Cancers

Research

7 pages, 488 KiB

Open AccessFeature PaperCommunication

Associations of Epstein-Barr Virus-Positive Gastric Adenocarcinoma with Circulating Mediators of Inflammation and Immune Response

by M. Constanza Camargo, Armands Sivins, Sergejs Isajevs, Valdis Folkmanis, Dace Rudzīte, Margaret L. Gulley, G. Johan Offerhaus, Marcis Leja and Charles S. Rabkin

Cancers 2018, 10(9), 284; https://doi.org/10.3390/cancers10090284 - 23 Aug 2018

Cited by 10 | Viewed by 3770

Abstract

Epstein-Barr virus (EBV)-positive gastric adenocarcinoma exhibits locally intense inflammation but systemic manifestations are uncertain. Our study examined whether circulating mediators of inflammation and immune response differ by tumor EBV status. From a Latvian series of 302 gastric cancer cases, we measured plasma levels [...] Read more.

Epstein-Barr virus (EBV)-positive gastric adenocarcinoma exhibits locally intense inflammation but systemic manifestations are uncertain. Our study examined whether circulating mediators of inflammation and immune response differ by tumor EBV status. From a Latvian series of 302 gastric cancer cases, we measured plasma levels of 92 immune-related proteins in the 28 patients with EBV-positive tumors and 34 patients with EBV-negative tumors. Eight markers were statistically significantly higher with tumor EBV positivity: chemokine C-C motif ligand (CCL) 20 (Odds Ratio (OR) = 3.6; p-trend = 0.001), chemokine C-X-C motif ligand 9 (OR = 3.6; p-trend = 0.003), programmed death-ligand 1 (PD-L1; OR = 3.4; p-trend = 0.004), interleukin (IL)-10 (OR = 2.4; p-trend = 0.019), CCL19 (OR = 2.3; p-trend = 0.019), CCL11 (OR = 2.2; p-trend = 0.026), IL-17A (OR = 2.0; p-trend = 0.038) and CCL8 (OR = 1.9; p-trend = 0.049). Systemic responses to EBV-positive gastric cancer are characterized by alterations in chemokines and PD-L1. Profiling of these molecules may enable non-invasive diagnosis of EBV status when tumor tissue is unavailable. Our findings provide theoretical justification for clinical evaluations of immune checkpoint therapy for EBV-positive gastric cancer. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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20 pages, 1651 KiB

Open AccessArticle

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

by Asuka Nanbo, Harutaka Katano, Michiyo Kataoka, Shiho Hoshina, Tsuyoshi Sekizuka, Makoto Kuroda and Yusuke Ohba

Cancers 2018, 10(7), 237; https://doi.org/10.3390/cancers10070237 - 19 Jul 2018

Cited by 24 | Viewed by 6063

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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22 pages, 2074 KiB

Open AccessArticle

Frequency of EBV LMP-1 Promoter and Coding Variations in Burkitt Lymphoma Samples in Africa and South America and Peripheral Blood in Uganda

by Hsiao-Mei Liao, Hebing Liu, Heiyan Lei, Bingjie Li, Pei-Ju Chin, Shien Tsai, Kishor Bhatia, Marina Gutierrez, Sidnei Epelman, Robert J. Biggar, Francis Nkrumah, Janet Neequaye, Martin D. Ogwang, Steven J. Reynolds, Shyh-Ching Lo and Sam M. Mbulaiteye

Cancers 2018, 10(6), 177; https://doi.org/10.3390/cancers10060177 - 2 Jun 2018

Cited by 9 | Viewed by 4752

Abstract

Epstein-Barr virus (EBV) is linked to several cancers, including endemic Burkitt lymphoma (eBL), but causal variants are unknown. We recently reported novel sequence variants in the LMP-1 gene and promoter in EBV genomes sequenced from 13 of 14 BL biopsies. Alignments of the [...] Read more.

Epstein-Barr virus (EBV) is linked to several cancers, including endemic Burkitt lymphoma (eBL), but causal variants are unknown. We recently reported novel sequence variants in the LMP-1 gene and promoter in EBV genomes sequenced from 13 of 14 BL biopsies. Alignments of the novel sequence variants for 114 published EBV genomes, including 27 from BL cases, revealed four LMP-1 variant patterns, designated A to D. Pattern A variant was found in 48% of BL EBV genomes. Here, we used PCR-Sanger sequencing to evaluate 50 additional BL biopsies from Ghana, Brazil, and Argentina, and peripheral blood samples from 113 eBL cases and 115 controls in Uganda. Pattern A was found in 60.9% of 64 BL biopsies evaluated. Compared to PCR-negative subjects in Uganda, detection of Pattern A in peripheral blood was associated with eBL case status (odds ratio [OR] 31.7, 95% confidence interval: 6.8–149), controlling for relevant confounders. Variant Pattern A and Pattern D were associated with eBL case status, but with lower ORs (9.7 and 13.6, respectively). Our results support the hypothesis that EBV LMP-1 Pattern A may be associated with eBL, but it is not the sole associated variant. Further research is needed to replicate and elucidate our findings. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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26 pages, 4189 KiB

Open AccessArticle

The EBV-Encoded Oncoprotein, LMP1, Induces an Epithelial-to-Mesenchymal Transition (EMT) via Its CTAR1 Domain through Integrin-Mediated ERK-MAPK Signalling

by Mhairi A. Morris, Louise Laverick, Wenbin Wei, Alexandra M. Davis, Samantha O’Neill, Liam Wood, Jack Wright, Christopher W. Dawson and Lawrence S. Young

Cancers 2018, 10(5), 130; https://doi.org/10.3390/cancers10050130 - 1 May 2018

Cited by 31 | Viewed by 6002

Abstract

The Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) oncogene can induce profound effects on epithelial growth and differentiation including many of the features of the epithelial-to-mesenchymal transition (EMT). To better characterise these effects, we used the well-defined Madin Darby Canine Kidney (MDCK) [...] Read more.

The Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) oncogene can induce profound effects on epithelial growth and differentiation including many of the features of the epithelial-to-mesenchymal transition (EMT). To better characterise these effects, we used the well-defined Madin Darby Canine Kidney (MDCK) epithelial cell model and found that LMP1 expression in these cells induces EMT as defined by characteristic morphological changes accompanied by loss of E-cadherin, desmosomal cadherin and tight junction protein expression. The induction of the EMT phenotype required a functional CTAR1 domain of LMP1 and studies using pharmacological inhibitors revealed contributions from signalling pathways commonly induced by integrin–ligand interactions: extracellular signal-regulated kinases/mitogen-activated protein kinases (ERK-MAPK), PI3-Kinase and tyrosine kinases, but not transforming growth factor beta (TGFβ). More detailed analysis implicated the CTAR1-mediated induction of Slug and Twist in LMP1-induced EMT. A key role for β1 integrin signalling in LMP1-mediated ERK-MAPK and focal adhesion kianse (FAK) phosphorylation was observed, and β1 integrin activation was found to enhance LMP1-induced cell viability and survival. These findings support an important role for LMP1 in disease pathogenesis through transcriptional reprogramming that enhances tumour cell survival and leads to a more invasive, metastatic phenotype. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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15 pages, 1656 KiB

Open AccessArticle

EBV Positive Diffuse Large B Cell Lymphoma and Chronic Lymphocytic Leukemia Patients Exhibit Increased Anti-dUTPase Antibodies

by Marshall Williams and Maria Eugenia Ariza

Cancers 2018, 10(5), 129; https://doi.org/10.3390/cancers10050129 - 1 May 2018

Cited by 8 | Viewed by 4716

Abstract

The Epstein-Barr virus (EBV), which is a ubiquitous γ-herpesvirus, establishes a latent infection in more than 90% of the global adult population. EBV-associated malignancies have increased by 14.6% over the last 20 years, and account for approximately 1.5% of all cancers worldwide and [...] Read more.

The Epstein-Barr virus (EBV), which is a ubiquitous γ-herpesvirus, establishes a latent infection in more than 90% of the global adult population. EBV-associated malignancies have increased by 14.6% over the last 20 years, and account for approximately 1.5% of all cancers worldwide and 1.8% of all cancer deaths. However, the potential involvement/contribution of lytic proteins to the pathophysiology of EBV-associated cancers is not well understood. We have previously demonstrated that the EBV-deoxyuridine triphosphate nucleotidohydrolase (dUTPase) modulates innate and adaptive immune responses by engaging the Toll-Like Receptor 2 (TLR2), which leads to the modulation of downstream genes involved in oncogenesis, chronic inflammation, and in effector T-cell function. Furthermore, examination of serum samples from diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia patients revealed the presence of increased levels of anti-dUTPase antibodies in both cohorts compared to controls with the highest levels (3.67-fold increase) observed in DLBCL female cases and the lowest (2.12-fold increase) in DLBCL males. Using computer-generated algorithms, dUTPase amino acid sequence alignments, and functional studies of BLLF3 mutants, we identified a putative amino acid motif involved with TLR2 interaction. These findings suggest that the EBV-dUTPase: TLR2 interaction is a potential molecular target that could be used for developing novel therapeutics (small molecules/vaccines). Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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14 pages, 17089 KiB

Open AccessArticle

NF-κB Signaling Regulates Epstein–Barr Virus BamHI-Q-Driven EBNA1 Expression

by Rob J. A. Verhoeven, Shuang Tong, Jingfeng Zong, Yixin Chen, Sai-Wah Tsao, Jianji Pan and Honglin Chen

Cancers 2018, 10(4), 119; https://doi.org/10.3390/cancers10040119 - 16 Apr 2018

Cited by 13 | Viewed by 6027

Abstract

Epstein–Barr virus (EBV) nuclear antigen 1 (EBNA1) is one of the few viral proteins expressed by EBV in nasopharyngeal carcinoma (NPC), most likely because of its essential role in maintaining the viral genome in EBV-infected cells. In NPC, EBNA1 expression is driven by [...] Read more.

Epstein–Barr virus (EBV) nuclear antigen 1 (EBNA1) is one of the few viral proteins expressed by EBV in nasopharyngeal carcinoma (NPC), most likely because of its essential role in maintaining the viral genome in EBV-infected cells. In NPC, EBNA1 expression is driven by the BamHI-Q promoter (Qp), which is regulated by both cellular and viral factors. We previously determined that the expression of another group of EBV transcripts, BamHI-A rightward transcripts (BARTs), is associated with constitutively activated nuclear factor-κB (NF-κB) signaling in NPC cells. Here, we show that, like the EBV BART promoter, the EBV Qp also responds to NF-κB signaling. NF-κB p65, but not p50, can activate Qp in vitro, and NF-κB signaling regulates Qp-EBNA1 expression in NPC cells, as well as in other EBV-infected epithelial cells. The introduction of mutations in the putative NF-κB site reduced Qp activation by the NF-κB p65 subunit. Binding of p65 to Qp was shown by chromatin immunoprecipitation (ChIP) analysis, while electrophoretic mobility shift assays (EMSAs) demonstrated that p50 can also bind to Qp. Inhibition of NF-κB signaling by the IκB kinase inhibitor PS-1145 resulted in the downregulation of Qp-EBNA1 expression in C666-1 NPC cells. Since EBNA1 has been reported to block p65 activation by inhibiting IKKα/β through an unknown mechanism, we suggest that, in NPC, NF-κB signaling and EBNA1 may form a regulatory loop which supports EBV latent gene expression, while also limiting NF-κB activity. These findings emphasize the role of NF-κB signaling in the regulation of EBV latency in EBV-associated tumors. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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Graphical abstract

17 pages, 3732 KiB

Open AccessArticle

Construction and Characterization of a Humanized Anti-Epstein-Barr Virus gp350 Antibody with Neutralizing Activity in Cell Culture

by Jerome E. Tanner, Jing Hu and Caroline Alfieri

Cancers 2018, 10(4), 112; https://doi.org/10.3390/cancers10040112 - 9 Apr 2018

Cited by 9 | Viewed by 5420

Abstract

Acute Epstein-Barr virus (EBV) infection in immunosuppressed transplant patients can give rise to a malignant B-cell proliferation known as post-transplant lymphoproliferative disease (PTLD). The EBV major virion surface glycoprotein (gp)350 is a principal target of naturally occurring neutralizing antibodies and is viewed as [...] Read more.

Acute Epstein-Barr virus (EBV) infection in immunosuppressed transplant patients can give rise to a malignant B-cell proliferation known as post-transplant lymphoproliferative disease (PTLD). The EBV major virion surface glycoprotein (gp)350 is a principal target of naturally occurring neutralizing antibodies and is viewed as the best target to prevent acute infection and PTLD in at-risk transplant recipients. We have constructed a humanized (hu) version of the murine anti-gp350 neutralizing monoclonal antibody 72a1. The hu72a1 IgG1 antibody displayed no significant anti-mouse activity, recognized both gp350 and its splice variant gp220 as well as a gp350 peptide that was shown to constitute the principal EBV gp350 neutralizing epitope when tested in immunoassays. Hu72a1 antibody blocked in vitro EBV infection of B cells at a level which equaled that of a mouse-human chimeric 72a1 antibody construct. This work provides a further structural and immunological understanding of the 72a1 antibody interaction with EBV gp350, and constitutes a launch point for future anti-EBV therapeutic antibodies designed to block EBV infection and prevent PTLD while eliminating the deleterious antigenic murine features of the original 72a1 antibody. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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13 pages, 1317 KiB

Open AccessArticle

EBV⁺ and MSI Gastric Cancers Harbor High PD-L1/PD-1 Expression and High CD8⁺ Intratumoral Lymphocytes

by Simona De Rosa, Nora Sahnane, Maria Grazia Tibiletti, Francesca Magnoli, Alessandro Vanoli, Fausto Sessa and Anna Maria Chiaravalli

Cancers 2018, 10(4), 102; https://doi.org/10.3390/cancers10040102 - 1 Apr 2018

Cited by 53 | Viewed by 6481

Abstract

Both EBV⁺ and MSI gastric cancers (GCs) have high lymphoid infiltration which is rare in MSS/EBV⁻ cancers. PD-L1/PD-1 interaction leads to a down-regulated immune response and it is one of the most promising targets for gastric cancer immunotherapy. PD-L1/PD-1 and CD8 [...] Read more.

Both EBV⁺ and MSI gastric cancers (GCs) have high lymphoid infiltration which is rare in MSS/EBV⁻ cancers. PD-L1/PD-1 interaction leads to a down-regulated immune response and it is one of the most promising targets for gastric cancer immunotherapy. PD-L1/PD-1 and CD8 expression were immunohistochemically investigated in a series of 169 FFPE GCs, including 33 EBV⁺, 59 MSI and 77 MSS/EBV⁻ cases. PD-L1 membrane immunoreactivity in more than 5% of tumor cells was present in 31/169 GCs and was associated with high levels of CD8 intraepithelial lymphocytes (TILs; p < 0.001). PD-L1⁺ cases were mainly poorly differentiated (71%), intestinal type (85%) and high lymphoid response (HLR; 90%) tumors. PD-L1 expression was only present in EBV⁺ (46%), MSI (24%) and rare MSS/EBV⁻ (3%) GCs with high CD8⁺ TILs (p < 0.001). Despite being associated with a better prognosis both in the whole series (p < 0.05) and in the MSI subset, PD-L1 is not an independent prognostic factor. PD-L1 gene amplification was detected in 3/17 cases, including 2/7 EBV⁺ and 1/8 MSI GC. PD-1⁺ TILs were significantly higher in EBV⁺ than MSI and MSS/EBV⁻ cases. PD-L1/PD-1 pathway is selectively activated in HLR GCs and could be considered an emerging therapeutic target, particularly for EBV and MSI GCs. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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19 pages, 8121 KiB

Open AccessFeature PaperArticle

Curcuminoids as EBV Lytic Activators for Adjuvant Treatment in EBV-Positive Carcinomas

by Octavia Ramayanti, Mitch Brinkkemper, Sandra A. W. M. Verkuijlen, Leni Ritmaleni, Mei Lin Go and Jaap M. Middeldorp

Cancers 2018, 10(4), 89; https://doi.org/10.3390/cancers10040089 - 22 Mar 2018

Cited by 20 | Viewed by 5066

Abstract

Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+VPA) to reactivate latent EBV into the lytic phase and antiviral valganciclovir to enhance cell death and [...] Read more.

Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+VPA) to reactivate latent EBV into the lytic phase and antiviral valganciclovir to enhance cell death and prevent virus production. CLVA treatment has proven safe in phase-I/II trials with promising clinical responses in patients with recurrent NPC. However, a major challenge is to maximize EBV lytic reactivation by CLVA. Curcumin, a dietary spice used in Asian countries, is known for its antitumor property and therapeutic potential. Novel curcuminoids that were developed to increase efficacy and bioavailability may serve as oral CLVA adjuvants. We investigated the potential of curcumin and its analogs (curcuminoids) to trigger the EBV lytic cycle in EBVaGC and NPC cells. EBV-reactivating effects were measured by immunoblot and immunofluorescence using monoclonal antibodies specific for EBV lytic proteins. Two of the hit compounds (41, EF24) with high lytic inducing activity were further studied for their synergistic or antagonistic effects when combined with GCb+VPA and analyzed by cytotoxicity and mRNA profiling assays to measure the EBV reactivation. Curcuminoid as a single agent significantly induced EBV reactivation in recombinant GC and NPC lines. The drug effects were dose- and time-dependent. Micromolar concentration of curcuminoid EF24 enhanced the CLVA effect in all cell systems except SNU719, a naturally infected EBVaGC cell that carries a more tightly latent viral genome. These findings indicated that EF24 has potential as EBV lytic activator and may serve as an adjuvant in CLVA treatment. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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14 pages, 1579 KiB

Open AccessArticle

Epstein–Barr Virus Gene BARF1 Expression is Regulated by the Epithelial Differentiation Factor ΔNp63α in Undifferentiated Nasopharyngeal Carcinoma

by Eveline Hoebe, Coral Wille, Stacy Hagemeier, Shannon Kenney, Astrid Greijer and Jaap Middeldorp

Cancers 2018, 10(3), 76; https://doi.org/10.3390/cancers10030076 - 17 Mar 2018

Cited by 13 | Viewed by 4958

Abstract

Epstein–Barr Virus (EBV) BamHI-A rightward frame 1 (BARF1) protein is considered a viral oncogene in epithelial cells and has immune-modulating properties. During viral lytic replication BARF1 is expressed as an early gene, regulated by the immediate early EBV protein R. However, in viral [...] Read more.

Epstein–Barr Virus (EBV) BamHI-A rightward frame 1 (BARF1) protein is considered a viral oncogene in epithelial cells and has immune-modulating properties. During viral lytic replication BARF1 is expressed as an early gene, regulated by the immediate early EBV protein R. However, in viral latency BARF1 is exclusively expressed in epithelial tumors such as nasopharyngeal (NPC) and gastric carcinoma (GC) but not in lymphomas, indicating that activation of the BARF1 promoter is cell type specific. Undifferentiated NPC is characterized by high expression of ΔNp63 isoforms of the epithelial differentiation marker p63, a member of the p53 family of transcription factors. Transcription factor binding site analysis indicated potential p53 family binding sites within the BARF1 promoter region. This study investigated ability of various p53 family members to transactivate the BARF1 promoter. Using BARF1 promoter luciferase reporter constructs we demonstrate that only p63 isoform ΔNp63α is capable of transactivating the BARF1 promoter, but not the TAp63 isoforms, p53 or p73. Direct promoter binding of ΔNp63α was confirmed by Chromatin Immune Precipitation (ChIP) analysis. Deletion mutants of the BARF1 promoter revealed multiple ΔNp63 response elements to be responsible for BARF1 promoter transactivation. However, ΔNp63α alone was not sufficient to induce BARF1 in tumor cells harboring full EBV genomes, indicating that additional cofactors might be required for full BARF1 regulation. In conclusion, in EBV positive NPC and GC, BARF1 expression might be induced by the epithelial differentiation marker ΔNp63α, explaining BARF1 expression in the absence of lytic reactivation. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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14 pages, 1102 KiB

Open AccessArticle

New Interactors of the Truncated EBNA-LP Protein Identified by Mass Spectrometry in P3HR1 Burkitt’s Lymphoma Cells

by Sonia Chelouah, Emilie Cochet, Sophie Couvé, Sandy Balkaran, Aude Robert, Evelyne May, Vasily Ogryzko and Joëlle Wiels

Cancers 2018, 10(1), 12; https://doi.org/10.3390/cancers10010012 - 5 Jan 2018

Cited by 6 | Viewed by 4799

Abstract

The Epstein-Barr virus nuclear antigen leader protein (EBNA-LP) acts as a co-activator of EBNA-2, a transcriptional activator essential for Epstein-Barr virus (EBV)-induced B-cell transformation. Burkitt’s lymphoma (BL) cells harboring a mutant EBV strain that lacks both the EBNA-2 gene and 3′ exons of [...] Read more.

The Epstein-Barr virus nuclear antigen leader protein (EBNA-LP) acts as a co-activator of EBNA-2, a transcriptional activator essential for Epstein-Barr virus (EBV)-induced B-cell transformation. Burkitt’s lymphoma (BL) cells harboring a mutant EBV strain that lacks both the EBNA-2 gene and 3′ exons of EBNA-LP express Y1Y2-truncated isoforms of EBNA-LP (tEBNA-LP) and better resist apoptosis than if infected with the wild-type virus. In such BL cells, tEBNA-LP interacts with the protein phosphatase 2A (PP2A) catalytic subunit (PP2A C), and this interaction likely plays a role in resistance to apoptosis. Here, 28 cellular and four viral proteins have been identified by mass spectrometry as further possible interactors of tEBNA-LP. Three interactions were confirmed by immunoprecipitation and Western blotting, namely with the A structural subunit of PP2A (PP2A A), the structure-specific recognition protein 1 (SSRP1, a component of the facilitate chromatin transcription (FACT) complex), and a new form of the transcription factor EC (TFEC). Thus, tEBNA-LP appears to be involved not only in cell resistance to apoptosis through its interaction with two PP2A subunits, but also in other processes where its ability to co-activate transcriptional regulators could be important. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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Review

Jump to: Research, Other

13 pages, 1138 KiB

Open AccessReview

The Phylogeographic Diversity of EBV and Admixed Ancestry in the Americas–Another Model of Disrupted Human-Pathogen Co-Evolution

by Alejandro H. Corvalán, Jenny Ruedlinger, Tomas de Mayo, Iva Polakovicova, Patricio Gonzalez-Hormazabal and Francisco Aguayo

Cancers 2019, 11(2), 217; https://doi.org/10.3390/cancers11020217 - 14 Feb 2019

Cited by 8 | Viewed by 4990

Abstract

Epstein-Barr virus (EBV) is an etiological agent for gastric cancer with significant worldwide variations. Molecular characterizations of EBV have shown phylogeographical variations among healthy populations and in EBV-associated diseases, particularly the cosegregated BamHI-I fragment and XhoI restriction site of exon 1 of the [...] Read more.

Epstein-Barr virus (EBV) is an etiological agent for gastric cancer with significant worldwide variations. Molecular characterizations of EBV have shown phylogeographical variations among healthy populations and in EBV-associated diseases, particularly the cosegregated BamHI-I fragment and XhoI restriction site of exon 1 of the LMP-1 gene. In the Americas, both cosegregated variants are present in EBV carriers, which aligns with the history of Asian and European human migration to this continent. Furthermore, novel recombinant variants have been found, reflecting the genetic makeup of this continent. However, in the case of EBV-associated gastric cancer (EBV-associated GC), the cosegregated European BamHI-“i” fragment and XhoI restriction site strain prevails. Thus, we propose that a disrupted coevolution between viral phylogeographical strains and mixed human ancestry in the Americas might explain the high prevalence of this particular gastric cancer subtype. This cosegregated region contains two relevant transcripts for EBV-associated GC, the BARF-1 and miR-BARTs. Thus, genome-wide association studies (GWAS) or targeted sequencing of both transcripts may be required to clarify their role as a potential source of this disrupted coevolution. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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17 pages, 2493 KiB

Open AccessReview

Co-Expression of the Epstein-Barr Virus-Encoded Latent Membrane Proteins and the Pathogenesis of Classic Hodgkin Lymphoma

by Katerina Vrzalikova, Maha Ibrahim, Eszter Nagy, Martina Vockerodt, Tracey Perry, Wenbin Wei, Ciaran Woodman and Paul Murray

Cancers 2018, 10(9), 285; https://doi.org/10.3390/cancers10090285 - 24 Aug 2018

Cited by 19 | Viewed by 4816

Abstract

The Epstein-Barr virus (EBV) is present in the tumour cells of a subset of patients with classic Hodgkin lymphoma (cHL), yet the contribution of the virus to the pathogenesis of these tumours remains only poorly understood. The EBV genome in virus-associated cHL expresses [...] Read more.

The Epstein-Barr virus (EBV) is present in the tumour cells of a subset of patients with classic Hodgkin lymphoma (cHL), yet the contribution of the virus to the pathogenesis of these tumours remains only poorly understood. The EBV genome in virus-associated cHL expresses a limited subset of genes, restricted to the non-coding Epstein-Barr virus-encoded RNAs (EBERs) and viral miRNA, as well as only three virus proteins; the Epstein-Barr virus nuclear antigen-1 (EBNA1), and the two latent membrane proteins, known as LMP1 and LMP2, the latter of which has two isoforms, LMP2A and LMP2B. LMP1 and LMP2A are of particular interest because they are co-expressed in tumour cells and can activate cellular signalling pathways, driving aberrant cellular transcription in infected B cells to promote lymphomagenesis. This article seeks to bring together the results of recent studies of the latent membrane proteins in different B cell systems, including experiments in animal models as well as a re-analysis of our own transcriptional data. In doing so, we summarise the potentially co-operative and antagonistic effects of the LMPs that are relevant to B cell lymphomagenesis. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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23 pages, 1054 KiB

Open AccessReview

The Dynamic Roles of TGF-β Signalling in EBV-Associated Cancers

by Sharmila Velapasamy, Christopher W. Dawson, Lawrence S. Young, Ian C. Paterson and Lee Fah Yap

Cancers 2018, 10(8), 247; https://doi.org/10.3390/cancers10080247 - 27 Jul 2018

Cited by 23 | Viewed by 12126

Abstract

The transforming growth factor-β (TGF-β) signalling pathway plays a critical role in carcinogenesis. It has a biphasic action by initially suppressing tumorigenesis but promoting tumour progression in the later stages of disease. Consequently, the functional outcome of TGF-β signalling is strongly context-dependent and [...] Read more.

The transforming growth factor-β (TGF-β) signalling pathway plays a critical role in carcinogenesis. It has a biphasic action by initially suppressing tumorigenesis but promoting tumour progression in the later stages of disease. Consequently, the functional outcome of TGF-β signalling is strongly context-dependent and is influenced by various factors including cell, tissue and cancer type. Disruption of this pathway can be caused by various means, including genetic and environmental factors. A number of human viruses have been shown to modulate TGF-β signalling during tumorigenesis. In this review, we describe how this pathway is perturbed in Epstein-Barr virus (EBV)-associated cancers and how EBV interferes with TGF-β signal transduction. The role of TGF-β in regulating the EBV life cycle in tumour cells is also discussed. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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20 pages, 1107 KiB

Open AccessReview

Genomic Landscapes of EBV-Associated Nasopharyngeal Carcinoma vs. HPV-Associated Head and Neck Cancer

by Hoi-Lam Ngan, Lan Wang, Kwok-Wai Lo and Vivian Wai Yan Lui

Cancers 2018, 10(7), 210; https://doi.org/10.3390/cancers10070210 - 21 Jun 2018

Cited by 46 | Viewed by 6990

Abstract

Epstein-Barr virus-positive nasopharyngeal carcinoma (EBV(+) NPC), and human papillomavirus-positive head and neck squamous cell carcinoma (HPV(+) HNSCC) are two distinct types of aggressive head and neck cancers with early age onsets. Their recently identified genomic landscapes by whole-exome sequencing (WES) clearly reveal critical [...] Read more.

Epstein-Barr virus-positive nasopharyngeal carcinoma (EBV(+) NPC), and human papillomavirus-positive head and neck squamous cell carcinoma (HPV(+) HNSCC) are two distinct types of aggressive head and neck cancers with early age onsets. Their recently identified genomic landscapes by whole-exome sequencing (WES) clearly reveal critical roles of: (1) inflammation via NF-kB activation, (2) survival via PI3K aberrations, and perhaps (3) immune evasion via MHC loss in these cancers as summarized in this review. Immediate outcomes of these WES studies include the identification of potential prognostic biomarkers, and druggable events for these cancers. The impact of these genomic findings on the development of precision medicine and immunotherapies will be discussed. For both of these cancers, the main lethality comes from metastases and disease recurrences which may represent therapy resistance. Thus, potential curing of these cancers still relies on future identification of key genomic drivers and likely druggable events in recurrent and metastatic forms of these intrinsically aggressive cancers of the head and neck. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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13 pages, 1680 KiB

Open AccessEditor’s ChoiceReview

Clinical Importance of Epstein–Barr Virus-Associated Gastric Cancer

by Jun Nishikawa, Hisashi Iizasa, Hironori Yoshiyama, Kanami Shimokuri, Yuki Kobayashi, Sho Sasaki, Munetaka Nakamura, Hideo Yanai, Kohei Sakai, Yutaka Suehiro, Takahiro Yamasaki and Isao Sakaida

Cancers 2018, 10(6), 167; https://doi.org/10.3390/cancers10060167 - 29 May 2018

Cited by 68 | Viewed by 8177

Abstract

Epstein–Barr virus-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. EBVaGC has definite histological characteristics similar to gastric carcinoma with lymphoid stroma. Clinically, EBVaGC has a significantly low frequency of lymph node metastasis compared with EBV-negative gastric cancer, resulting [...] Read more.

Epstein–Barr virus-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. EBVaGC has definite histological characteristics similar to gastric carcinoma with lymphoid stroma. Clinically, EBVaGC has a significantly low frequency of lymph node metastasis compared with EBV-negative gastric cancer, resulting in a better prognosis. The Cancer Genome Atlas of gastric adenocarcinomas proposed a molecular classification divided into four molecular subtypes: (1) EBVaGC; (2) microsatellite instability; (3) chromosomal instability; and (4) genomically stable tumors. EBVaGC harbors a DNA methylation phenotype, PD-L1 and PD-L2 overexpression, and frequent alterations in the PIK3CA gene. We review clinical importance of EBVaGC and discuss novel therapeutic applications for EBVaGC. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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30 pages, 16898 KiB

Open AccessReview

EBNA1: Oncogenic Activity, Immune Evasion and Biochemical Functions Provide Targets for Novel Therapeutic Strategies against Epstein-Barr Virus- Associated Cancers

by Joanna B. Wilson, Evelyne Manet, Henri Gruffat, Pierre Busson, Marc Blondel and Robin Fahraeus

Cancers 2018, 10(4), 109; https://doi.org/10.3390/cancers10040109 - 6 Apr 2018

Cited by 49 | Viewed by 11155

Abstract

The presence of the Epstein-Barr virus (EBV)-encoded nuclear antigen-1 (EBNA1) protein in all EBV-carrying tumours constitutes a marker that distinguishes the virus-associated cancer cells from normal cells and thereby offers opportunities for targeted therapeutic intervention. EBNA1 is essential for viral genome maintenance and [...] Read more.

The presence of the Epstein-Barr virus (EBV)-encoded nuclear antigen-1 (EBNA1) protein in all EBV-carrying tumours constitutes a marker that distinguishes the virus-associated cancer cells from normal cells and thereby offers opportunities for targeted therapeutic intervention. EBNA1 is essential for viral genome maintenance and also for controlling viral gene expression and without EBNA1, the virus cannot persist. EBNA1 itself has been linked to cell transformation but the underlying mechanism of its oncogenic activity has been unclear. However, recent data are starting to shed light on its growth-promoting pathways, suggesting that targeting EBNA1 can have a direct growth suppressing effect. In order to carry out its tasks, EBNA1 interacts with cellular factors and these interactions are potential therapeutic targets, where the aim would be to cripple the virus and thereby rid the tumour cells of any oncogenic activity related to the virus. Another strategy to target EBNA1 is to interfere with its expression. Controlling the rate of EBNA1 synthesis is critical for the virus to maintain a sufficient level to support viral functions, while at the same time, restricting expression is equally important to prevent the immune system from detecting and destroying EBNA1-positive cells. To achieve this balance EBNA1 has evolved a unique repeat sequence of glycines and alanines that controls its own rate of mRNA translation. As the underlying molecular mechanisms for how this repeat suppresses its own rate of synthesis in cis are starting to be better understood, new therapeutic strategies are emerging that aim to modulate the translation of the EBNA1 mRNA. If translation is induced, it could increase the amount of EBNA1-derived antigenic peptides that are presented to the major histocompatibility (MHC) class I pathway and thus, make EBV-carrying cancers better targets for the immune system. If translation is further suppressed, this would provide another means to cripple the virus. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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18 pages, 363 KiB

Open AccessReview

Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma

by Shaina Chor Mei Huang, Sai Wah Tsao and Chi Man Tsang

Cancers 2018, 10(4), 106; https://doi.org/10.3390/cancers10040106 - 4 Apr 2018

Cited by 58 | Viewed by 5910

Abstract

Undifferentiated nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. In addition, heavy infiltration of leukocytes is a common characteristic of EBV-associated NPC. It has long been suggested that substantial and interactive impacts between cancer and stromal cells create a tumor [...] Read more.

Undifferentiated nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. In addition, heavy infiltration of leukocytes is a common characteristic of EBV-associated NPC. It has long been suggested that substantial and interactive impacts between cancer and stromal cells create a tumor microenvironment (TME) to promote tumorigenesis. The coexistence of tumor-infiltrating lymphocytes with EBV-infected NPC cells represents a distinct TME which supports immune evasion and cancer development from the early phase of EBV infection. Intracellularly, EBV-encoded viral products alter host cell signaling to facilitate tumor development and progression. Intercellularly, EBV-infected cancer cells communicate with stromal cells through secretion of cytokines and chemokines, or via release of tumor exosomes, to repress immune surveillance and enhance metastasis. Although high expression of miR-BARTs has been detected in NPC patients, contributions of these more recently discovered viral products to the establishment of TME are still vaguely defined. Further investigations are needed to delineate the mechanistic linkage of the interplay between viral and host factors, especially in relation to TME, which can be harnessed in future therapeutic strategies. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

25 pages, 2039 KiB

Open AccessFeature PaperReview

The Immunomodulatory Capacity of an Epstein-Barr Virus Abortive Lytic Cycle: Potential Contribution to Viral Tumorigenesis

by Abigail Morales-Sánchez and Ezequiel M. Fuentes-Panana

Cancers 2018, 10(4), 98; https://doi.org/10.3390/cancers10040098 - 30 Mar 2018

Cited by 38 | Viewed by 8755

Abstract

Epstein-Barr virus (EBV) is characterized by a bipartite life cycle in which latent and lytic stages are alternated. Latency is compatible with long-lasting persistency within the infected host, while lytic expression, preferentially found in oropharyngeal epithelial tissue, is thought to favor host-to-host viral [...] Read more.

Epstein-Barr virus (EBV) is characterized by a bipartite life cycle in which latent and lytic stages are alternated. Latency is compatible with long-lasting persistency within the infected host, while lytic expression, preferentially found in oropharyngeal epithelial tissue, is thought to favor host-to-host viral dissemination. The clinical importance of EBV relates to its association with cancer, which we think is mainly a consequence of the latency/persistency mechanisms. However, studies in murine models of tumorigenesis/lymphomagenesis indicate that the lytic cycle also contributes to cancer formation. Indeed, EBV lytic expression is often observed in established cell lines and tumor biopsies. Within the lytic cycle EBV expresses a handful of immunomodulatory (BCRF1, BARF1, BNLF2A, BGLF5 & BILF1) and anti-apoptotic (BHRF1 & BALF1) proteins. In this review, we discuss the evidence supporting an abortive lytic cycle in which these lytic genes are expressed, and how the immunomodulatory mechanisms of EBV and related herpesviruses Kaposi Sarcoma herpesvirus (KSHV) and human cytomegalovirus (HCMV) result in paracrine signals that feed tumor cells. An abortive lytic cycle would reconcile the need of lytic expression for viral tumorigenesis without relaying in a complete cycle that would induce cell lysis to release the newly formed infective viral particles. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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22 pages, 1168 KiB

Open AccessFeature PaperReview

New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma

by Kathy H. Y. Shair, Akhil Reddy and Vaughn S. Cooper

Cancers 2018, 10(4), 86; https://doi.org/10.3390/cancers10040086 - 21 Mar 2018

Cited by 29 | Viewed by 6085

Abstract

Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) oncogenic protein that has no intrinsic enzymatic activity or sequence homology to cellular or viral proteins. The oncogenic potential of LMP1 has been ascribed to pleiotropic signaling properties initiated through protein-protein interactions in [...] Read more.

Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) oncogenic protein that has no intrinsic enzymatic activity or sequence homology to cellular or viral proteins. The oncogenic potential of LMP1 has been ascribed to pleiotropic signaling properties initiated through protein-protein interactions in cytosolic membrane compartments, but the effects of LMP1 extend to nuclear and extracellular processes. Although LMP1 is one of the latent genes required for EBV-immortalization of B cells, the biology of LMP1 in the pathogenesis of the epithelial cancer nasopharyngeal carcinoma (NPC) is more complex. NPC is prevalent in specific regions of the world with high incidence in southeast China. The epidemiology and time interval from seroconversion to NPC onset in adults would suggest the involvement of multiple risk factors that complement the establishment of a latent and persistent EBV infection. The contribution of LMP1 to EBV pathogenesis in polarized epithelia has only recently begun to be elucidated. Furthermore, the LMP1 gene has emerged as one of the most divergent sequences in the EBV genome. This review will discuss the significance of recent advances in NPC research from elucidating LMP1 function in epithelial cells and lessons that could be learned from mining LMP1 sequence diversity. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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6 pages, 211 KiB

Open AccessCommentary

Antiviral Drugs for EBV

by Joseph S. Pagano, Christopher B. Whitehurst and Graciela Andrei

Cancers 2018, 10(6), 197; https://doi.org/10.3390/cancers10060197 - 13 Jun 2018

Cited by 56 | Viewed by 8524

Abstract

Epstein–Barr virus (EBV) infects up to 95% of the adult human population, with primary infection typically occurring during childhood and usually asymptomatic. However, EBV can cause infectious mononucleosis in approximately 35–50% cases when infection occurs during adolescence and early adulthood. Epstein–Barr virus is [...] Read more.

Epstein–Barr virus (EBV) infects up to 95% of the adult human population, with primary infection typically occurring during childhood and usually asymptomatic. However, EBV can cause infectious mononucleosis in approximately 35–50% cases when infection occurs during adolescence and early adulthood. Epstein–Barr virus is also associated with several B-cell malignancies including Burkitt lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disease. A number of antiviral drugs have proven to be effective inhibitors of EBV replication, yet have resulted in limited success clinically, and none of them has been approved for treatment of EBV infections. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

7 pages, 850 KiB

Open AccessCommentary

Epstein Barr Virus-Associated Hodgkin Lymphoma

by Antonino Carbone and Annunziata Gloghini

Cancers 2018, 10(6), 163; https://doi.org/10.3390/cancers10060163 - 25 May 2018

Cited by 24 | Viewed by 5258

Abstract

Classical Hodgkin lymphoma (cHL) is a distinct clinical and pathological entity with heterogeneous genetic and virological features, with regards to Epstein–Barr virus (EBV) infection. The variable association of cHL with EBV infection is probably related to the different levels of patient immunosuppression, both [...] Read more.

Classical Hodgkin lymphoma (cHL) is a distinct clinical and pathological entity with heterogeneous genetic and virological features, with regards to Epstein–Barr virus (EBV) infection. The variable association of cHL with EBV infection is probably related to the different levels of patient immunosuppression, both locally in the tumour tissue and at the systemic level. This review paper focuses on EBV-related cHL highlighting pathogenetic and pathological features that may impact pathobiology-driven treatment for the affected patients. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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5 pages, 1387 KiB

Open AccessPerspective

Perspective: Contribution of Epstein–Barr virus (EBV) Reactivation to the Carcinogenicity of Nasopharyngeal Cancer Cells

by Chung-Chun Wu, Chih-Yeu Fang, Sheng-Yen Huang, Shih-Hsin Chiu, Chia-Huei Lee and Jen-Yang Chen

Cancers 2018, 10(4), 120; https://doi.org/10.3390/cancers10040120 - 17 Apr 2018

Cited by 18 | Viewed by 6279

Abstract

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma derived from the epithelium of the post-nasal cavity, with a unique geographic and ethnic distribution. Epstein–Barr virus (EBV) is an etiological agent of NPC, but how it contributes to carcinogenesis is not completely clear. Although [...] Read more.

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma derived from the epithelium of the post-nasal cavity, with a unique geographic and ethnic distribution. Epstein–Barr virus (EBV) is an etiological agent of NPC, but how it contributes to carcinogenesis is not completely clear. Although it is thought that EBV latency participates in the development of NPC, increasing evidence reveals that the lytic cycle also plays an important role in the carcinogenic process. In this review, we summarize our recent studies on how EBV reactivation causes genomic instability and accelerates tumorigenesis in epithelial cells. The roles of three lytic genes, namely, BRLF1, BGLF5 and BALF3, in this process are also introduced. Moreover, blocking EBV reactivation using natural compounds may help delay the progression of NPC tumorigenesis. These studies provide a new insight into NPC carcinogenesis and raise the possibility that inhibition of EBV reactivation may be a novel approach to prevent the relapse of NPC. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)

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