Cancers

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Open AccessEditorial

Epstein–Barr Virus Infection in Cancer

by Lucia Mundo, Lorenzo Leoncini and Rosita Accardi-Gheit

Cancers 2023, 15(18), 4659; https://doi.org/10.3390/cancers15184659 - 21 Sep 2023

Cited by 4 | Viewed by 3059

Abstract

EBV was the first human oncogenic virus identified [...] Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

Research

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15 pages, 1187 KiB

Open AccessArticle

Impact of Tumour Epstein–Barr Virus Status on Clinical Outcome in Patients with Classical Hodgkin Lymphoma (cHL): A Review of the Literature and Analysis of a Clinical Trial Cohort of Children with cHL

by Mahdi Nohtani, Katerina Vrzalikova, Maha Ibrahim, Judith E. Powell, Éanna Fennell, Susan Morgan, Richard Grundy, Keith McCarthy, Sarah Dewberry, Jan Bouchal, Katerina Bouchalova, Pamela Kearns and Paul G. Murray

Cancers 2022, 14(17), 4297; https://doi.org/10.3390/cancers14174297 - 1 Sep 2022

Cited by 5 | Viewed by 2567

Abstract

In this study, we have re-evaluated how EBV status influences clinical outcome. To accomplish this, we performed a literature review of all studies that have reported the effect of EBV status on patient outcome and also explored the effect of EBV positivity on [...] Read more.

In this study, we have re-evaluated how EBV status influences clinical outcome. To accomplish this, we performed a literature review of all studies that have reported the effect of EBV status on patient outcome and also explored the effect of EBV positivity on outcome in a clinical trial of children with cHL from the UK. Our literature review revealed that almost all studies of older adults/elderly patients have reported an adverse effect of an EBV-positive status on outcome. In younger adults with cHL, EBV-positive status was either associated with a moderate beneficial effect or no effect, and the results in children and adolescents were conflicting. Our own analysis of a series of 166 children with cHL revealed no difference in overall survival between EBV-positive and EBV-negative groups (p = 0.942, log rank test). However, EBV-positive subjects had significantly longer event-free survival (p = 0.0026). Positive latent membrane protein 1 (LMP1) status was associated with a significantly lower risk of treatment failure in a Cox regression model (HR = 0.21, p = 0.005). In models that controlled for age, gender, and stage, EBV status had a similar effect size and statistical significance. This study highlights the age-related impact of EBV status on outcome in cHL patients and suggests different pathogenic effects of EBV at different stages of life. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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20 pages, 8008 KiB

Open AccessArticle

Interplay between IL-10, IFN-γ, IL-17A and PD-1 Expressing EBNA1-Specific CD4⁺ and CD8⁺ T Cell Responses in the Etiologic Pathway to Endemic Burkitt Lymphoma

by Catherine S. Forconi, David H. Mulama, Priya Saikumar Lakshmi, Joslyn Foley, Juliana A. Otieno, Jonathan D. Kurtis, Leslie J. Berg, John M. Ong’echa, Christian Münz and Ann M. Moormann

Cancers 2021, 13(21), 5375; https://doi.org/10.3390/cancers13215375 - 27 Oct 2021

Cited by 3 | Viewed by 2802

Abstract

Children diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-γ (IFN-γ) responses to Epstein–Barr Nuclear Antigen1 (EBNA1), the viral protein that defines the latency I pattern in this B cell tumor. However, the contributions of immune-regulatory cytokines and phenotypes of the EBNA1-specific [...] Read more.

Children diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-γ (IFN-γ) responses to Epstein–Barr Nuclear Antigen1 (EBNA1), the viral protein that defines the latency I pattern in this B cell tumor. However, the contributions of immune-regulatory cytokines and phenotypes of the EBNA1-specific T cells have not been characterized for eBL. Using a bespoke flow cytometry assay we measured intracellular IFN-γ, IL-10, IL-17A expression and phenotyped CD4⁺ and CD8⁺ T cell effector memory subsets specific to EBNA1 for eBL patients compared to two groups of healthy children with divergent malaria exposures. In response to EBNA1 and a malaria antigen (PfSEA-1A), the three study groups exhibited strikingly different cytokine expression and T cell memory profiles. EBNA1-specific IFN-γ-producing CD4⁺ T cell response rates were lowest in eBL (40%) compared to children with high malaria (84%) and low malaria (66%) exposures (p < 0.0001 and p = 0.0004, respectively). However, eBL patients did not differ in CD8⁺ T cell response rates or the magnitude of IFN-γ expression. In contrast, eBL children were more likely to have EBNA1-specific CD4⁺ T cells expressing IL-10, and less likely to have polyfunctional IFN-γ⁺IL-10⁺ CD4⁺ T cells (p = 0.02). They were also more likely to have IFN-γ⁺IL-17A⁺, IFN-γ⁺ and IL-17A⁺ CD8⁺ T cell subsets compared to healthy children. Cytokine-producing T cell subsets were predominantly CD45RA⁺CCR7⁺ T_NAIVE-LIKE cells, yet PD-1, a marker of persistent activation/exhaustion, was more highly expressed by the central memory (T_CM) and effector memory (T_EM) T cell subsets. In summary, our study suggests that IL-10 mediated immune regulation and depletion of IFN-γ⁺ EBNA1-specific CD4⁺ T cells are complementary mechanisms that contribute to impaired T cell cytotoxicity in eBL pathogenesis. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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13 pages, 1278 KiB

Open AccessArticle

Serum and Tissue Level of TLR9 in EBV-Associated Oropharyngeal Cancer

by Ewa Stępień, Małgorzata Strycharz-Dudziak, Maria Malm, Bartłomiej Drop and Małgorzata Polz-Dacewicz

Cancers 2021, 13(16), 3981; https://doi.org/10.3390/cancers13163981 - 6 Aug 2021

Cited by 6 | Viewed by 2499

Abstract

The Epstein–Barr virus (EBV) is associated with the development of various epithelial malignancies including cancer in the head and neck region. Several studies have shown that Toll-like receptors (TLRs) are required for an innate immune response to infection with human DNA viruses, e.g., [...] Read more.

The Epstein–Barr virus (EBV) is associated with the development of various epithelial malignancies including cancer in the head and neck region. Several studies have shown that Toll-like receptors (TLRs) are required for an innate immune response to infection with human DNA viruses, e.g., EBV. During viral infections, TLR response may influence the transformation to malignancy. The aim of the study was to assess TLR9 serum and tissue level in EBV(+) and EBV(−) oropharyngeal cancer patients. The study involved 78 patients: 42 EBV(+) and 36 EBV(−). EBV DNA was detected in fresh frozen tumor tissue. TLR9 level was measured in homogenate of tumor tissue and in serum. Moreover, in serum samples IL-10, VEGF, TGFβ, TNFα and antibodies against EBV were detected using ELISA test. TLR9 level was significantly lower in EBV(+) patients, both in tissue and serum, while EBVCA, EBNA and VEGF level was statistically higher in EBV(+) patients. An increase in EBVCA and EBNA antibodies titer was correlated with a TLR9 level decrease. TLR9 level was higher in poorly-differentiated tumors (G3), in tumor of larger dimensions (T3-T4) and with lymph nodes involvement (N3-N4) but without statistical significance. High levels of anti-EA antibodies in the majority of EBV(+) patients may point to the reactivation of EBV infection. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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20 pages, 8989 KiB

Open AccessArticle

PD-L1 Expression Associated with Epstein—Barr Virus Status and Patients’ Survival in a Large Cohort of Gastric Cancer Patients in Northern Brazil

by Caroline de Fátima Aquino Moreira-Nunes, Cláudia Nazaré de Souza Almeida Titan Martins, Danielle Feio, Isamu Komatsu Lima, Leticia Martins Lamarão, Carolina Rosal Teixeira de Souza, Igor Brasil Costa, Jersey Heitor da Silva Maués, Paulo Cardoso Soares, Paulo Pimentel de Assumpção and Rommel Mário Rodríguez Burbano

Cancers 2021, 13(13), 3107; https://doi.org/10.3390/cancers13133107 - 22 Jun 2021

Cited by 7 | Viewed by 2497

Abstract

Gastric cancer (GC) is a worldwide health problem, making it one of the most common types of cancer, in fifth place of all tumor types, and the third highest cause of cancer deaths in the world. There is a subgroup of GC that [...] Read more.

Gastric cancer (GC) is a worldwide health problem, making it one of the most common types of cancer, in fifth place of all tumor types, and the third highest cause of cancer deaths in the world. There is a subgroup of GC that consists of tumors infected with the Epstein–Barr virus (EBV) and is characterized mainly by the overexpression of programmed cell death protein-ligand-1 (PD-L1). In the present study, we present histopathological and survival data of a thousand GC patients, associated with EBV status and PD-L1 expression. Of the thousand tumors analyzed, 190 were EBV-positive and the vast majority (86.8%) had a high relative expression of mRNA and PD-L1 protein (p < 0.0001) in relation to non-neoplastic control. On the other hand, in EBV-negative samples, the majority had a low PD-L1 expression of RNA and protein (p < 0.0001). In the Kaplan–Meier analysis, the probability of survival and increased overall survival of EBV-positive GC patients was impacted by the PD-L1 overexpression (p < 0.0001 and p = 0.004, respectively). However, the PD-L1 low expression was correlated with low overall survival in those patients. Patients with GC positive for EBV, presenting PD-L1 overexpression can benefit from immunotherapy treatments and performing the quantification of PD-L1 in gastric neoplasms should be adopted as routine. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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13 pages, 2679 KiB

Open AccessArticle

Genetic Patterns Found in the Nuclear Localization Signals (NLSs) Associated with EBV-1 and EBV-2 Provide New Insights into Their Contribution to Different Cell-Type Specificities

by Louise Zanella, María Elena Reyes, Ismael Riquelme, Michel Abanto, Daniela León, Tamara Viscarra, Carmen Ili and Priscilla Brebi

Cancers 2021, 13(11), 2569; https://doi.org/10.3390/cancers13112569 - 24 May 2021

Cited by 4 | Viewed by 2562

Abstract

The Epstein–Barr virus (EBV) is a globally dispersed pathogen involved in several human cancers of B-cell and non-B-cell origin. EBV has been classified into EBV-1 and EBV-2, which have differences in their transformative ability. EBV-1 can transform B-cells into LCL more efficiently than [...] Read more.

The Epstein–Barr virus (EBV) is a globally dispersed pathogen involved in several human cancers of B-cell and non-B-cell origin. EBV has been classified into EBV-1 and EBV-2, which have differences in their transformative ability. EBV-1 can transform B-cells into LCL more efficiently than EBV-2, and EBV-2 preferentially infects T-cell lymphocytes. The EBNA3A oncoprotein is a transcriptional regulator of virus and host cell genes, and is required in order to transform B-cells. EBNA3A has six peptide motifs called nuclear localization signals (NLSs) that ensure nucleocytoplasmic protein trafficking. The presence of multiple NLSs has been suggested to enhance EBNA3 function or different specificities in different cell types. However, studies about the NLS variability associated with EBV types are scarce. Based on a systematic sequence analysis considering more than a thousand EBNA3A sequences of EBV from different human clinical manifestations and geographic locations, we found differences in NLSs’ nucleotide structures among EBV types. Compared with the EBNA3A EBV-1, EBNA3A EBV-2 has two of the six NLSs altered, and these mutations were possibly acquired by recombination. These genetic patterns in the NLSs associated with EBV-1 and EBV-2 provide new information about the traits of EBNA3A in EBV biology. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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20 pages, 7583 KiB

Open AccessArticle

Effects of Epstein-Barr Virus Infection on the Risk and Prognosis of Primary Laryngeal Squamous Cell Carcinoma: A Hospital-Based Case-Control Study in Taiwan

by Li-Ang Lee, Tuan-Jen Fang, Hsueh-Yu Li, Hai-Hua Chuang, Chung-Jan Kang, Kai-Ping Chang, Chun-Ta Liao, Tse-Ching Chen, Chung-Guei Huang and Tzu-Chen Yen

Cancers 2021, 13(7), 1741; https://doi.org/10.3390/cancers13071741 - 6 Apr 2021

Cited by 8 | Viewed by 3489

Abstract

Mounting molecular evidence supports Epstein–Barr virus (EBV) involvement in the pathogenesis of laryngeal squamous cell carcinoma (LSCC); however, the epidemiological data are inconsistent. In this retrospective case-control study, we aimed to determine whether EBV infection underlies the risk and prognosis of LSCC. The [...] Read more.

Mounting molecular evidence supports Epstein–Barr virus (EBV) involvement in the pathogenesis of laryngeal squamous cell carcinoma (LSCC); however, the epidemiological data are inconsistent. In this retrospective case-control study, we aimed to determine whether EBV infection underlies the risk and prognosis of LSCC. The prevalence of EBV infection, as analyzed using an EBV DNA polymerase chain reaction assay, was significantly higher in 42 Taiwanese patients with newly diagnosed primary LSCC, compared to 39 age- and sex-matched control patients without cancer (48% vs. 19%). Furthermore, most of the EBER signals detected using in situ hybridization were localized to the nuclei of tumor-infiltrating lymphocytes. In multivariate analysis, EBV DNA positivity, age ≥ 55 years, cigarette smoking, and high BCL-2, B2M, and CD161 expression (assessed using immunohistochemistry) were identified as independent risk factors for LSCC. Furthermore, five-year local recurrence and disease-free survival rates were 34% and 58%, respectively, with a high EBER signal and low CD3 expression independently predicting five-year local recurrence and disease-free survival. Our comprehensive profiling data accurately identified patients at risk for LSCC development, local recurrence, or disease-free survival. The information obtained in this study improves our understanding of EBV infection in LSCC, and may guide precision medicine for patients with LSCC. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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18 pages, 2060 KiB

Open AccessArticle

Comprehensive Epstein-Barr Virus Transcriptome by RNA-Sequencing in Angioimmunoblastic T Cell Lymphoma (AITL) and Other Lymphomas

by Nader Bayda, Valentin Tilloy, Alain Chaunavel, Racha Bahri, Mohamad Adnan Halabi, Jean Feuillard, Arnaud Jaccard and Sylvie Ranger-Rogez

Cancers 2021, 13(4), 610; https://doi.org/10.3390/cancers13040610 - 4 Feb 2021

Cited by 20 | Viewed by 8519

Abstract

The Epstein–Barr virus (EBV) is associated with angioimmunoblastic T cell lymphoma (AITL) in more than 80% of cases. Few studies have focused on this association and it is not clear now what role the virus plays in this pathology. We used next-generation sequencing [...] Read more.

The Epstein–Barr virus (EBV) is associated with angioimmunoblastic T cell lymphoma (AITL) in more than 80% of cases. Few studies have focused on this association and it is not clear now what role the virus plays in this pathology. We used next-generation sequencing (NGS) to study EBV transcriptome in 14 AITLs compared to 21 other lymphoma samples and 11 cell lines including 4 lymphoblastoid cell lines (LCLs). Viral transcripts were recovered using capture probes and sequencing was performed on Illumina. Bam-HI A rightward transcripts (BARTs) were the most latency transcripts expressed in AITLs, suggesting they may play a role in this pathology. Thus, BARTs, already described as highly expressed in carcinoma cells, are also very present in AITLs and other lymphomas. They were poorly expressed in cell lines other than LCLs. AITLs showed a latency IIc, with BNLF2a gene expression. For most AITLs, BCRF1, which encodes a homologous protein of human interleukin 10, vIL-10, was in addition expressed. This co-expression can contribute to immune escape and survival of infected cells. Considering these results, it can be assumed that EBV plays a pathogenic role in AITLs. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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11 pages, 5130 KiB

Open AccessArticle

Epstein–Barr Virus Infection of Pseudostratified Nasopharyngeal Epithelium Disrupts Epithelial Integrity

by Fenggang Yu, Yanan Lu, Yingying Li, Yuji Uchio, Utomo Andi Pangnguriseng, Andy Visi Kartika, Hisashi Iizasa, Hironori Yoshiyama and Kwok Seng Loh

Cancers 2020, 12(9), 2722; https://doi.org/10.3390/cancers12092722 - 22 Sep 2020

Cited by 7 | Viewed by 3634

Abstract

Epstein–Barr virus (EBV) is a human oncogenic virus that causes several types of tumor, such as Burkitt’s lymphoma and nasopharyngeal carcinoma (NPC). NPC tumor cells are clonal expansions of latently EBV-infected epithelial cells. However, the mechanisms by which EBV transforms the nasopharyngeal epithelium [...] Read more.

Epstein–Barr virus (EBV) is a human oncogenic virus that causes several types of tumor, such as Burkitt’s lymphoma and nasopharyngeal carcinoma (NPC). NPC tumor cells are clonal expansions of latently EBV-infected epithelial cells. However, the mechanisms by which EBV transforms the nasopharyngeal epithelium is hampered, because of the lack of good in vitro model to pursue oncogenic process. Our primary nasopharyngeal epithelial cell cultures developed pseudostratified epithelium at the air-liquid interface, which was susceptible to EBV infection. Using the highly sensitive RNA in situ hybridization technique, we detected viral infection in diverse cell types, including ciliated cells, goblet cells, and basal cells. EBV-encoded small RNA-positive cells were more frequently detected in the suprabasal layer than in the basal layer. We established the most physiologically relevant EBV infection model of nasopharyngeal epithelial cells. This model will advance our understanding of EBV pathogenesis in the development of NPC. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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17 pages, 17901 KiB

Open AccessArticle

The Clinicopathological Features and Genetic Alterations in Epstein–Barr Virus-Associated Gastric Cancer Patients after Curative Surgery

by Wen-Liang Fang, Ming-Huang Chen, Kuo-Hung Huang, Chien-Hsing Lin, Yee Chao, Su-Shun Lo, Anna Fen-Yau Li, Chew-Wun Wu and Yi-Ming Shyr

Cancers 2020, 12(6), 1517; https://doi.org/10.3390/cancers12061517 - 10 Jun 2020

Cited by 25 | Viewed by 3118

Abstract

Background: Epstein–Barr virus (EBV)-associated gastric cancer (GC) is one of four major gastric cancer types and is traditionally considered to be related to lymphoepithelioma-like GC. Few studies have investigated the clinical significance of EBV infection in intestinal/solid type, diffuse (poorly cohesive) type, and [...] Read more.

Background: Epstein–Barr virus (EBV)-associated gastric cancer (GC) is one of four major gastric cancer types and is traditionally considered to be related to lymphoepithelioma-like GC. Few studies have investigated the clinical significance of EBV infection in intestinal/solid type, diffuse (poorly cohesive) type, and lymphoepithelioma-like GC. Methods: A total of 460 GC patients receiving curative surgery were enrolled. The clinicopathological features, genetic alterations and prognoses were compared between patients with and without EBV infection. Results: EBV-positive GC patients (n = 43) had more tumors located in the upper and middle stomach, more common in lymphoepithelioma-like carcinoma, more lymphoid stroma, fewer Helicobacter pylori infections, and higher programmed death-ligand 1 (PD-L1) expression than EBV-negative GC patients. For intestinal/solid type GC, EBV-positive tumors were more likely to be located in the upper and middle stomach, have more lymphoid stroma, fewer Helicobacter pylori infections, higher PD-L1 expression, and more liver metastases than EBV-negative tumors. For diffuse (poorly cohesive) type GC, EBV-positive tumors were more likely to be located in the upper stomach, and have more lymphoid stroma than EBV-negative tumors. For lymphoepithelioma-like GC, EBV-positive tumors had more PI3K/AKT pathway mutations than EBV-negative tumors. Conclusions: Intestinal/solid type GC patients with EBV-positive tumors were associated with higher PD-L1 expression and more liver metastases, while lymphoepithelioma-like GC patients with EBV-positive tumors had more PI3K/AKT pathway mutations. Immunotherapy and targeted therapy may be beneficial for these groups of patients. Routine EBV survey is recommended in GC. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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Review

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27 pages, 1079 KiB

Open AccessReview

Clinical and Therapeutic Implications of Epstein–Barr Virus in HIV-Related Lymphomas

by Miriam Verdu-Bou, Gustavo Tapia, Agueda Hernandez-Rodriguez and Jose-Tomas Navarro

Cancers 2021, 13(21), 5534; https://doi.org/10.3390/cancers13215534 - 4 Nov 2021

Cited by 20 | Viewed by 3744

Abstract

The incidence of lymphomas is increased in people living with HIV (PLWH). Aggressive B-cell non-Hodgkin lymphomas (NHLs) are the most common and are considered an AIDS-defining cancer (ADC). Although Hodgkin lymphoma (HL) is not considered an ADC, its incidence is also increased in [...] Read more.

The incidence of lymphomas is increased in people living with HIV (PLWH). Aggressive B-cell non-Hodgkin lymphomas (NHLs) are the most common and are considered an AIDS-defining cancer (ADC). Although Hodgkin lymphoma (HL) is not considered an ADC, its incidence is also increased in PLWH. Among all HIV-related lymphomas (HRL), the prevalence of Epstein–Barr virus (EBV) is high. It has been shown that EBV is involved in different lymphomagenic mechanisms mediated by some of its proteins, contributing to the development of different lymphoma subtypes. Additionally, cooperation between both HIV and EBV can lead to the proliferation of aberrant B-cells, thereby being an additional lymphomagenic mechanism in EBV-associated HRL. Despite the close relationship between EBV and HRL, the impact of EBV on clinical aspects has not been extensively studied. These lymphomas are treated with the same therapeutic regimens as the general population in combination with cART. Nevertheless, new therapeutic strategies targeting EBV are promising for these lymphomas. In this article, the different types of HRL are extensively reviewed, focusing on the influence of EBV on the epidemiology, pathogenesis, clinical presentation, and pathological characteristics of each lymphoma subtype. Moreover, novel therapies targeting EBV and future strategies to treat HRL harboring EBV are discussed. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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22 pages, 18025 KiB

Open AccessReview

New Look of EBV LMP1 Signaling Landscape

by Ling Wang and Shunbin Ning

Cancers 2021, 13(21), 5451; https://doi.org/10.3390/cancers13215451 - 29 Oct 2021

Cited by 30 | Viewed by 5237

Abstract

The Epstein–Barr Virus (EBV) principal oncoprotein Latent Membrane Protein 1 (LMP1) is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily with constitutive activity. LMP1 shares many features with Pathogen Recognition Receptors (PRRs), including the use of TRAFs, adaptors, and kinase cascades, [...] Read more.

The Epstein–Barr Virus (EBV) principal oncoprotein Latent Membrane Protein 1 (LMP1) is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily with constitutive activity. LMP1 shares many features with Pathogen Recognition Receptors (PRRs), including the use of TRAFs, adaptors, and kinase cascades, for signal transduction leading to the activation of NFκB, AP1, and Akt, as well as a subset of IRFs and likely the master antioxidative transcription factor NRF2, which we have gradually added to the list. In recent years, we have discovered the Linear UBiquitin Assembly Complex (LUBAC), the adaptor protein LIMD1, and the ubiquitin sensor and signaling hub p62, as novel components of LMP1 signalosome. Functionally, LMP1 is a pleiotropic factor that reprograms, balances, and perturbs a large spectrum of cellular mechanisms, including the ubiquitin machinery, metabolism, epigenetics, DNA damage response, extracellular vehicles, immune defenses, and telomere elongation, to promote oncogenic transformation, cell proliferation and survival, anchorage-independent cell growth, angiogenesis, and metastasis and invasion, as well as the development of the tumor microenvironment. We have recently shown that LMP1 induces p62-mediated selective autophagy in EBV latency, at least by contributing to the induction of p62 expression, and Reactive Oxygen Species (ROS) production. We have also been collecting evidence supporting the hypothesis that LMP1 activates the Keap1-NRF2 pathway, which serves as the key antioxidative defense mechanism. Last but not least, our preliminary data shows that LMP1 is associated with the deregulation of cGAS-STING DNA sensing pathway in EBV latency. A comprehensive understanding of the LMP1 signaling landscape is essential for identifying potential targets for the development of novel strategies towards targeted therapeutic applications. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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34 pages, 1109 KiB

Open AccessReview

Epstein–Barr Virus—Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies

by Marcus Bauer, Simon Jasinski-Bergner, Ofer Mandelboim, Claudia Wickenhauser and Barbara Seliger

Cancers 2021, 13(20), 5189; https://doi.org/10.3390/cancers13205189 - 16 Oct 2021

Cited by 38 | Viewed by 5594

Abstract

The detailed mechanisms of Epstein–Barr virus (EBV) infection in the initiation and progression of EBV-associated malignancies are not yet completely understood. During the last years, new insights into the mechanisms of malignant transformation of EBV-infected cells including somatic mutations and epigenetic modifications, their [...] Read more.

The detailed mechanisms of Epstein–Barr virus (EBV) infection in the initiation and progression of EBV-associated malignancies are not yet completely understood. During the last years, new insights into the mechanisms of malignant transformation of EBV-infected cells including somatic mutations and epigenetic modifications, their impact on the microenvironment and resulting unique immune signatures related to immune system functional status and immune escape strategies have been reported. In this context, there exists increasing evidence that EBV-infected tumor cells can influence the tumor microenvironment to their own benefit by establishing an immune-suppressive surrounding. The identified mechanisms include EBV gene integration and latent expression of EBV-infection-triggered cytokines by tumor and/or bystander cells, e.g., cancer-associated fibroblasts with effects on the composition and spatial distribution of the immune cell subpopulations next to the infected cells, stroma constituents and extracellular vesicles. This review summarizes (i) the typical stages of the viral life cycle and EBV-associated transformation, (ii) strategies to detect EBV genome and activity and to differentiate various latency types, (iii) the role of the tumor microenvironment in EBV-associated malignancies, (iv) the different immune escape mechanisms and (v) their clinical relevance. This gained information will enhance the development of therapies against EBV-mediated diseases to improve patient outcome. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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17 pages, 1691 KiB

Open AccessReview

SSTR2 in Nasopharyngeal Carcinoma: Relationship with Latent EBV Infection and Potential as a Therapeutic Target

by Oscar Emanuel, Jacklyn Liu, Volker H. Schartinger, Wen Long Nei, Yuk Yu Chan, Chi Man Tsang, Herbert Riechelmann, Liam Masterson, Johannes Haybaeck, Udo Oppermann, Stefan M. Willems, Marc L. Ooft, Guido Wollmann, David Howard, Bart Vanhaesebroeck, Valerie J. Lund, Gary Royle, Melvin L. K. Chua, Kwok Wai Lo, Pierre Busson and Matt Lechner Show full author list Hide full author list

Cancers 2021, 13(19), 4944; https://doi.org/10.3390/cancers13194944 - 30 Sep 2021

Cited by 9 | Viewed by 4062

Abstract

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor, most commonly located in the pharyngeal recess and endemic to parts of Asia. It is often detected at a late stage which is associated with poor prognosis (5-year survival rate of 63%). Treatment for this [...] Read more.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor, most commonly located in the pharyngeal recess and endemic to parts of Asia. It is often detected at a late stage which is associated with poor prognosis (5-year survival rate of 63%). Treatment for this malignancy relies predominantly on radiotherapy and/or systemic chemotherapy, which can be associated with significant morbidity and impaired quality of life. In endemic regions NPC is associated with infection by Epstein–Barr virus (EBV) which was shown to upregulate the somatostatin receptor 2 (SSTR2) cell surface receptor. With recent advances in molecular techniques allowing for an improved understanding of the molecular aetiology of this disease and its relation to SSTR2 expression, we provide a comprehensive and up-to-date overview of this disease and highlight the emergence of SSTR2 as a key tumor biomarker and promising target for imaging and therapy. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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14 pages, 1098 KiB

Open AccessReview

Thymic Lymphoepithelial Carcinoma Associated with Epstein-Barr Virus: Experiences and Literature Review

by Naoko Ose, Sachi Kawagishi, Soichiro Funaki, Takashi Kanou, Eriko Fukui, Kenji Kimura, Masato Minami and Yasushi Shintani

Cancers 2021, 13(19), 4794; https://doi.org/10.3390/cancers13194794 - 24 Sep 2021

Cited by 10 | Viewed by 3133

Abstract

Thymic lymphoepithelial carcinoma (TLEC) is a primary thymic carcinoma that accounts for about 14% of all thymic epithelial tumors and is classified into 14 types. The histological morphology is similar to lymphoepithelioma, a type of undifferentiated nasopharyngeal carcinoma. It has been reported that [...] Read more.

Thymic lymphoepithelial carcinoma (TLEC) is a primary thymic carcinoma that accounts for about 14% of all thymic epithelial tumors and is classified into 14 types. The histological morphology is similar to lymphoepithelioma, a type of undifferentiated nasopharyngeal carcinoma. It has been reported that squamous carcinoma accounts for approximately 80% of thymic carcinoma, followed by TLEC, which accounts for 6%. TLEC has been reported to be associated with Epstein-Barr virus (EBV), with EBV infection in TLEC tumor cells first noted by Lyvraz et al. in 1985. Tumors shown to be EBV-positive are classified as TLEC if lymphoplasmacytic infiltration is lacking. However, only about 50% of the cases are positive for EBV, which is lower compared to nasopharyngeal lymphoepithelioma. Instances of EBV infection in other types of thymic epithelial tumor have been reported at lower rates, which suggests that EBV infection may have an important influence on the carcinogenesis of TLEC, though the etiology is unknown. TLEC is a highly malignant tumor with poor prognosis, as affected patients have a median survival time of 22 months, according to 58 cases from the literature, while the 5-year survival rate is 34.4%. Presently, prognosis is not considered to be affected by the presence or absence of EBV positivity. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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16 pages, 786 KiB

Open AccessReview

Epstein–Barr Virus in Inborn Immunodeficiency—More Than Infection

by Ciro Novaes Rosa Lino and Sujal Ghosh

Cancers 2021, 13(19), 4752; https://doi.org/10.3390/cancers13194752 - 23 Sep 2021

Cited by 16 | Viewed by 4500

Abstract

Epstein–Barr Virus (EBV) is a ubiquitous virus affecting more than 90% of the world’s population. Upon infection, it establishes latency in B cells. It is a rather benign virus for immune-competent individuals, in whom infections usually go unnoticed. Nevertheless, EBV has been extensively [...] Read more.

Epstein–Barr Virus (EBV) is a ubiquitous virus affecting more than 90% of the world’s population. Upon infection, it establishes latency in B cells. It is a rather benign virus for immune-competent individuals, in whom infections usually go unnoticed. Nevertheless, EBV has been extensively associated with tumorigenesis. Patients suffering from certain inborn errors of immunity are at high risk of developing malignancies, while infection in the majority of immune-competent individuals does not seem to lead to immune dysregulation. Herein, we discuss how inborn mutations in TNFRSF9, CD27, CD70, CORO1A, CTPS1, ITK, MAGT1, RASGRP1, STK4, CARMIL2, SH2D1A, and XIAP affect the development, differentiation, and function of key factors involved in the immunity against EBV, leading to increased susceptibility to lymphoproliferative disease and lymphoma. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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26 pages, 1781 KiB

Open AccessReview

Molecular Properties and Therapeutic Targeting of the EBV-Encoded Receptor BILF1

by Julius Maximilian Knerr, Thomas Nitschke Kledal and Mette Marie Rosenkilde

Cancers 2021, 13(16), 4079; https://doi.org/10.3390/cancers13164079 - 13 Aug 2021

Cited by 9 | Viewed by 4303

Abstract

The γ-herpesvirus Epstein–Barr Virus (EBV) establishes lifelong infections in approximately 90% of adults worldwide. Up to 1,000,000 people yearly are estimated to suffer from health conditions attributed to the infection with this virus, such as nasopharyngeal and gastric carcinomas as well as several [...] Read more.

The γ-herpesvirus Epstein–Barr Virus (EBV) establishes lifelong infections in approximately 90% of adults worldwide. Up to 1,000,000 people yearly are estimated to suffer from health conditions attributed to the infection with this virus, such as nasopharyngeal and gastric carcinomas as well as several forms of B, T and NK cell lymphoma. To date, no EBV-specific therapeutic option has reached the market, greatly reducing the survival prognoses of affected patients. Similar to other herpesviruses, EBV encodes for a G protein–coupled receptor (GPCR), BILF1, affecting a multitude of cellular signaling pathways. BILF1 has been identified to promote immune evasion and tumorigenesis, effectively ensuring a life-long persistence of EBV in, and driving detrimental health conditions to its host. This review summarizes the epidemiology of EBV-associated malignancies, their current standard-of-care, EBV-specific therapeutics in development, GPCRs and their druggability, and most importantly consolidates the findings of over 15 years of research on BILF1 in the context of EBV-specific drug development. Taken together, BILF1 constitutes a promising target for the development of novel EBV-specific therapeutics. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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26 pages, 2140 KiB

Open AccessReview

MicroRNA and Other Non-Coding RNAs in Epstein–Barr Virus-Associated Cancers

by Kin Israel Notarte, Suranga Senanayake, Imee Macaranas, Pia Marie Albano, Lucia Mundo, Eanna Fennell, Lorenzo Leoncini and Paul Murray

Cancers 2021, 13(15), 3909; https://doi.org/10.3390/cancers13153909 - 3 Aug 2021

Cited by 22 | Viewed by 5734

Abstract

EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization [...] Read more.

EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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19 pages, 1486 KiB

Open AccessReview

Epstein-Barr Virus Positive B-Cell Lymphoproliferative Disorder of the Gastrointestinal Tract

by Eri Ishikawa, Akira Satou, Masanao Nakamura, Shigeo Nakamura and Mitsuhiro Fujishiro

Cancers 2021, 13(15), 3815; https://doi.org/10.3390/cancers13153815 - 29 Jul 2021

Cited by 15 | Viewed by 3649

Abstract

Epstein-Barr virus positive B-cell lymphoproliferative disorder (EBV⁺ B-LPD) encompasses a broad clinicopathological spectrum and distinct clinical behavior that relatively favors the gastrointestinal (GI) tract. In this review, we provide an update on the clinicopathological features and biological behavior of EBV-positive mucocutaneous ulcer [...] Read more.

Epstein-Barr virus positive B-cell lymphoproliferative disorder (EBV⁺ B-LPD) encompasses a broad clinicopathological spectrum and distinct clinical behavior that relatively favors the gastrointestinal (GI) tract. In this review, we provide an update on the clinicopathological features and biological behavior of EBV-positive mucocutaneous ulcer (EBVMCU) and primary EBV⁺ diffuse large B-cell lymphoma (DLBCL) of the GI tract. EBVMCU is a newly recognized entity but well known as an indolent and self-limited EBV⁺ B-LPD occurring in various immunodeficiencies. In contrast, EBV⁺ DLBCL constitutes the largest group of EBV⁺ B-LPDs and is regarded as an aggressive neoplasm. These two distinct diseases have historically been distinguished in the reappraisal of age-related EBV-associated B-LPDs but are challenging in routine practice regarding their differential diagnostic and therapeutic approaches. An increasing number of reports indicate that they are epidemiologically prevalent beyond western and eastern countries, but their comprehensive analysis is still limited. We also describe the PD-L1 positivity of tumorous large cells and non-malignant immune cells, which is relevant for the prognostic delineation among patients with primary DLBCL of the GI tract with and without EBV on tumor cells. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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15 pages, 1016 KiB

Open AccessReview

Roles of Lytic Viral Replication and Co-Infections in the Oncogenesis and Immune Control of the Epstein–Barr Virus

by Yun Deng and Christian Münz

Cancers 2021, 13(9), 2275; https://doi.org/10.3390/cancers13092275 - 10 May 2021

Cited by 6 | Viewed by 3858

Abstract

Epstein–Barr virus (EBV) is the prototypic human tumor virus whose continuous lifelong immune control is required to prevent lymphomagenesis in the more than 90% of the human adult population that are healthy carriers of the virus. Here, we review recent evidence that this [...] Read more.

Epstein–Barr virus (EBV) is the prototypic human tumor virus whose continuous lifelong immune control is required to prevent lymphomagenesis in the more than 90% of the human adult population that are healthy carriers of the virus. Here, we review recent evidence that this immune control has not only to target latent oncogenes, but also lytic replication of EBV. Furthermore, genetic variations identify the molecular machinery of cytotoxic lymphocytes as essential for this immune control and recent studies in mice with reconstituted human immune system components (humanized mice) have begun to provide insights into the mechanistic role of these molecules during EBV infection. Finally, EBV often does not act in isolation to cause disease. Some of EBV infection-modulating co-infections, including human immunodeficiency virus (HIV) and Kaposi sarcoma-associated herpesvirus (KSHV), have been modeled in humanized mice. These preclinical in vivo models for EBV infection, lymphomagenesis, and cell-mediated immune control do not only promise a better understanding of the biology of this human tumor virus, but also the possibility to explore vaccine candidates against it. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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19 pages, 6842 KiB

Open AccessReview

EBV and the Pathogenesis of NK/T Cell Lymphoma

by Ivonne A. Montes-Mojarro, Falko Fend and Leticia Quintanilla-Martinez

Cancers 2021, 13(6), 1414; https://doi.org/10.3390/cancers13061414 - 19 Mar 2021

Cited by 41 | Viewed by 5770

Abstract

Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus with tropism for B cells. EBV is linked to the pathogenesis of B cell, T cell and NK cell lymphoproliferations, with extranodal NK/T cell lymphoma, nasal type (ENKTCL) being the prototype of an EBV-driven [...] Read more.

Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus with tropism for B cells. EBV is linked to the pathogenesis of B cell, T cell and NK cell lymphoproliferations, with extranodal NK/T cell lymphoma, nasal type (ENKTCL) being the prototype of an EBV-driven lymphoma. ENKTCL is an aggressive neoplasm, particularly widespread in East Asia and the native population of Latin America, which suggests a strong genetic predisposition. The link between ENKTCL and different populations has been partially explored. EBV genome sequencing analysis recognized two types of strains and identified variants of the latent membrane protein 1 (LMP1), which revealed different oncogenic potential. In general, most ENKTCL patients carry EBV type A with LMP1 wild type, although the LMP1 variant with a 30 base pair deletion is also common, especially in the EBV type B, where it is necessary for oncogenic transformation. Contemporary high-throughput mutational analyses have discovered recurrent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as BCOR, DDX3X and TP53. The genomic landscape in ENKTCL highlights mechanisms of lymphomagenesis, such as immune response evasion, secondary to alterations in signaling pathways or epigenetics that directly or indirectly interfere with oncogenes or tumor suppressor genes. This overview discusses the most important findings of EBV pathogenesis and genetics in ENKTCL. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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8 pages, 372 KiB

Open AccessReview

Is EBV Associated with Breast Cancer in Specific Geographic Locations?

by Alison J. Sinclair, Manal H. Moalwi and Thomas Amoaten

Cancers 2021, 13(4), 819; https://doi.org/10.3390/cancers13040819 - 16 Feb 2021

Cited by 15 | Viewed by 3186

Abstract

Epstein–Barr virus (EBV) is a virus that establishes a life-long infection in people, and infection with EBV is nearly ubiquitous by adulthood. EBV was identified from biopsy material from a child with Burkitt’s lymphoma (BL) in sub-Saharan Africa. EBV has a well-characterised role [...] Read more.

Epstein–Barr virus (EBV) is a virus that establishes a life-long infection in people, and infection with EBV is nearly ubiquitous by adulthood. EBV was identified from biopsy material from a child with Burkitt’s lymphoma (BL) in sub-Saharan Africa. EBV has a well-characterised role in the development of some cancers, notably, Burkitt’s lymphoma (BL), Hodgkin’s disease (HD), gastric carcinoma (GC), and nasopharyngeal carcinoma (NPC). Links have also been made between EBV and breast cancer (BC), but these have been controversial. For all EBV-associated cancers, the ubiquitous nature of infection with EBV, contrasted with the relatively rare development of cancer, highlights a problem of determining whether EBV is an aetiological agent of cancer. In addition, the geographic distributions of some EBV-associated cancers point to contributions from additional co-factors. Recent meta-analyses of the incidence of EBV within BC biopsies has revealed that the diversity in the conclusions remain, however, they also show more of an association between EBV and BC biopsies in some study locations. Here, we review the evidence linking EBV with BC, and conclude that the evidence for the presence of EBV in BC biopsies is concentrated in specific geographic regions but is currently insufficient to provide a causal link. We pose some questions that could help to resolve the question of whether EBV contributes to BC and probe the contribution EBV might make to the aetiology of BC. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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21 pages, 880 KiB

Open AccessReview

Targeted Therapies for Epstein-Barr Virus-Associated Lymphomas

by Yonggang Pei, Josiah H. Y. Wong and Erle S. Robertson

Cancers 2020, 12(9), 2565; https://doi.org/10.3390/cancers12092565 - 9 Sep 2020

Cited by 28 | Viewed by 6722

Abstract

The Epstein-Barr virus (EBV) is the first human tumor virus identified that can transform quiescent B lymphocytes into lymphoblastoid cell lines (LCLs) in vitro. EBV can establish asymptomatic life-long persistence and is associated with multiple human malignancies, including non-Hodgkin lymphoma and Hodgkin lymphoma, [...] Read more.

The Epstein-Barr virus (EBV) is the first human tumor virus identified that can transform quiescent B lymphocytes into lymphoblastoid cell lines (LCLs) in vitro. EBV can establish asymptomatic life-long persistence and is associated with multiple human malignancies, including non-Hodgkin lymphoma and Hodgkin lymphoma, as well as infectious mononucleosis. Although EBV-associated lymphomagenesis has been investigated for over 50 years, viral-mediated transformation is not completely understood, and the development of EBV-specific therapeutic strategies to treat the associated cancers is still a major challenge. However, the rapid development of several novel therapies offers exciting possibilities to target EBV-induced lymphomas. This review highlights targeted therapies with potential for treating EBV-associated lymphomas, including small molecule inhibitors, immunotherapy, cell therapy, preventative and therapeutic vaccines, and other potent approaches, which are novel strategies for controlling, preventing, and treating these viral-induced malignances. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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23 pages, 1727 KiB

Open AccessReview

Epstein-Barr Virus Mediated Signaling in Nasopharyngeal Carcinoma Carcinogenesis

by Timmy Richardo, Pongphol Prattapong, Chawalit Ngernsombat, Nurulfitri Wisetyaningsih, Hisashi Iizasa, Hironori Yoshiyama and Tavan Janvilisri

Cancers 2020, 12(9), 2441; https://doi.org/10.3390/cancers12092441 - 28 Aug 2020

Cited by 30 | Viewed by 8634

Abstract

Nasopharyngeal carcinoma (NPC) is one of the most common tumors occurring in China and Southeast Asia. Etiology of NPC seems to be complex and involves many determinants, one of which is Epstein-Barr virus (EBV) infection. Although evidence demonstrates that EBV infection plays a [...] Read more.

Nasopharyngeal carcinoma (NPC) is one of the most common tumors occurring in China and Southeast Asia. Etiology of NPC seems to be complex and involves many determinants, one of which is Epstein-Barr virus (EBV) infection. Although evidence demonstrates that EBV infection plays a key role in NPC carcinogenesis, the exact relationship between EBV and dysregulation of signaling pathways in NPC needs to be clarified. This review focuses on the interplay between EBV and NPC cells and the corresponding signaling pathways, which are modulated by EBV oncoproteins and non-coding RNAs. These altered signaling pathways could be critical for the initiation and progression of NPC. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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23 pages, 3023 KiB

Open AccessReview

Lytic Induction Therapy against Epstein–Barr Virus-Associated Malignancies: Past, Present, and Future

by Stephanie Pei Tung Yiu, Mike Dorothea, Kwai Fung Hui and Alan Kwok Shing Chiang

Cancers 2020, 12(8), 2142; https://doi.org/10.3390/cancers12082142 - 2 Aug 2020

Cited by 28 | Viewed by 5973

Abstract

Epstein–Barr virus (EBV) lytic induction therapy is an emerging virus-targeted therapeutic approach that exploits the presence of EBV in tumor cells to confer specific killing effects against EBV-associated malignancies. Efforts have been made in the past years to uncover the mechanisms of EBV [...] Read more.

Epstein–Barr virus (EBV) lytic induction therapy is an emerging virus-targeted therapeutic approach that exploits the presence of EBV in tumor cells to confer specific killing effects against EBV-associated malignancies. Efforts have been made in the past years to uncover the mechanisms of EBV latent-lytic switch and discover different classes of chemical compounds that can reactivate the EBV lytic cycle. Despite the growing list of compounds showing potential to be used in the lytic induction therapy, only a few are being tested in clinical trials, with varying degrees of success. This review will summarize the current knowledge on EBV lytic reactivation, the major hurdles of translating the lytic induction therapy into clinical settings, and highlight some potential strategies in the future development of this therapy for EBV-related lymphoid and epithelial malignancies. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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12 pages, 881 KiB

Open AccessReview

The Therapeutic Potential of Targeting BARF1 in EBV-Associated Malignancies

by Angela Kwok-Fung Lo, Christopher W. Dawson, Hong Lok Lung, Ka-Leung Wong and Lawrence S. Young

Cancers 2020, 12(7), 1940; https://doi.org/10.3390/cancers12071940 - 17 Jul 2020

Cited by 16 | Viewed by 4333

Abstract

Epstein-Barr virus (EBV) is closely linked to the development of a number of human cancers. EBV-associated malignancies are characterized by a restricted pattern of viral latent protein expression which is sufficient for the virus to both initiate and sustain cell growth and to [...] Read more.

Epstein-Barr virus (EBV) is closely linked to the development of a number of human cancers. EBV-associated malignancies are characterized by a restricted pattern of viral latent protein expression which is sufficient for the virus to both initiate and sustain cell growth and to protect virus-infected cells from immune attack. Expression of these EBV proteins in malignant cells provides an attractive target for therapeutic intervention. Among the viral proteins expressed in the EBV-associated epithelial malignancies, the protein encoded by the BamHI-A rightward frame 1 (BARF1) is of particular interest. BARF1 is a viral oncoprotein selectively expressed in latently infected epithelial cancers, nasopharyngeal carcinoma (NPC) and EBV-positive gastric cancer (EBV-GC). Here, we review the roles of BARF1 in oncogenesis and immunomodulation. We also discuss potential strategies for targeting the BARF1 protein as a novel therapy for EBV-driven epithelial cancers. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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26 pages, 3149 KiB

Open AccessReview

Oncogenic Properties of the EBV ZEBRA Protein

by Diego Germini, Fatimata Bintou Sall, Anna Shmakova, Joëlle Wiels, Svetlana Dokudovskaya, Emmanuel Drouet and Yegor Vassetzky

Cancers 2020, 12(6), 1479; https://doi.org/10.3390/cancers12061479 - 5 Jun 2020

Cited by 41 | Viewed by 6523

Abstract

Epstein Barr Virus (EBV) is one of the most common human herpesviruses. After primary infection, it can persist in the host throughout their lifetime in a latent form, from which it can reactivate following specific stimuli. EBV reactivation is triggered by transcriptional transactivator [...] Read more.

Epstein Barr Virus (EBV) is one of the most common human herpesviruses. After primary infection, it can persist in the host throughout their lifetime in a latent form, from which it can reactivate following specific stimuli. EBV reactivation is triggered by transcriptional transactivator proteins ZEBRA (also known as Z, EB-1, Zta or BZLF1) and RTA (also known as BRLF1). Here we discuss the structural and functional features of ZEBRA, its role in oncogenesis and its possible implication as a prognostic or diagnostic marker. Modulation of host gene expression by ZEBRA can deregulate the immune surveillance, allow the immune escape, and favor tumor progression. It also interacts with host proteins, thereby modifying their functions. ZEBRA is released into the bloodstream by infected cells and can potentially penetrate any cell through its cell-penetrating domain; therefore, it can also change the fate of non-infected cells. The features of ZEBRA described in this review outline its importance in EBV-related malignancies. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Infection in Cancer)

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