studies have demonstrated that viral latent membrane protein 2A (LMP2A) is responsible for the promotion of DNA methylation. LMP2A up-regulates cellular DNMT1 through the phosphorylation of STAT3, resulting in the repression of tumor suppressor genes, such as PTEN, through promoter methylation. DNA methylation in EBV-infected stomach cells may be due to overdrive of the cellular defense against foreign DNA. Further studies on the mechanisms of epigenetic abnormalities will clarify the strategies for prevention and treatment of this particular type of GC with EBV infection.
Collapse
Affiliation(s)
- Masashi Fukayama
- Department of Pathology and Diagnostic Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
| | | |
Collapse
|
|
37
|
Contribution of Epstein-Barr virus infection to chemoresistance of gastric carcinoma cells to 5-fluorouracil. Arch Pharm Res 2011; 34:635-43. [PMID: 21544729 DOI: 10.1007/s12272-011-0414-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2010] [Revised: 01/06/2011] [Accepted: 01/06/2011] [Indexed: 12/26/2022]
Abstract
Although Epstein-Barr virus (EBV) is associated with 6-16% of the gastric carcinoma (GC) cases, the effect of EBV infection on the tumorigenesis process and the responsiveness to chemotherapy remain unclear. We compared chemosensitivity of the EBV-positive GC (AGSEBV) and EBV-negative GC (AGS) cells to 5-fluorouracil (5-FU). Although 5-FU inhibited the growth of both cell lines in a dose- and time-dependent manner, the sensitivity of EBV-positive GC cells to 5-FU was lower than that of EBV-negative GC cells. The cleavage of PARP and caspase-3 was also lower in AGS-EBV cells than in AGS cells following 5-FU treatment. Both the level of Bcl-2 expression and the ratio of Bcl-2/Bax were higher in AGS-EBV than in AGS cells not only at basal state but also following 5-FU treatment. Moreover, p53 and p21 expression was enhanced further by 5-FU in AGS than in AGS-EBV cells. Immunofluorescence assay and Western blot showed that 5-FU induced the expression of EBV-lytic genes including BZLF1, BRLF1, BMRF1 and BHRF1. Our results suggest that latent and lytic EBV infection contributes to the chemoresistance to 5-FU in gastric carcinoma by modulating apoptosis related cellular genes.
Collapse
|
|
38
|
Karpinski P, Myszka A, Ramsey D, Kielan W, Sasiadek MM. Detection of viral DNA sequences in sporadic colorectal cancers in relation to CpG island methylation and methylator phenotype. Tumour Biol 2011; 32:653-9. [PMID: 21625944 PMCID: PMC3131518 DOI: 10.1007/s13277-011-0165-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2010] [Accepted: 02/22/2011] [Indexed: 02/07/2023] Open
Abstract
There is evidence that insertion of viral DNA into a mammalian genome can lead to alterations of methylation patterns. The aim of the present study was to examine the presence of DNA sequences of five human DNA viruses (assessed by PCR): JC polyoma virus (JCV), human adenovirus (AdV), Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV/HHV8) and human papillomavirus (HPV) in a cohort of 186 sporadic colorectal cancers (CRCs) and related these data with the methylation status of six CpG island methylator phenotype (CIMP)-specific genes (MLH1, CACNA1G, NEUROG1, IGF2, SOCS1, RUNX3) and seven cancer-related genes markers (p16, MINT1, MINT2, MINT31, EN1, SCTR and INHBB) assessed by methylation-specific PCR in 186 and 134 CRC cases, respectively. The AdV, KSHV and HPV were detected in four (2%), two (1%) and zero CRC cases, respectively, and thus were excluded from further analyses. Although 19% and 9% of the CRCs were positive for EBV and JCV, respectively, no associations between virus presence and CpG island methylation were found after correction for multiple testing. Our results demonstrate that the presence of DNA sequences of JCV and EBV in CRC is unrelated to the methylation of the 13 cancer-related CpG islands and CIMP.
Collapse
Affiliation(s)
- Pawel Karpinski
- Department of Genetics, Wroclaw Medical University, ul. Marcinkowskiego 1, 50-368, Wroclaw, Poland.
| | | | | | | | | |
Collapse
|
|
39
|
Miyauchi K, Urano E, Yoshiyama H, Komano J. Cytokine signatures of transformed B cells with distinct Epstein-Barr virus latencies as a potential diagnostic tool for B cell lymphoma. Cancer Sci 2011; 102:1236-41. [PMID: 21392167 DOI: 10.1111/j.1349-7006.2011.01924.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Immunocompromised individuals, including those infected with human immunodeficiency virus (HIV), are at increased risk of Epstein-Barr virus (EBV)-associated aggressive B cell malignancies such as Burkitt's lymphoma (BL) or diffuse large B cell lymphoma (DLBCL). Differential diagnosis of these lymphomas requires histopathological, immunohistochemical and cytogenetic assessments. Rapid, less invasive approaches to the diagnosis of EBV-associated B cell lymphomas are needed. Here, high-throughput cytokine profiling of BL cell lines and EBV-transformed B lymphoblastoid cell lines (B-LCL), representing DLBCL, was carried out. By monitoring the production of 42 different cytokines, unique cytokine signatures were identified for BL and B-LCL/DLBCL. The BL cells produced interleukin (IL)-10, 10 kDa interferon gamma-induced protein (IP-10)/CXCL10, macrophage-derived chemokine (MDC)/CCL22, macrophage inflammatory protein (MIP)-1α/CCL3 and MIP-1β/CCL4. In addition to these five cytokines, the cytokine signature of B-LCL/DLBCL cells included IL-8/CXCL8, IL-13, platelet-derived growth factor (PDGF)-AA, and regulated upon activation, normal T cell expressed and secreted (RANTES)/CCL5. Epstein-Barr virus latency was responsible for the increased production of IL-10, MDC/CCL22 and MIP-1α/CCL3 in BL cells, suggesting that EBV-mediated BL-genesis involves these three cytokines. These results suggest that high-throughput cytokine profiling might be a valuable tool for the differential diagnosis and might deepen our understanding of the pathogenesis of EBV-associated B cell malignancies.
Collapse
Affiliation(s)
- Kosuke Miyauchi
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | | | | | | |
Collapse
|
|
40
|
Abstract
Epstein-Barr virus (EBV) has been accepted as an infective agent causing gastric carcinoma (GC). Epstein-Barr virus-associated GC, comprising nearly 10% of all cases of GC, is the monoclonal growth of EBV-infected epithelial cells, which express several EBV-latent genes (latency I program). Sequential events in the gastric mucosa could be traced from EBV infection of the pit cells to fully developed carcinomas by EBV encoded small RNA (EBER)-in situ hybridization. The histological features of the carcinoma consist of a lace pattern of carcinoma cells within the mucosa and the dense infiltration of lymphocytes and macrophages at the invasive site, which might be due to cytokines produced by neoplastic cells. The primary molecular abnormality in EBV-associated GC is global and non-random CpG island methylation in the promoter region of many cancer-related genes. The experimental system of recombinant EBV infection using GC cell lines demonstrated that viral latent membrane protein 2A (LMP2A) is responsible for the promotion of DNA methylation. LMP2A up-regulates cellular DNMT1 through the phosphorylation of STAT3, causing CpG methylation of a tumor suppressor gene, PTEN. DNA methylation in EBV-infected stomach cells may be due to overdrive of the cellular defense against foreign DNA, which eventually leads to the development of EBV-associated GC.
Collapse
Affiliation(s)
- Masashi Fukayama
- Department of Pathology and Diagnostic Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
| |
Collapse
|
|
41
|
Possible DNA viral factors of human breast cancer. Cancers (Basel) 2010; 2:498-512. [PMID: 24281079 PMCID: PMC3835088 DOI: 10.3390/cancers2020498] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Revised: 04/03/2010] [Accepted: 04/12/2010] [Indexed: 02/07/2023] Open
Abstract
Viruses are considered to be one of the high-risk factors closely related to human breast cancer. However, different studies of viruses in breast cancer present conflicting results and some of these works remain in dispute. DNA viruses, such as specific types of human papillomaviruses (HPV), Epstein–Barr virus (EBV), human cytomegalovirus (HCMV), herpes simplex virus (HSV), and human herpes virus type 8 (HHV-8), have emerged as causal factors of some human cancers. These respective exogenous viruses and the possibility of multiple viral factors are discussed in this review.
Collapse
|
|
42
|
Katsumura KR, Maruo S, Wu Y, Kanda T, Takada K. Quantitative evaluation of the role of Epstein-Barr virus immediate-early protein BZLF1 in B-cell transformation. J Gen Virol 2009; 90:2331-2341. [PMID: 19553389 DOI: 10.1099/vir.0.012831-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The Epstein-Barr virus (EBV) immediate-early transactivator BZLF1 plays a key role in switching EBV infection from the latent to the lytic form by stimulating the expression cascade of lytic genes; it also regulates the expression of several cellular genes. Recently, we reported that BZLF1 is expressed in primary human B cells early after EBV infection. To investigate whether this BZLF1 expression early after infection plays a role in the EBV-induced growth transformation of primary B cells, we generated BZLF1-knockout EBV and quantitatively evaluated its transforming ability compared with that of wild-type EBV. We found that the 50% transforming dose of BZLF1-knockout EBV was quite similar to that of wild-type EBV. Established lymphoblastoid cell lines (LCLs) harbouring BZLF1-knockout EBV were indistinguishable from LCLs harbouring wild-type EBV in their pattern of latent gene expression and in their growth in vitro. Furthermore, the copy numbers of EBV episomes were very similar in the LCLs harbouring BZLF1-knockout EBV and in those harbouring wild-type EBV. These data indicate that disrupting BZLF1 expression in the context of the EBV genome, and the resultant inability to enter lytic replication, have little impact on the growth of LCLs and the steady-state copy number of EBV episomes in established LCLs.
Collapse
Affiliation(s)
- Koichi Ricardo Katsumura
- Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
| | - Seiji Maruo
- Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
| | - Yi Wu
- Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
| | - Teru Kanda
- Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
| | - Kenzo Takada
- Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
| |
Collapse
|
|
43
|
Imadome KI, Shimizu N, Yajima M, Watanabe K, Nakamura H, Takeuchi H, Fujiwara S. CD40 signaling activated by Epstein-Barr virus promotes cell survival and proliferation in gastric carcinoma-derived human epithelial cells. Microbes Infect 2009; 11:429-33. [PMID: 19397878 DOI: 10.1016/j.micinf.2009.01.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2008] [Revised: 01/15/2009] [Accepted: 01/15/2009] [Indexed: 11/19/2022]
Abstract
CD40 signaling plays a critical role in the survival and proliferation of EBV-infected lymphocytes. Here we show that CD40 is constitutively expressed in the human gastric carcinoma-derived cell lines AGS, MKN28, and MKN74, and expression of CD40L is induced by in vitro infection with EBV. Blocking the interaction between CD40 and CD40L with CD40Ig, a fusion protein of CD40 and IgG, impaired proliferation of EBV-infected AGS cells and enhanced their calcium ionophore-induced apoptosis. These results suggest that CD40 signaling plays a critical role in the survival and proliferation of EBV-infected epithelial cells, as well as in the virus-infected lymphocytes.
Collapse
Affiliation(s)
- Ken-Ichi Imadome
- Department of Infectious Diseases, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Fukagawa Y, Nishikawa J, Kuramitsu Y, Iwakiri D, Takada K, Imai S, Satake M, Okamoto T, Fujimoto M, Okita K, Nakamura K, Sakaida I. Epstein-Barr virus upregulates phosphorylated heat shock protein 27 kDa in carcinoma cells using the phosphoinositide 3-kinase/Akt pathway. Electrophoresis 2008; 29:3192-200. [PMID: 18604870 DOI: 10.1002/elps.200800086] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric cancer is the most common cancer in Japan and infection with Epstein-Barr virus (EBV) is responsible for about 10% of gastric cancers worldwide. Although EBV infection may be involved at an early stage of gastric carcinogenesis, the mechanisms underlying its involvement remain unknown. To investigate the role of EBV in gastric carcinogenesis, we performed proteomic analyses of an EBV-infected gastric carcinoma cell line NU-GC-3 (EBV(+)) and its uninfected control (EBV(-)). 2-DE was combined with MS to identify differentially expressed proteins. We found that EBV infection upregulated one of the phosphorylated heat shock protein 27 kDa (HSP27). The phosphorylated HSP27 isoform which increased in EBV(+) cells can be induced by both heat shock and arsenite. The increase of phosphorylated HSP27 in EBV(+) cells was reduced by treatment with the phosphoinositide 3-kinase (PI3K) inhibitors (LY294002 and wortmannin). In addition, we found increased levels of phosphorylated Akt in EBV(+) cells. These findings suggest that EBV infection upregulates the phosphorylation of HSP27 via the PI3K/Akt pathway. Thus, activation of the PI3K/Akt pathway may contribute to the establishment of a malignant phenotype in EBV-infected gastric carcinomas.
Collapse
Affiliation(s)
- Yuki Fukagawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Kaposi's sarcoma-associated herpesvirus forms a multimolecular complex of integrins (alphaVbeta5, alphaVbeta3, and alpha3beta1) and CD98-xCT during infection of human dermal microvascular endothelial cells, and CD98-xCT is essential for the postentry stage of infection. J Virol 2008; 82:12126-44. [PMID: 18829766 DOI: 10.1128/jvi.01146-08] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with cell surface heparan sulfate (HS) and alpha3beta1 integrin during the early stages of infection of human dermal microvascular endothelial cells (HMVEC-d) and human foreskin fibroblasts (HFF), and these interactions are followed by virus entry overlapping with the induction of preexisting host cell signal pathways. KSHV also utilizes the amino acid transporter protein xCT for infection of adherent cells, and the xCT molecule is part of the cell surface heterodimeric membrane glycoprotein CD98 (4F2 antigen) complex known to interact with alpha3beta1 and alphaVbeta3 integrins. KSHV gB mediates adhesion of HMVEC-d, CV-1, and HT-1080 cells and HFF via its RGD sequence. Anti-alphaV and -beta1 integrin antibodies inhibited the cell adhesion mediated by KSHV-gB. Variable levels of neutralization of HMVEC-d and HFF infection were observed with antibodies against alphaVbeta3 and alphaVbeta5 integrins. Similarly, variable levels of inhibition of virus entry into adherent HMVEC-d, 293 and Vero cells, and HFF was observed by preincubating virus with soluble alpha3beta1, alphaVbeta3, and alphaVbeta5 integrins, and cumulative inhibition was observed with a combination of integrins. We were unable to infect HT1080 cells. Virus binding and DNA internalization studies suggest that alphaVbeta3 and alphaVbeta5 integrins also play roles in KSHV entry. We observed time-dependent temporal KSHV interactions with HMVEC-d integrins and CD98/xCT with three different patterns of association and dissociation. Integrin alphaVbeta5 interaction with CD98/xCT predominantly occurred by 1 min postinfection (p.i.) and dissociated at 10 min p.i., whereas alpha3beta1-CD98/xCT interaction was maximal at 10 min p.i. and dissociated at 30 min p.i., and alphaVbeta3-CD98/xCT interaction was maximal at 10 min p.i. and remained at the observed 30 min p.i. Fluorescence microscopy also showed a similar time-dependent interaction of alphaVbeta5-CD98. Confocal-microscopy studies confirmed the association of CD98/xCT with alpha3beta1 and KSHV. Preincubation of KSHV with soluble heparin and alpha3beta1 significantly inhibited this association, suggesting that the first contact with HS and integrin is an essential element in subsequent CD98-xCT interactions. Anti-CD98 and xCT antibodies did not block virus binding and entry and nuclear delivery of viral DNA; however, viral-gene expression was significantly inhibited, suggesting that CD98-xCT play roles in the post-entry stage of infection, possibly in mediating signal cascades essential for viral-gene expression. Together, these studies suggest that KSHV interacts with functionally related integrins (alphaVbeta3, alpha3beta1, and alphaVbeta5) and CD98/xCT molecules in a temporal fashion to form a multimolecular complex during the early stages of endothelial cell infection, probably mediating multiple roles in entry, signal transduction, and viral-gene expression.
Collapse
|
|
46
|
Dittmer DP, Hilscher CJ, Gulley ML, Yang EV, Chen M, Glaser R. Multiple pathways for Epstein-Barr virus episome loss from nasopharyngeal carcinoma. Int J Cancer 2008; 123:2105-12. [PMID: 18688856 DOI: 10.1002/ijc.23685] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Epstein-Barr virus (EBV) is the prototypical example for episomal persistence of genetic information. Yet, little is known about how this viral episome is lost. Episome loss occurs naturally in nasopharyngeal carcinoma (NPC) upon explantation into culture. Using whole-genome profiling, we found evidence for 2 different pathways of episome loss: (i) rapid loss of the entire episome or (ii) successive mutation/deletion of the episome until at least 1 essential cis-element is destroyed. This second phenotype was seen in a clone of HONE-1 NPC cells that maintains the EBV episome for prolonged time in culture. The conceptual insights provided by our quantitative analysis should aid our understanding of mammalian episomes, as well as lead to designs to cure latent viral infection.
Collapse
Affiliation(s)
- Dirk P Dittmer
- Lineberger Comprehensive Cancer Center, Center for AIDS Research and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.
| | | | | | | | | | | |
Collapse
|
|
47
|
Jiang R, Gu X, Nathan CA, Hutt-Fletcher L. Laser-capture microdissection of oropharyngeal epithelium indicates restriction of Epstein-Barr virus receptor/CD21 mRNA to tonsil epithelial cells. J Oral Pathol Med 2008; 37:626-33. [PMID: 18710421 DOI: 10.1111/j.1600-0714.2008.00681.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Epstein-Barr virus colonizes the oropharynx of a majority of individuals. It infects B lymphocytes and epithelial cells and can contribute to the development of both lymphoid and epithelial tumors. The virus uses CD21 for attachment to B cells which constitutively express the protein. Infection of epithelial cells in vitro is also more efficient if CD21 is available. However, its potential contribution to infection in vivo has been difficult to evaluate as discrepant results with antibodies have made it difficult to determine which, if any, epithelial cells in the oropharynx express CD21. METHODS To reevaluate CD21 expression by an alternative method, epithelial cells were isolated by laser-capture microdissection from formalin-fixed sections of tissues from various parts of the oropharynx and mRNA was amplified with primers specific for the exons of CD21 which code for the Epstein-Barr virus binding site. RESULTS CD21 mRNA was expressed in tonsil epithelium, but not in epithelium from buccal mucosa, uvula, soft palate or tongue. CONCLUSIONS CD21 does not contribute to infection of most normal epithelial tissues in the oropharynx, but may contribute to infection of epithelial cells in the tonsil, where virus has been demonstrated in healthy carriers.
Collapse
Affiliation(s)
- Ru Jiang
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA
| | | | | | | |
Collapse
|
|
48
|
Sousa H, Pinto-Correia AL, Medeiros R, Dinis-Ribeiro M. Epstein-Barr virus is associated with gastric carcinoma: The question is what is the significance? World J Gastroenterol 2008; 14:4347-51. [PMID: 18666324 PMCID: PMC2731187 DOI: 10.3748/wjg.14.4347] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To examine the possible role of the Epstein-Barr Virus (EBV) in the development of gastric adenocarcinoma (GC). It is unclear whether EBV is involved in GC development or is a consequence of gastric inflammation secondary to immunosuppressive treatments.
METHODS: A systematic review was carried out of all published observational studies on the temporal association between EBV and GC, with a view to determine a causal relationship.
RESULTS: The present study showed that the worldwide crude prevalence of EBV in gastric adenocarcinoma was 8.29%. The prevalence varied from 7.08% for intestinal type and 9.82% for diffuse type of GC. It was observed that Western and Central Asian countries had a significantly higher frequency of EBV positive cases compared to South-Eastern countries. America had the highest EBV-GC prevalence whereas Europe had the lowest.
CONCLUSION: The present review has demonstrated a high prevalence of EBV in gastric adenocarcinoma. However, studies designed to assess a temporal relationship and histological association using sensitive techniques should be carried out to establish the role of EBV in GC carcinogenesis.
Collapse
|
|
49
|
Uozaki H, Fukayama M. Epstein-Barr virus and gastric carcinoma--viral carcinogenesis through epigenetic mechanisms. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2008; 1:198-216. [PMID: 18784828 PMCID: PMC2480567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/13/2007] [Accepted: 09/20/2007] [Indexed: 05/26/2023]
Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) is the monoclonal growth of EBV-infected epithelial cells, and the entity was recognized only recently. EBV-associated GC is distributed worldwide and more than 90,000 patients are estimated to develop GC annually in association with EBV (10% of total GC). EBV-associated GC occurs in two forms in terms of the histological features, i.e., lymphoepithelioma-like GC and ordinary type of GC. Both share characteristic clinicopathological features, such as the preferential occurrence as multiple cancer and remnant stomach cancer. While the expression of EBV-latent genes is restricted to several in the infected cells (Latency I), EBV-associated GC shows gastric cell phenotype, resistance to apoptosis, and the production of immunomodulator molecules. Recently, global and non-random CpG island methylation of the promoter region of many cancer-related genes has been demonstrated with their decreased expression, such as p16 INK4A, p73 and E-cadherin. This abnormality is accompanied by methylation of the EBV genome itself, suggesting a process of virus-driven hypermethylation in the development of neoplastic cells. Further studies are necessary to determine the precise sequence of EBV infection, methylation, transformation and selection of the predominant clone within the stomach mucosa. Future studies are also desirable for the target and strategy of therapy, such as initiating viral replication or reversing the DNA methylation of cellular genes.
Collapse
Affiliation(s)
- Hiroshi Uozaki
- Department of Pathology, Graduate School of Medicine, The University of Tokyo Bunkyo-ku, Tokyo, Japan
| | | |
Collapse
|
|
50
|
Tierney R, Nagra J, Hutchings I, Shannon-Lowe C, Altmann M, Hammerschmidt W, Rickinson A, Bell A. Epstein-Barr virus exploits BSAP/Pax5 to achieve the B-cell specificity of its growth-transforming program. J Virol 2007; 81:10092-100. [PMID: 17626071 PMCID: PMC2045388 DOI: 10.1128/jvi.00358-07] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Epstein-Barr virus (EBV) can infect various cell types but limits its classical growth-transforming function to B lymphocytes, the cells in which it persists in vivo. Transformation initiates with the activation of Wp, a promoter present as tandemly repeated copies in the viral genome. Assays with short Wp reporter constructs have identified two promoter-activating regions, one of which (UAS2) appears to be lineage independent, while the other (UAS1) was B-cell specific and contained two putative binding sites for the B-cell-specific activator protein BSAP/Pax5. To address the physiologic relevance of these findings, we first used chromosome immunoprecipitation assays and found that BSAP is indeed bound to Wp sequences on the EBV genome in transformed cells. Thereafter, we constructed recombinant EBVs carrying two Wp copies, both wild type, with UAS1 or UAS2 deleted, or mutated in the BSAP binding sites. All the viruses delivered their genomes to the B-cell nucleus equally well. However, the BSAP binding mutant (and the virus with UAS1 deleted) showed no detectable activity in B cells, whether measured by early Wp transcription, expression of EBV latent proteins, or outgrowth of transformed cells. This was a B-cell-specific defect since, on entry into epithelial cells, an environment where Wp is not the latent promoter of choice, all the Wp mutant viruses initiated infection as efficiently as wild-type virus. We infer that EBV ensures the B-cell specificity of its growth-transforming function by exploiting BSAP/Pax5 as a lineage-specific activator of the transforming program.
Collapse
Affiliation(s)
- Rosemary Tierney
- Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | | | | | | | | | | | | | | |
Collapse
|