Journal articles on the topic 'EBV cancers'
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Rodriquenz, Maria Grazia, Giandomenico Roviello, Alberto D’Angelo, Daniele Lavacchi, Franco Roviello, and Karol Polom. "MSI and EBV Positive Gastric Cancer’s Subgroups and Their Link with Novel Immunotherapy." Journal of Clinical Medicine 9, no. 5 (May 11, 2020): 1427. http://dx.doi.org/10.3390/jcm9051427.
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Gastric cancers have been historically classified based on histomorphologic features. The Cancer Genome Atlas network reported the comprehensive identification of genetic alterations associated with gastric cancer, identifying four distinct subtypes— Epstein-Barr virus (EBV)-positive, microsatellite-unstable/instability (MSI), genomically stable and chromosomal instability. In particular, EBV-positive and MSI gastric cancers seem responsive to novel immunotherapies drugs. The aim of this review is to describe MSI and EBV positive gastric cancer’s subgroups and their relationship with novel immunotherapy.
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Wong, Yide, Michael T. Meehan, Scott R. Burrows, Denise L. Doolan, and John J. Miles. "Estimating the global burden of Epstein–Barr virus-related cancers." Journal of Cancer Research and Clinical Oncology 148, no. 1 (October 27, 2021): 31–46. http://dx.doi.org/10.1007/s00432-021-03824-y.
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Abstract Background More than 90% of the adult population globally is chronically infected by the Epstein–Barr virus (EBV). It is well established that EBV is associated with a number of malignancies, and advances in knowledge of EBV-related malignancies are being made every year. Several studies have analysed the global epidemiology and geographic distribution of EBV-related cancers. However, most have only described a single cancer type or subtype in isolation or limited their study to the three or four most common EBV-related cancers. This review will present an overview on the spectrum of cancers linked to EBV based on observations of associations and proportions in the published literature while also using these observations to estimate the incidence and mortality burden of some of these cancers. Method We have reviewed the literature on defining features, distribution and outcomes across six cancers with a relatively large EBV-related case burden: Nasopharyngeal carcinoma (NPC), Gastric carcinoma (GC), Hodgkin lymphoma (HL), Burkitt lymphoma (BL), Diffuse large B-cell lymphoma (DLBCL) and Extranodal NK/T-cell lymphoma, Nasal type (ENKTL-NT). We retrieved published region-specific EBV-related case proportions for NPC, GC, HL and BL and performed meta-analyses on pooled region-specific studies of EBV-related case proportions for DLBCL and ENKTL-NT. We match these pooled proportions with their respective regional incidence and mortality numbers retrieved from a publicly available cancer database. Additionally, we also reviewed the literature on several other less common EBV-related cancers to summarize their key characteristics herein. Conclusion We estimated that EBV-related cases from these six cancers accounted for 239,700–357,900 new cases and 137,900–208,700 deaths in 2020. This review highlights the significant global impact of EBV-related cancers and extends the spectrum of disease that could benefit from an EBV-specific therapeutic.
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Oluoch, Peter O., Cliff I. Oduor, Catherine S. Forconi, John M. Ong’echa, Christian Münz, Dirk P. Dittmer, Jeffrey A. Bailey, and Ann M. Moormann. "Kaposi Sarcoma-Associated Herpesvirus Infection and Endemic Burkitt Lymphoma." Journal of Infectious Diseases 222, no. 1 (February 19, 2020): 111–20. http://dx.doi.org/10.1093/infdis/jiaa060.
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Abstract Background Endemic Burkitt lymphoma (eBL) is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum malaria coinfections. However, the role of Kaposi sarcoma-associated herpesvirus (KSHV), also endemic in Africa, has not been evaluated as a cofactor in eBL pathogenesis. Methods Multiplexed seroprofiles for EBV, malaria, and KSHV were generated for 266 eBL patients, 78 non-eBL cancers, and 202 healthy children. KSHV and EBV loads were quantified by PCR. Results KSHV seroprevalence did not differ by study group but was associated with age. Seropositivity, defined by K8.1/LANA or in combination with 5 other KSHV antigens (ORF59, ORF65, ORF61, ORF38, and K5) was associated with antimalarial antibody levels to AMA1 (odds ratio [OR], 2.41, P < .001; OR, 2.07, P < .001) and MSP1 (OR, 2.41, P = .0006; OR, 5.78, P < .001), respectively. KSHV loads did not correlate with antibody levels nor differ across groups but were significantly lower in children with detectable EBV viremia (P = .014). Conclusions Although KSHV-EBV dual infection does not increase eBL risk, EBV appears to suppress reactivation of KSHV while malaria exposure is associated with KSHV infection and/or reactivation. Both EBV and malaria should, therefore, be considered as potential effect modifiers for KSHV-associated cancers in sub-Saharan Africa.
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Sinclair, Alison J., Manal H. Moalwi, and Thomas Amoaten. "Is EBV Associated with Breast Cancer in Specific Geographic Locations?" Cancers 13, no. 4 (February 16, 2021): 819. http://dx.doi.org/10.3390/cancers13040819.
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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.
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Farrell, Paul J. "Epstein–Barr Virus and Cancer." Annual Review of Pathology: Mechanisms of Disease 14, no. 1 (January 24, 2019): 29–53. http://dx.doi.org/10.1146/annurev-pathmechdis-012418-013023.
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Epstein–Barr virus (EBV) contributes to about 1.5% of all cases of human cancer worldwide, and viral genes are expressed in the malignant cells. EBV also very efficiently causes the proliferation of infected human B lymphocytes. The functions of the viral proteins and small RNAs that may contribute to EBV-associated cancers are becoming increasingly clear, and a broader understanding of the sequence variation of the virus genome has helped to interpret their roles. The improved understanding of the mechanisms of these cancers means that there are great opportunities for the early diagnosis of treatable stages of EBV-associated cancers and the use of immunotherapy to target EBV-infected cells or overcome immune evasion. There is also scope for preventing disease by immunization and for developing therapeutic agents that target the EBV gene products expressed in the cancers.
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Lo, Angela Kwok-Fung, Christopher W. Dawson, Hong Lok Lung, Ka-Leung Wong, and Lawrence S. Young. "The Therapeutic Potential of Targeting BARF1 in EBV-Associated Malignancies." Cancers 12, no. 7 (July 17, 2020): 1940. http://dx.doi.org/10.3390/cancers12071940.
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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.
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Wojtak, Krzysztof, Alfredo Perales-Puchalt, and David B. Weiner. "Novel Synthetic DNA Immunogens Targeting Latent Expressed Antigens of Epstein–Barr Virus Elicit Potent Cellular Responses and Inhibit Tumor Growth." Vaccines 7, no. 2 (May 24, 2019): 44. http://dx.doi.org/10.3390/vaccines7020044.
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Infectious diseases are linked to 15%–20% of cancers worldwide. Among them, Epstein–Barr virus (EBV) is an oncogenic herpesvirus that chronically infects over 90% of the adult population, with over 200,000 cases of cancer and 150,000 cancer-related deaths attributed to it yearly. Acute EBV infection can present as infectious mononucleosis, and lead to the future onset of multiple cancers, including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. Many of these cancers express latent viral genes, including Epstein–Barr virus nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2 (LMP1 and LMP2). Previous attempts to create potent immunogens against EBV have been reported but generated mixed success. We designed novel Synthetic Consensus (SynCon) DNA vaccines against EBNA1, LMP1 and LMP2 to improve on the immune potency targeting important antigens expressed in latently infected cells. These EBV tumor antigens are hypothesized to be useful targets for potential immunotherapy of EBV-driven cancers. We optimized the genetic sequences for these three antigens, studied them for expression, and examined their immune profiles in vivo. We observed that these immunogens generated unique profiles based on which antigen was delivered as the vaccine target. EBNA1vax and LMP2Avax generated the most robust T cell immunity. Interestingly, LMP1vax was a very weak immunogen, generating very low levels of CD8 T cell immunity both as a standalone vaccine and as part of a trivalent vaccine cocktail. LMP2Avax was able to drive immunity that impacted EBV-antigen-positive tumor growth. These studies suggest that engineered EBV latent protein vaccines deserve additional study as potential agents for immunotherapy of EBV-driven cancers.
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Stanfield, Brent A., and Micah A. Luftig. "Recent advances in understanding Epstein-Barr virus." F1000Research 6 (March 29, 2017): 386. http://dx.doi.org/10.12688/f1000research.10591.1.
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Epstein-Barr virus (EBV) is a common human herpes virus known to infect the majority of the world population. Infection with EBV is often asymptomatic but can manifest in a range of pathologies from infectious mononucleosis to severe cancers of epithelial and lymphocytic origin. Indeed, in the past decade, EBV has been linked to nearly 10% of all gastric cancers. Furthermore, recent advances in high-throughput next-generation sequencing and the development of humanized mice, which effectively model EBV pathogenesis, have led to a wealth of knowledge pertaining to strain variation and host-pathogen interaction. This review highlights some recent advances in our understanding of EBV biology, focusing on new findings on the early events of infection, the role EBV plays in gastric cancer, new strain variation, and humanized mouse models of EBV infection.
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Sawada, Leila, Antonio Carlos Rosário Vallinoto, and Igor Brasil-Costa. "Regulation of the Immune Checkpoint Indoleamine 2,3-Dioxygenase Expression by Epstein–Barr Virus." Biomolecules 11, no. 12 (November 30, 2021): 1792. http://dx.doi.org/10.3390/biom11121792.
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Epstein–Barr virus (EBV) is an oncovirus ubiquitously distributed and associated with different types of cancer. The reason why only a group of infected people develop cancer is still unknown. EBV-associated cancers represent about 1.8% of all cancer deaths worldwide, with more than 150,000 new cases of cancer being reported annually. Since EBV-associated cancers are described as more aggressive and more resistant to the usual treatment compared to EBV-negative ones, the recent introduction of monoclonal antibodies (mAbs) targeting immune checkpoints (ICs) in the treatment of cancer patients represents a possible therapy for EBV-associated diseases. However, the current mAb therapies available still need improvement, since a group of patients do not respond well to treatment. Therefore, the main objective of this review is to summarize the progress made regarding the contribution of EBV infection to the expression of the IC indoleamine 2,3-dioxygenase (IDO) thus far. This IC has the potential to be used as a target in new immune therapies, such as mAbs. We hope that this work helps the development of future immunotherapies, improving the prognosis of EBV-associated cancer patients.
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Zhang, Baoyi, Kevin Yao, Min Xu, Jia Wu, and Chao Cheng. "Deep Learning Predicts EBV Status in Gastric Cancer Based on Spatial Patterns of Lymphocyte Infiltration." Cancers 13, no. 23 (November 29, 2021): 6002. http://dx.doi.org/10.3390/cancers13236002.
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EBV infection occurs in around 10% of gastric cancer cases and represents a distinct subtype, characterized by a unique mutation profile, hypermethylation, and overexpression of PD-L1. Moreover, EBV positive gastric cancer tends to have higher immune infiltration and a better prognosis. EBV infection status in gastric cancer is most commonly determined using PCR and in situ hybridization, but such a method requires good nucleic acid preservation. Detection of EBV status with histopathology images may complement PCR and in situ hybridization as a first step of EBV infection assessment. Here, we developed a deep learning-based algorithm to directly predict EBV infection in gastric cancer from H&E stained histopathology slides. Our model can not only predict EBV infection in gastric cancers from tumor regions but also from normal regions with potential changes induced by adjacent EBV+ regions within each H&E slide. Furthermore, in cohorts with zero EBV abundances, a significant difference of immune infiltration between high and low EBV score samples was observed, consistent with the immune infiltration difference observed between EBV positive and negative samples. Therefore, we hypothesized that our model’s prediction of EBV infection is partially driven by the spatial information of immune cell composition, which was supported by mostly positive local correlations between the EBV score and immune infiltration in both tumor and normal regions across all H&E slides. Finally, EBV scores calculated from our model were found to be significantly associated with prognosis. This framework can be readily applied to develop interpretable models for prediction of virus infection across cancers.
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Shechter, Oren, Daniel G. Sausen, Elisa S. Gallo, Harel Dahari, and Ronen Borenstein. "Epstein–Barr Virus (EBV) Epithelial Associated Malignancies: Exploring Pathologies and Current Treatments." International Journal of Molecular Sciences 23, no. 22 (November 19, 2022): 14389. http://dx.doi.org/10.3390/ijms232214389.
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Epstein–Barr virus (EBV) is one of eight known herpesviruses with the potential to infect humans. Globally, it is estimated that between 90–95% of the population has been infected with EBV. EBV is an oncogenic virus that has been strongly linked to various epithelial malignancies such as nasopharyngeal and gastric cancer. Recent evidence suggests a link between EBV and breast cancer. Additionally, there are other, rarer cancers with weaker evidence linking them to EBV. In this review, we discuss the currently known epithelial malignancies associated with EBV. Additionally, we discuss and establish which treatments and therapies are most recommended for each cancer associated with EBV.
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Ward, B. J. H., Danielle L. Schaal, Ebubechukwu H. Nkadi, and Rona S. Scott. "EBV Association with Lymphomas and Carcinomas in the Oral Compartment." Viruses 14, no. 12 (December 1, 2022): 2700. http://dx.doi.org/10.3390/v14122700.
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Epstein–Barr virus (EBV) is an oncogenic human herpesvirus infecting approximately 90% of the world’s population. The oral cavity serves a central role in the life cycle, transmission, and pathogenesis of EBV. Transmitted to a new host via saliva, EBV circulates between cellular compartments within oral lymphoid tissues. Epithelial cells primarily support productive viral replication, while B lymphocytes support viral latency and reactivation. EBV infections are typically asymptomatic and benign; however, the latent virus is associated with multiple lymphomas and carcinomas arising in the oral cavity. EBV association with cancer is complex as histologically similar cancers often test negative for the virus. However, the presence of EBV is associated with distinct features in certain cancers. The intrinsic ability of EBV to immortalize B-lymphocytes, via manipulation of survival and growth signaling, further implicates the virus as an oncogenic cofactor. A distinct mutational profile and burden have been observed in EBV-positive compared to EBV-negative tumors, suggesting that viral infection can drive alternative pathways that converge on oncogenesis. Taken together, EBV is also an important prognostic biomarker that can direct alternative therapeutic approaches. Here, we discuss the prevalence of EBV in oral malignancies and the EBV-dependent mechanisms associated with tumorigenesis.
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Hippocrate, Aurélie, Lassad Oussaief, and Irène Joab. "Possible role of EBV in breast cancer and other unusually EBV-associated cancers." Cancer Letters 305, no. 2 (June 2011): 144–49. http://dx.doi.org/10.1016/j.canlet.2010.11.007.
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Li, Lili, Brigette Ma, Anthony Chan, Francis Chan, Paul Murray, and Qian Tao. "Epstein-Barr Virus-Induced Epigenetic Pathogenesis of Viral-Associated Lymphoepithelioma-Like Carcinomas and Natural Killer/T-Cell Lymphomas." Pathogens 7, no. 3 (July 18, 2018): 63. http://dx.doi.org/10.3390/pathogens7030063.
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Cancer genome studies of Epstein-Barr virus (EBV)-associated tumors, including lymphoepithelioma-like carcinomas (LELC) of nasopharyngeal (NPC), gastric (EBVaGC) and lung tissues, and natural killer (NK)/T-cell lymphoma (NKTCL), reveal a unique feature of genomic alterations with fewer gene mutations detected than other common cancers. It is known now that epigenetic alterations play a critical role in the pathogenesis of EBV-associated tumors. As an oncogenic virus, EBV establishes its latent and lytic infections in B-lymphoid and epithelial cells, utilizing hijacked cellular epigenetic machinery. EBV-encoded oncoproteins modulate cellular epigenetic machinery to reprogram viral and host epigenomes, especially in the early stage of infection, using host epigenetic regulators. The genome-wide epigenetic alterations further inactivate a series of tumor suppressor genes (TSG) and disrupt key cellular signaling pathways, contributing to EBV-associated cancer initiation and progression. Profiling of genome-wide CpG methylation changes (CpG methylome) have revealed a unique epigenotype of global high-grade methylation of TSGs in EBV-associated tumors. Here, we have summarized recent advances of epigenetic alterations in EBV-associated tumors (LELCs and NKTCL), highlighting the importance of epigenetic etiology in EBV-associated tumorigenesis. Epigenetic study of these EBV-associated tumors will discover valuable biomarkers for their early detection and prognosis prediction, and also develop effective epigenetic therapeutics for these cancers.
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Png, Yi Tian, Audrey Zhi Yi Yang, Mei Ying Lee, Magdalene Jahn May Chua, and Chwee Ming Lim. "The Role of NK Cells in EBV Infection and EBV-Associated NPC." Viruses 13, no. 2 (February 15, 2021): 300. http://dx.doi.org/10.3390/v13020300.
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A vast majority of the population worldwide are asymptomatic carriers of Epstein-Barr Virus (EBV). However, some infected individuals eventually develop EBV-related cancers, including Nasopharyngeal Carcinoma (NPC). NPC is one of the most common EBV-associated epithelial cancers, and is highly prevalent in Southern China and Southeast Asia. While NPC is highly sensitive to radiotherapy and chemotherapy, there is a lack of effective and durable treatment among the 15%–30% of patients who subsequently develop recurrent disease. Natural Killer (NK) cells are natural immune lymphocytes that are innately primed against virus-infected cells and nascent aberrant transformed cells. As EBV is found in both virally infected and cancer cells, it is of interest to examine the NK cells’ role in both EBV infection and EBV-associated NPC. Herein, we review the current understanding of how EBV-infected cells are cleared by NK cells, and how EBV can evade NK cell-mediated elimination in the context of type II latency in NPC. Next, we summarize the current literature about NPC and NK cell biology. Finally, we discuss the translational potential of NK cells in NPC. This information will deepen our understanding of host immune interactions with EBV-associated NPC and facilitate development of more effective NK-mediated therapies for NPC treatment.
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Sun, Li, and David Meckes. "Methodological Approaches to Study Extracellular Vesicle miRNAs in Epstein–Barr Virus-Associated Cancers." International Journal of Molecular Sciences 19, no. 9 (September 18, 2018): 2810. http://dx.doi.org/10.3390/ijms19092810.
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Epstein Barr-virus (EBV) was the first virus identified to be associated with human cancer in 1964 and is found ubiquitously throughout the world’s population. It is now established that EBV contributes to the development and progression of multiple human cancers of both lymphoid and epithelial cell origins. EBV encoded miRNAs play an important role in tumor proliferation, angiogenesis, immune escape, tissue invasion, and metastasis. Recently, EBV miRNAs have been found to be released from infected cancer cells in extracellular vesicles (EVs) and regulate gene expression in neighboring uninfected cells present in the tumor microenvironment and possibly at distal sites. As EVs are abundant in many biological fluids, the viral and cellular miRNAs present within EBV-modified EVs may serve as noninvasion markers for cancer diagnosis and prognosis. In this review, we discuss recent advances in EV isolation and miRNA detection, and provide a complete workflow for EV purification from plasma and deep-sequencing for biomarker discovery.
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Fierti, Adelaide Ohui, Michael Bright Yakass, Ernest Adjei Okertchiri, Samuel Mawuli Adadey, and Osbourne Quaye. "The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications." Biomolecules 12, no. 1 (January 13, 2022): 127. http://dx.doi.org/10.3390/biom12010127.
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Epstein-Barr virus (EBV) is ubiquitous and carried by approximately 90% of the world’s adult population. Several mechanisms and pathways have been proposed as to how EBV facilitates the pathogenesis and progression of malignancies, such as Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma, and gastric cancers, the majority of which have been linked to viral proteins that are expressed upon infection including latent membrane proteins (LMPs) and Epstein-Barr virus nuclear antigens (EBNAs). EBV expresses microRNAs that facilitate the progression of some cancers. Mostly, EBV induces epigenetic silencing of tumor suppressor genes, degradation of tumor suppressor mRNA transcripts, post-translational modification, and inactivation of tumor suppressor proteins. This review summarizes the mechanisms by which EBV modulates different tumor suppressors at the molecular and cellular levels in associated cancers. Briefly, EBV gene products upregulate DNA methylases to induce epigenetic silencing of tumor suppressor genes via hypermethylation. MicroRNAs expressed by EBV are also involved in the direct targeting of tumor suppressor genes for degradation, and other EBV gene products directly bind to tumor suppressor proteins to inactivate them. All these processes result in downregulation and impaired function of tumor suppressors, ultimately promoting malignances.
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Rowe, Paul M. "EBV associated with aggressive breast cancers." Lancet 354, no. 9180 (August 1999): 748. http://dx.doi.org/10.1016/s0140-6736(05)75991-2.
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Teow, Sin-Yeang, Hooi-Yeen Yap, and Suat-Cheng Peh. "Epstein-Barr Virus as a Promising Immunotherapeutic Target for Nasopharyngeal Carcinoma Treatment." Journal of Pathogens 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/7349268.
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Epstein-Barr virus (EBV) is a pathogen that infects more than 90% of global human population. EBV primarily targets B-lymphocytes and epithelial cells while some of them infect monocyte/macrophage, T-lymphocytes, and dendritic cells (DCs). EBV infection does not cause death by itself but the infection has been persistently associated with certain type of cancers such as nasopharyngeal carcinoma (NPC), Burkitt’s lymphoma (BL), and Hodgkin’s lymphoma (HL). Recent findings have shown promise on targeting EBV proteins for cancer therapy by immunotherapeutic approach. Some studies have also shown the success of adopting EBV-based therapeutic vaccines for the prevention of EBV-associated cancer particularly on NPC. In-depth investigations are in progress to refine the current therapeutic and vaccination strategies. In present review, we discuss the highly potential EBV targets for NPC immunotherapy and therapeutic vaccine development as well as addressing the underlying challenges in the process of bringing the therapy and vaccination from the bench to bedside.
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Chattopadhyay, Pratip K., Kiprotich Chelimo, Paula B. Embury, David H. Mulama, Peter Odada Sumba, Emma Gostick, Kristin Ladell, et al. "Holoendemic Malaria Exposure Is Associated with Altered Epstein-Barr Virus-Specific CD8+T-Cell Differentiation." Journal of Virology 87, no. 3 (November 21, 2012): 1779–88. http://dx.doi.org/10.1128/jvi.02158-12.
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ABSTRACTCoinfection withPlasmodium falciparummalaria and Epstein-Barr virus (EBV) is a major risk factor for endemic Burkitt lymphoma (eBL), still one of the most prevalent pediatric cancers in equatorial Africa. Although malaria infection has been associated with immunosuppression, the precise mechanisms that contribute to EBV-associated lymphomagenesis remain unclear. In this study, we used polychromatic flow cytometry to characterize CD8+T-cell subsets specific for EBV-derived lytic (BMFL1 and BRLF1) and latent (LMP1, LMP2, and EBNA3C) antigens in individuals with divergent malaria exposure. No malaria-associated differences in EBV-specific CD8+T-cell frequencies were observed. However, based on a multidimensional analysis of CD45RO, CD27, CCR7, CD127, CD57, and PD-1 expression, we found that individuals living in regions with intense and perennial (holoendemic) malaria transmission harbored more differentiated EBV-specific CD8+T-cell populations that contained fewer central memory cells than individuals living in regions with little or no (hypoendemic) malaria. This profile shift was most marked for EBV-specific CD8+T-cell populations that targeted latent antigens. Importantly, malaria exposure did not skew the phenotypic properties of either cytomegalovirus (CMV)-specific CD8+T cells or the global CD8+memory T-cell pool. These observations define a malaria-associated aberration localized to the EBV-specific CD8+T-cell compartment that illuminates the etiology of eBL.
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Messick, Troy E., Samantha S. Soldan, Julianna Deakyne, and Paul M. Lieberman. "Development of a small molecule drug for EBV-associated gastric cancers." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 63. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.63.
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63 Background: Worldwide, EBV is associated with ~10% of gastric cancer. Currently, no pharmaceutical-based therapies exist that selectively target EBV associated gastric cancers. EBV, in its latent oncogenic form, is dependent on the continuous expression of Epstein-Barr Nuclear Antigen 1 (EBNA1), a multifunctional dimeric protein critical for viral replication, genome maintenance and viral gene expression. Methods: The aim of this program is to advance the development of a New Chemical Entity (NCE) for latent infection of Epstein-Barr Virus (EBV) to treat EBV-associated gastric cancer. We have used structure-based drug design and medicinal chemistry methods to identify and develop a small molecule clinical candidate that selectively inhibits the DNA-binding activity of EBNA1. Results: The clinical candidate inhibits EBNA1 function with nanomolar potency in biochemical assays and low micromolecular activity in several cell-based assays. We demonstrate that our clinical candidate provides protection in 4 different xenograft models of EBV-driven tumor growth, including patient-derived xenografts. Furthermore, RNA analysis experiments confirm in vivo target engagement by the elimination of EBV in treated tumor tissue. The clinical candidate is selective, showing no activity in an EBV-negative xenograft experiments. The clinical candidate has met industry-accepted criteria for drug suitability, safety and toxicology including physicochemical properties, metabolic stability, selectivity in broad-based screens and bioavailability, and lack in vivoliabilities, including genotoxicity and 14-day toxicity studies. Conclusions: IND-enabling studies including safety pharmacology and toxicology and GMP manufacturing have begun with a projected First-In-Human clinical trial in Q4 2017. These data establish proof-of-concept for targeting EBNA1—a protein previously thought to be undruggable.
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Dzikowiec, Magdalena, Przemysław Lik, Justyna Kiszałkiewicz, Aleksandra Kuczyńska, Marek Mordalski, Dariusz Nejc, Janusz Piekarski, Ewa Brzeziańska-Lasota, and Dorota Pastuszak-Lewandoska. "Helicobacter pylori and Epstein-Barr Virus Co-Infection in Polish Patients with Gastric Cancer – A Pilot Study." Polish Journal of Microbiology 71, no. 1 (February 27, 2022): 123–29. http://dx.doi.org/10.33073/pjm-2022-004.
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Abstract The infectious agents may be the etiological factor of up to 15–20% of cancers. In stomach cancer, attention is paid to Helicobacter pylori and Epstein-Barr virus, both of which cause gastritis and can lead to tumor development. In co-infection, the inflammatory process is much more intense. We assessed the seroprevalence towards H. pylori and EBV in 32 patients with diagnosed gastric cancer. H. pylori antibodies were found in 69% patients, and anti-EBV – in all of them. The study confirmed that co-infection of H. pylori and EBV seems to be important in etiopathology of gastric cancer.
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Yap, Lee Fah, Anna Kang Chee Wong, Ian C. Paterson, and Lawrence S. Young. "Functional Implications of Epstein-Barr Virus Lytic Genes in Carcinogenesis." Cancers 14, no. 23 (November 24, 2022): 5780. http://dx.doi.org/10.3390/cancers14235780.
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Epstein-Barr virus (EBV) is associated with a diverse range of tumors of both lymphoid and epithelial origin. Similar to other herpesviruses, EBV displays a bipartite life cycle consisting of latent and lytic phases. Current dogma indicates that the latent genes are key drivers in the pathogenesis of EBV-associated cancers, while the lytic genes are primarily responsible for viral transmission. In recent years, evidence has emerged to show that the EBV lytic phase also plays an important role in EBV tumorigenesis, and the expression of EBV lytic genes is frequently detected in tumor tissues and cell lines. The advent of next generation sequencing has allowed the comprehensive profiling of EBV gene expression, and this has revealed the consistent expression of several lytic genes across various types of EBV-associated cancers. In this review, we provide an overview of the functional implications of EBV lytic gene expression to the oncogenic process and discuss possible avenues for future investigations.
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Dislich, Bastian, Kirsten D. Mertz, Beat Gloor, and Rupert Langer. "Interspatial Distribution of Tumor and Immune Cells in Correlation with PD-L1 in Molecular Subtypes of Gastric Cancers." Cancers 14, no. 7 (March 29, 2022): 1736. http://dx.doi.org/10.3390/cancers14071736.
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(1) Background: EBV-positive and mismatch repair-deficient (MMRd) gastric cancers (GCs) show higher levels of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression and thus a more profound response to immunotherapy. However, the majority of GCs are EBV-negative (EBV−) and MMR proficient (MMRp). We analyzed PD-L1 expression and TILs in EBV-MMRpGCs in comparison to EBV-positive (EBV+) and MMRdGCs to identify an immunogenic phenotype susceptible to immunotherapy. (2) Methods: A next-generation tissue microarray of 409 primary resected GCs was analyzed by Epstein-Barr encoding region (EBER) in situ hybridization for MSH1, PMS2, MSH2, MSH6, PD-L1, and CD8 immunohistochemistry. PD-L1 positivity was defined as a combined positive score (CPS) of ≥1. CD8+ TILs and their proximity to cancer cells were digitally analyzed on the HALO™ image analysis platform. (3) Results: Eleven cases were EBV+, 49 cases MMRd, and 349 cases EBV-MMRpGCs. The highest rate of PD-L1 positivity was seen in EBV+GCs, followed by MMRdGCs and EBV-MMRpGCs (81.8%, 73.5%, and 27.8%, respectively). EBV+ and MMRdGCs also demonstrated increased numbers and proximity of CD8+ TILs to tumor cells compared to EBV-MMRpGCs (p < 0.001 each). PD-L1 status positively correlated with the total numbers of CD8+ TILs and their proximity to tumor cells in all subtypes, including EBV-MMRpGCs (p < 0.001 each). A total of 28.4% of EBV-MMRpGCs showed high CD8+ TILs independent of PD-L1. (4) Conclusions: PD-L1 and CD8 immunohistochemistry, supplemented by digital image analysis, may identify EBV-MMRpGCs with high immunoreactivity indices, indicating susceptibility to immunotherapy.
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Mambouene, Fidele, Dimitry Moudiongui, and Anicet Mboumba. "Detection of Epstein Barr Virus DNA in Gastric Adenocarcinoma in Brazzaville." International Journal of Health Sciences and Research 12, no. 3 (March 19, 2022): 390–95. http://dx.doi.org/10.52403/ijhsr.20220351.
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Introduction: The Epstein Barr virus (EBV) is associated with a variety of human malignancies including gastric cancer (GC). Several studies have shown an association between Epstein-Barr virus (EBV) infection and the occurrence of many cancers in humans, including certain gastric carcinomas (GC). Indeed, recent studies have reported that 10% of GCs are associated with EBV. There is no study on the association of EBV with CG in Brazzaville. The aim of the study was to detect EBV DNA in gastric adenocarcinoma in Brazzaville. Materials and Methods: Samples of carcinomatous gastric tissues were analyzed by qPCR to detect EBV DNA. The samples were collected retrospectively between January 2008 and December 2018. Results: Fifty two samples were analyzed. The PCR results showed that the detection of EBV DNA on our sample was 3.8%. Conclusion: The results obtained from this preliminary study confirm the presence of EBV DNA in gastric adenocarcinoma, which is consistent with data from the literature. Key words: DNA, EBV, gastric adenocarcinoma, qPCR.
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Pei, Yonggang, and Erle S. Robertson. "The Central Role of the Ubiquitin–Proteasome System in EBV-Mediated Oncogenesis." Cancers 14, no. 3 (January 26, 2022): 611. http://dx.doi.org/10.3390/cancers14030611.
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Deregulation of the ubiquitin–proteasome system (UPS) plays a critical role in the development of numerous human cancers. Epstein–Barr virus (EBV), the first known human tumor virus, has evolved distinct molecular mechanisms to manipulate the ubiquitin–proteasome system, facilitate its successful infection, and drive opportunistic cancers. The interactions of EBV antigens with the ubiquitin–proteasome system can lead to oncogenesis through the targeting of cellular factors involved in proliferation. Recent studies highlight the central role of the ubiquitin–proteasome system in EBV infection. This review will summarize the versatile strategies in EBV-mediated oncogenesis that contribute to the development of specific therapeutic approaches to treat EBV-associated malignancies.
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Notarte, Kin Israel, Suranga Senanayake, Imee Macaranas, Pia Marie Albano, Lucia Mundo, Eanna Fennell, Lorenzo Leoncini, and Paul Murray. "MicroRNA and Other Non-Coding RNAs in Epstein–Barr Virus-Associated Cancers." Cancers 13, no. 15 (August 3, 2021): 3909. http://dx.doi.org/10.3390/cancers13153909.
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EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs.
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Dávila-Collado, Ramsés, Oscar Jarquín-Durán, Le Thanh Dong, and J. Luis Espinoza. "Epstein–Barr Virus and Helicobacter Pylori Co-Infection in Non-Malignant Gastroduodenal Disorders." Pathogens 9, no. 2 (February 6, 2020): 104. http://dx.doi.org/10.3390/pathogens9020104.
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Epstein–Barr virus (EBV) and Helicobacter pylori (H. pylori) are two pathogens associated with the development of various human cancers. The coexistence of both microorganisms in gastric cancer specimens has been increasingly reported, suggesting that crosstalk of both pathogens may be implicated in the carcinogenesis process. Considering that chronic inflammation is an initial step in the development of several cancers, including gastric cancer, we conducted a systematic review to comprehensively evaluate publications in which EBV and H. pylori co-infection has been documented in patients with non-malignant gastroduodenal disorders (NMGDs), including gastritis, peptic ulcer disease (PUD), and dyspepsia. We searched the PubMed database up to August 2019, as well as publication references and, among the nine studies that met the inclusion criteria, we identified six studies assessing EBV infection directly in gastric tissues (total 949 patients) and three studies in which EBV infection status was determined by serological methods (total 662 patients). Due to the substantial methodological and clinical heterogeneity among studies identified, we could not conduct a meta-analysis. The overall prevalence of EBV + H. pylori co-infection in NMGDs was 34% (range 1.8% to 60%). A higher co-infection rate (EBV + H. pylori) was reported in studies in which EBV was documented by serological methods in comparison with studies in which EBV infection was directly assessed in gastric specimens. The majority of these studies were conducted in Latin-America and India, with most of them comparing NMGDs with gastric cancer, but there were no studies comparing the co-infection rate in NMGDs with that in asymptomatic individuals. In comparison with gastritis caused by only one of these pathogens, EBV + H. pylori co-infection was associated with increased severity of gastric inflammation. In conclusion, only relatively small studies testing EBV and H. pylori co-infection in NMGDs have been published to date and the variable report results are likely influenced by geographic factors and detection methods.
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Nagi, Karim, Ishita Gupta, Nawaf Jurdi, Amber Yasmeen, Semir Vranic, Gerald Batist, and Ala-Eddin Al Moustafa. "Copresence of High-Risk Human Papillomaviruses and Epstein–Barr Virus in Colorectal Cancer: A Tissue Microarray and Molecular Study from Lebanon." International Journal of Molecular Sciences 22, no. 15 (July 29, 2021): 8118. http://dx.doi.org/10.3390/ijms22158118.
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Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Human papillomaviruses (HPVs) and Epstein–Barr virus (EBV) have been reported to be present in different types of human cancers, including CRCs, where they can play a key role in the onset and/or progression of these cancers. Thus, we herein explored the prevalence of high-risk HPVs and EBV in a cohort of 94 CRC tissue samples and 13 colorectal normal tissues from the Lebanese population using polymerase chain reaction, immunohistochemistry, and tissue microarray methodologies. We found that high-risk HPVs are present in 64%, while EBV is present in 29% of our CRC samples. Additionally, our data showed that high-risk HPV types (16, 18, 35, 58, 51, 45, 52, 31, and 33) are the most frequent in CRC in the Lebanese cohort, respectively. Our data point out that HPVs and EBV are copresent in 28% of the samples. Thus, this study clearly suggests that high-risk HPVs and EBV are present/copresent in CRCs, where they could play an important role in colorectal carcinogenesis. Nevertheless, further investigations using a larger cohort are needed to elucidate the possible cooperation between these oncoviruses in the development of CRC.
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Sarvari, Jamal, Shahab Mahmoudvand, Neda Pirbonyeh, Akbar Safaei, and Seyed Younes Hosseini. "The Very Low Frequency of Epstein-Barr JC and BK Viruses DNA in Colorectal Cancer Tissues in Shiraz, Southwest Iran." Polish Journal of Microbiology 67, no. 1 (March 9, 2018): 73–79. http://dx.doi.org/10.5604/01.3001.0011.6146.
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Viruses including Epstein-Barr virus (EBV), JCV and BKV have been reported to be associated with some cancers. The association of these viruses with colorectal cancers remains controversial. Our objective was to investigate their infections association with adenocarcinoma and adenomatous polyps of the colon. Totally, 210 paraffin-embedded tissue specimens encompassing 70 colorectal adenocarcinoma, 70 colorectal adenomatous and 70 colorectal normal tissues were included. The total DNA was extracted, then qualified samples introduced to polymerase chain reaction (PCR). The EBV, JCV and BKV genome sequences were detected using specific primers by 3 different in-house PCR assays. Out of 210 subjects, 98 cases were female and the rest were male. The mean age of the participants was 52 ± 1.64 years. EBV and JCV DNA was detected just in one (1.42%) out of seventy adenocarcinoma colorectal tissues. All adenomatous polyp and normal colorectal tissues were negative for EBV and JCV DNA sequences. Moreover, all the patients and healthy subjects were negative for BKV DNA sequences. The results suggested that EBV and JCV genomes were not detectable in the colorectal tissue of patients with colorectal cancer in our population. Hence, BKV might not be necessitated for the development of colorectal cancer. The findings merit more investigations.
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Tsao, Sai Wah, Chi Man Tsang, and Kwok Wai Lo. "Epstein–Barr virus infection and nasopharyngeal carcinoma." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1732 (September 11, 2017): 20160270. http://dx.doi.org/10.1098/rstb.2016.0270.
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Epstein–Barr virus (EBV) is associated with multiple types of human cancer, including lymphoid and epithelial cancers. The closest association with EBV infection is seen in undifferentiated nasopharyngeal carcinoma (NPC), which is endemic in the southern Chinese population. A strong association between NPC risk and the HLA locus at chromosome 6p has been identified, indicating a link between the presentation of EBV antigens to host immune cells and NPC risk. EBV infection in NPC is clonal in origin, strongly suggesting that NPC develops from the clonal expansion of a single EBV-infected cell. In epithelial cells, the default program of EBV infection is lytic replication. However, latent infection is the predominant mode of EBV infection in NPC. The establishment of latent EBV infection in pre-invasive nasopharyngeal epithelium is believed to be an early stage of NPC pathogenesis. Recent genomic study of NPC has identified multiple somatic mutations in the upstream negative regulators of NF-κB signalling. Dysregulated NF-κB signalling may contribute to the establishment of latent EBV infection in NPC. Stable EBV infection and the expression of latent EBV genes are postulated to drive the transformation of pre-invasive nasopharyngeal epithelial cells to cancer cells through multiple pathways. This article is part of the themed issue ‘Human oncogenic viruses’.
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Karamouzis, Michalis, Geena Dalagiorgou, Sonia A. Perez, Urania Georgopoulou, and Athanasios Papavassiliou. "Targeting low-expressing ERBB-2 and acquired resistant high-expressing ERBB-2 breast carcinomas." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e11513-e11513. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e11513.
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e11513 Background: Human epidermal growth factor receptors and their ligands are involved in carcinogenesis. Four ERBB receptors have been identified; ERBB1 (EB1), ERBB2 (EB2), ERBB3 (EB3) and ERBB4 (EB4). EB2 is over-expressed/amplified in 20-30% of BCa. Molecularly targeting agents, such as pertuzumab (P), in combination with standard therapy have shown important clinical results in EB2 (+) BCa patients. The aim of the project is to evaluate the expression/localization and dimerization pattern of EB1, EB2, EB3, EB4 in breast cancer cell lines (BCCLs) with or without heregulin-1 (He) and various EB2, EB3 and He inhibitors. The identification of a molecular phenotype of low-expressing and acquired resistant high-expressing EB2 BCa will enhance the targeted use of EB2 inhibitors in certain BCa patients Methods: Using confocal microscopy, localization/expression patterns were studied for EB1, EB2, EB3, EB4 in various human BCCs; here presented in MCF7 and SKBR3. Additionally, the dimerization pattern of EB2, EB3 and/or EB4 was studied with and without stimulation with He plus or minus P (kindly provided by Genentech, US). The dimers formation was studied using proximity ligation assay and immunofluorescence (DUOLINK; OLINK Biosciences, Sweden). Results: In MCF7-He stimulated cells EB2/EB3, EB2/EB4 and EB1/EB3 dimmers showed a 3-fold decrease formation compared to untreated cells. The EB1/EB4 dimmers were not significantly affected. After P addition in MCF7 cells a 3-fold decrease of dimmer formation was noticed compared to untreated cells for EB2/EB3, EB2/EB4 and EB1/EB3. The EB1/EB4 formation seemed only slightly affected by P. SKBR3-He stimulated cells resulted in a similar decrease of EB2/EB3, EB2/EB4 and EB1/EB3 dimmer formation compared to untreated cells. In the same BCLL, EB1/EB4 dimmer did not show any decrease after He treatment compared to untreated control cells. Further results quantified and analyzed for statistical significance will be shown Conclusions: The addition of P seems to block ligand-dependent heterodimerization of EB2 with other ERBB family members, such as EB3 and EB4.
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Dworzanska, Anna, and Małgorzata Polz-Dacewicz. "The role of Toll-like receptors (TLRs) in virus-related cancers: a mini review." Current Issues in Pharmacy and Medical Sciences 33, no. 4 (December 1, 2020): 225–27. http://dx.doi.org/10.2478/cipms-2020-0038.
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Abstract The modulation of the host innate immune system is a well-established carcinogenesis feature of several tumors, including human Epstein-Barr (EBV) and Papillomavirus-(HPV) related cancers. These viruses are able to interrupt the initial events of the immune response, including the expression of Toll-like receptors (TLRs), cytokines, and inflammation. The aim of the study is to review current data and summarize knowledge on the TLRs and their role in the development of cancer, especially viral-related cancers (EBV and HPV). Research work shows a correlation between the TLRs polymorphism and the development of oropharyngeal and gastric cancer (GC), especially related to viral infections. Many studies suggest the important role for TLRs in inflammatory, autoimmune disease and human cancers. However, further efforts are necessary to draw a precise conclusion.
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Panda, Anshuman, Janice M. Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Michael Kane, et al. "Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer." JNCI: Journal of the National Cancer Institute 110, no. 3 (November 15, 2017): 316–20. http://dx.doi.org/10.1093/jnci/djx213.
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Abstract Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti–programmed death–ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV-positive tumors had low mutation burden (median = 2.07 vs 3.13 in log10 scale, P < 10-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P < 10-4; log2 fold-change of CD8A = 1.85, P < 10-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log2 fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P < 10-4 each), and higher lymphocytic infiltration by histology (median tumor-infiltrating lymphocyte score = 3 vs 2, P < .001) compared with MSS tumors. These data suggest that EBV-positive low–mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy.
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Tan, Geok, Lydia Visser, Lu Tan, Anke Berg, and Arjan Diepstra. "The Microenvironment in Epstein–Barr Virus-Associated Malignancies." Pathogens 7, no. 2 (April 13, 2018): 40. http://dx.doi.org/10.3390/pathogens7020040.
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The Epstein–Barr virus (EBV) can cause a wide variety of cancers upon infection of different cell types and induces a highly variable composition of the tumor microenvironment (TME). This TME consists of both innate and adaptive immune cells and is not merely an aspecific reaction to the tumor cells. In fact, latent EBV-infected tumor cells utilize several specific mechanisms to form and shape the TME to their own benefit. These mechanisms have been studied largely in the context of EBV+ Hodgkin lymphoma, undifferentiated nasopharyngeal carcinoma, and EBV+ gastric cancer. This review describes the composition, immune escape mechanisms, and tumor cell promoting properties of the TME in these three malignancies. Mechanisms of susceptibility which regularly involve genes related to immune system function are also discussed, as only a small proportion of EBV-infected individuals develops an EBV-associated malignancy.
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Kanda, Teru, Yuki Furuse, Hitoshi Oshitani, and Tohru Kiyono. "Highly Efficient CRISPR/Cas9-Mediated Cloning and Functional Characterization of Gastric Cancer-Derived Epstein-Barr Virus Strains." Journal of Virology 90, no. 9 (February 17, 2016): 4383–93. http://dx.doi.org/10.1128/jvi.00060-16.
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ABSTRACTThe Epstein-Barr virus (EBV) is etiologically linked to approximately 10% of gastric cancers, in which viral genomes are maintained as multicopy episomes. EBV-positive gastric cancer cells are incompetent for progeny virus production, making viral DNA cloning extremely difficult. Here we describe a highly efficient strategy for obtaining bacterial artificial chromosome (BAC) clones of EBV episomes by utilizing a CRISPR/Cas9-mediated strand break of the viral genome and subsequent homology-directed repair. EBV strains maintained in two gastric cancer cell lines (SNU719 and YCCEL1) were cloned, and their complete viral genome sequences were determined. Infectious viruses of gastric cancer cell-derived EBVs were reconstituted, and the viruses established stable latent infections in immortalized keratinocytes. While Ras oncoprotein overexpression caused massive vacuolar degeneration and cell death in control keratinocytes, EBV-infected keratinocytes survived in the presence of Ras expression. These results implicate EBV infection in predisposing epithelial cells to malignant transformation by inducing resistance to oncogene-induced cell death.IMPORTANCERecent progress in DNA-sequencing technology has accelerated EBV whole-genome sequencing, and the repertoire of sequenced EBV genomes is increasing progressively. Accordingly, the presence of EBV variant strains that may be relevant to EBV-associated diseases has begun to attract interest. Clearly, the determination of additional disease-associated viral genome sequences will facilitate the identification of any disease-specific EBV variants. We found that CRISPR/Cas9-mediated cleavage of EBV episomal DNA enabled the cloning of disease-associated viral strains with unprecedented efficiency. As a proof of concept, two gastric cancer cell-derived EBV strains were cloned, and the infection of epithelial cells with reconstituted viruses provided important clues about the mechanism of EBV-mediated epithelial carcinogenesis. This experimental system should contribute to establishing the relationship between viral genome variation and EBV-associated diseases.
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Arbach, Hratch, Viktor Viglasky, Florence Lefeu, Jean-Marc Guinebretière, Vanessa Ramirez, Nadège Bride, Nadia Boualaga, et al. "Epstein-Barr Virus (EBV) Genome and Expression in Breast Cancer Tissue: Effect of EBV Infection of Breast Cancer Cells on Resistance to Paclitaxel (Taxol)." Journal of Virology 80, no. 2 (January 15, 2006): 845–53. http://dx.doi.org/10.1128/jvi.80.2.845-853.2006.
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ABSTRACT The Epstein-Barr virus (EBV) has been detected in subsets of breast cancers. In order to elaborate on these observations, we quantified by real-time PCR (Q-PCR) the EBV genome in biopsy specimens of breast cancer tissue as well as in tumor cells isolated by microdissection. Our findings show that EBV genomes can be detected by Q-PCR in about half of tumor specimens, usually in low copy numbers. However, we also found that the viral load is highly variable from tumor to tumor. Moreover, EBV genomes are heterogeneously distributed in morphologically identical tumor cells, with some clusters of isolated tumor cells containing relatively high genome numbers while other tumor cells isolated from the same specimen may be negative for EBV DNA. Using reverse transcription-PCR, we detected EBV gene transcripts: EBNA-1 in almost all of the EBV-positive tumors and RNA of the EBV oncoprotein LMP-1 in a smaller subset of the tissues analyzed. Moreover, BARF-1 RNA was detected in half of the cases studied. Furthermore, we observed that in vitro EBV infection of breast carcinoma cells confers resistance to paclitaxel (taxol) and provokes overexpression of a multidrug resistance gene (MDR1). Consequently, even if a small number of breast cancer cells are EBV infected, the impact of EBV infection on the efficiency of anticancer treatment might be of importance.
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Rajendra, Kishen, and Prateek Sharma. "Viral Pathogens in Oesophageal and Gastric Cancer." Pathogens 11, no. 4 (April 15, 2022): 476. http://dx.doi.org/10.3390/pathogens11040476.
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Tumour virology was born with the discovery by Peyton Rous in 1911 of a filterable agent in chicken cellular extracts that caused neoplasia in healthy chickens. Universally, 20% of all human cancers have a viral aetiology. Viruses are involved at various stages of the carcinogenesis pathway, depending on the viral pathogen, and likely require co-factors. Multiple risk factors have been associated with oesophageal and gastric malignancy, including carcinogenic pathogens. These viruses and bacteria include human papillomavirus (HPV) [oesophageal cancer], Epstein–Barr virus (EBV) [proximal stomach cancer], and Helicobacter pylori (HP) [non-cardia stomach cancer]. Viruses such as EBV have been firmly established as causal for up to 10% of gastric cancers. HPV is associated with 13 to 35% of oesophageal adenocarcinoma but its role is unclear in oesophageal squamous cell carcinomas. The causal relationship between hepatitis B (HBV), cytomegalovirus (CMV), HPV, and John Cunningham (JCV) and gastric neoplasia remains indeterminate and warrants further study. The expression of viral antigens by human tumours offers preventive and therapeutic potential (including vaccination) and has already been harnessed with vaccines for HPV and HBV. Future goals include viral protein-based immunotherapy and monoclonal antibodies for the treatment of some of the subset of EBV and HPV-induced gastro-esophageal cancers.
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Ghosh, Sajal K., Susan P. Perrine, and Douglas V. Faller. "Advances in Virus-Directed Therapeutics against Epstein-Barr Virus-Associated Malignancies." Advances in Virology 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/509296.
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Epstein-Barr virus (EBV) is the causal agent in the etiology of Burkitt’s lymphoma and nasopharyngeal carcinoma and is also associated with multiple human malignancies, including Hodgkin’s and non-Hodgkin’s lymphoma, and posttransplantation lymphoproliferative disease, as well as sporadic cancers of other tissues. A causal relationship of EBV to these latter malignancies remains controversial, although the episomic EBV genome in most of these cancers is clonal, suggesting infection very early in the development of the tumor and a possible role for EBV in the genesis of these diseases. Furthermore, the prognosis of these tumors is invariably poor when EBV is present, compared to their EBV-negative counterparts. The physical presence of EBV in these tumors represents a potential “tumor-specific” target for therapeutic approaches. While treatment options for other types of herpesvirus infections have evolved and improved over the last two decades, however, therapies directed at EBV have lagged. A major constraint to pharmacological intervention is the shift from lytic infection to a latent pattern of gene expression, which persists in those tumors associated with the virus. In this paper we provide a brief account of new virus-targeted therapeutic approaches against EBV-associated malignancies.
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Hur, Daeyoung, Sun-mi Yun, Dabin Choi, Seon Hyun Kim, Mi Kyung Lee, and Yeong Seok Kim. "EBV infection modulates the cell viability of gastric cancer cell through modulating miR34a-NOX2-ROS signaling." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 182.25. http://dx.doi.org/10.4049/jimmunol.200.supp.182.25.
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Abstract Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is a viral protein expressed in all EBV-infected cells that induces malignant transformation. EBNA1 is reported to contribute to tumor progression through an increase in reactive oxygen species via nicotinamide adenine dinucleotide phosphate oxidase. However, the underlying molecular mechanism of EBNA1-induced ROS accumulation in gastric cancer is poorly understood. Here, we demonstrated that miR34a regulation by EBNA1 determined cell fate in EBV-infected gastric cancer cells. ROS content and NOX2 expression were higher in EBNA1-expressing SNU719 cells than in EBNA1-nonexpressing SNU638 cells. Downregulation of NOX2 using siRNA technology in SNU719 cells decreased cell viability and ROS content. Regulation of EBNA1 expression in EBV-associated gastric cancers modulated NOX2 expression, ROS content and cell viability. We also showed that upregulation of NOX2 by EBNA1 was mediated by downregulating miRNA34a. Finally, overexpression of miR34a in EBNA1-expressing SNU719 cells induced typical apoptosis, suggesting that reactivation of miR34a in EBNA1-expressing gastric cancer cells could be a strategy for treatment of EBV-infected gastric cancer cells.
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Yiu, Stephanie Pei Tung, Kwai Fung Hui, Christian Münz, Kwok-Wai Lo, Sai Wah Tsao, Richard Yi Tsun Kao, Dan Yang, and Alan Kwok Shing Chiang. "Autophagy-Dependent Reactivation of Epstein-Barr Virus Lytic Cycle and Combinatorial Effects of Autophagy-Dependent and Independent Lytic Inducers in Nasopharyngeal Carcinoma." Cancers 11, no. 12 (November 26, 2019): 1871. http://dx.doi.org/10.3390/cancers11121871.
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Autophagy, a conserved cellular mechanism, is manipulated by a number of viruses for different purposes. We previously demonstrated that an iron-chelator-like small compound, C7, reactivates Epstein-Barr virus (EBV) lytic cycle by activating the ERK1/2-autophagy axis in epithelial cancers. Here, we aim to identify the specific stage of autophagy required for EBV lytic reactivation, determine the autophagy dependency of EBV lytic inducers including histone deacetylase inhibitor (HDACi) and C7/iron chelators, for EBV lytic reactivation and measure the combinatorial effects of these types of lytic inducers in nasopharyngeal carcinoma (NPC). Inhibition of autophagy initiation by 3-MA and autolysosome formation by chloroquine demonstrated that only autophagy initiation is required for EBV lytic reactivation. Gene knockdown of various autophagic proteins such as beclin-1, ATG5, ATG12, ATG7, LC3B, ATG10, ATG3 and Rab9, revealed the importance of ATG5 in EBV lytic reactivation. 3-MA could only abrogate lytic cycle induction by C7/iron chelators but not by HDACi, providing evidence for autophagy-dependent and independent mechanisms in EBV lytic reactivation. Finally, the combination of C7 and SAHA at their corresponding reactivation kinetics enhanced EBV lytic reactivation. These findings render new insights in the mechanisms of EBV lytic cycle reactivation and stimulate a rational design of combination drug therapy against EBV-associated cancers.
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Heawchaiyaphum, Chukkris, Chamsai Pientong, Hironori Yoshiyama, Hisashi Iizasa, Watcharapong Panthong, and Tipaya Ekalaksananan. "General Features and Novel Gene Signatures That Identify Epstein-Barr Virus-Associated Epithelial Cancers." Cancers 14, no. 1 (December 22, 2021): 31. http://dx.doi.org/10.3390/cancers14010031.
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Epstein-Barr virus (EBV) is associated with various types of human malignancies, including nasopharyngeal carcinoma (NPC), EBV-associated gastric carcinoma (EBVaGC), and oral squamous cell carcinoma (OSCC). The present study aimed to identify gene signatures and common signaling pathways that can be used to predict the prognosis of EBV-associated epithelial cancers (EBVaCAs) by performing an integrated bioinformatics analysis of cell lines and tumor tissues. We identified 12 differentially expressed genes (DEGs) in the EBVaCA cell lines. Among them, only four DEGs, including BAMBI, SLC26A9, SGPP2, and TMC8, were significantly upregulated. However, SLC26A9 and TMC8, but not BAMBI and SGPP2, were significantly upregulated in EBV-positive tumor tissues compared to EBV-negative tumor tissues. Next, we identified IL6/JAK/STAT3 and TNF-α/NF-κB signaling pathways as common hallmarks of EBVaCAs. The expression of key genes related to the two hallmarks was upregulated in both EBV-infected cell lines and EBV-positive tumor tissues. These results suggest that SLC26A9 and TMC8 might be gene signatures that can effectively predict the prognosis of EBVaCAs and provide new insights into the molecular mechanisms of EBV-driven epithelial cancers.
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Fernandes, Queenie, Ishita Gupta, Semir Vranic, and Ala-Eddin Al Moustafa. "Human Papillomaviruses and Epstein–Barr Virus Interactions in Colorectal Cancer: A Brief Review." Pathogens 9, no. 4 (April 20, 2020): 300. http://dx.doi.org/10.3390/pathogens9040300.
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Human papillomaviruses (HPVs) and the Epstein–Barr virus (EBV) are the most common oncoviruses, contributing to approximately 10%–15% of all malignancies. Oncoproteins of high-risk HPVs (E5 and E6/E7), as well as EBV (LMP1, LMP2A and EBNA1), play a principal role in the onset and progression of several human carcinomas, including head and neck, cervical and colorectal. Oncoproteins of high-risk HPVs and EBV can cooperate to initiate and/or enhance epithelial-mesenchymal transition (EMT) events, which represents one of the hallmarks of cancer progression and metastasis. Although the role of these oncoviruses in several cancers is well established, their role in the pathogenesis of colorectal cancer is still nascent. This review presents an overview of the most recent advances related to the presence and role of high-risk HPVs and EBV in colorectal cancer, with an emphasis on their cooperation in colorectal carcinogenesis.
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Velapasamy, Sharmila, Christopher Dawson, Lawrence Young, Ian Paterson, and Lee Yap. "The Dynamic Roles of TGF-β Signalling in EBV-Associated Cancers." Cancers 10, no. 8 (July 27, 2018): 247. http://dx.doi.org/10.3390/cancers10080247.
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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.
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Münz, Christian. "Epstein-Barr Virus Nuclear Antigen 1." Journal of Experimental Medicine 199, no. 10 (May 17, 2004): 1301–4. http://dx.doi.org/10.1084/jem.20040730.
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Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)—the one EBV antigen that is expressed in all EBV-associated malignancies—has long been thought to go undetected by the cell-mediated immune system. However, recent studies show that EBNA1 can be presented to both CD4+ and CD8+ T cells, making it a potential new target for immunotherapy of EBV-related cancers.
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Yen, Ching-Yu, Min-Chi Lu, Ching-Cherng Tzeng, Jia-Yan Huang, Hsueh-Wei Chang, Ruey-Shyang Chen, Shyun-Yeu Liu, Shih-Tung Liu, Biehuoy Shieh, and Ching Li. "Detection of EBV Infection and Gene Expression in Oral Cancer from Patients in Taiwan by Microarray Analysis." Journal of Biomedicine and Biotechnology 2009 (2009): 1–15. http://dx.doi.org/10.1155/2009/904589.
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Epstein-Barr virus is known to cause nasopharyngeal carcinoma. Although oral cavity is located close to the nasal pharynx, the pathogenetic role of Epstein-Barr virus (EBV) in oral cancers is unclear. This molecular epidemiology study uses EBV genomic microarray (EBV-chip) to simultaneously detect the prevalent rate and viral gene expression patterns in 57 oral squamous cell carcinoma biopsies (OSCC) collected from patients in Taiwan. The majority of the specimens (82.5%) were EBV-positive that probably expressed coincidently the genes for EBNAs, LMP2A and 2B, and certain structural proteins. Importantly, the genes fabricated at the spots 61 (BBRF1, BBRF2, and BBRF3) and 68 (BDLF4 and BDRF1) on EBV-chip were actively expressed in a significantly greater number of OSCC exhibiting exophytic morphology or ulceration than those tissues with deep invasive lesions (P=.0265and .0141, resp.). The results may thus provide the lead information for understanding the role of EBV in oral cancer pathogenesis.
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Krishna, Gayathri, Vinod Soman Pillai, and Mohanan Valiya Veettil. "Upregulation of GLS1 Isoforms KGA and GAC Facilitates Mitochondrial Metabolism and Cell Proliferation in Epstein–Barr Virus Infected Cells." Viruses 12, no. 8 (July 27, 2020): 811. http://dx.doi.org/10.3390/v12080811.
Full textAbstract:
Epstein–Barr virus or human herpesvirus 4 (EBV/HHV-4) is a ubiquitous human virus associated with a wide range of malignant neoplasms. The interaction between EBV latent proteins and host cellular molecules often leads to oncogenic transformation, promoting the development of EBV-associated cancers. The present study identifies a functional role of GLS1 isoforms KGA and GAC in regulating mitochondrial energy metabolism to promote EBV-infected cell proliferation. Our data demonstrate increased expression of GLS1 isoforms KGA and GAC with mitochondrial localization in latently EBV-infected cells and de novo EBV-infected PBMCs. c-Myc upregulates KGA and GAC protein levels, which in turn elevate the levels of intracellular glutamate. Further analysis demonstrated upregulated expression of mitochondrial GLUD1 and GLUD2, with a subsequent increase in alpha-ketoglutarate levels that may mark the activation of glutaminolysis. Cell proliferation and viability of latently EBV-infected cells were notably inhibited by KGA/GAC, as well as GLUD1 inhibitors. Taken together, our results suggest that c-Myc-dependent regulation of KGA and GAC enhances mitochondrial functions to support the rapid proliferation of the EBV-infected cells, and these metabolic processes could be therapeutically exploited by targeting KGA/GAC and GLUD1 to prevent EBV-associated cancers.
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Shen, Jiayi, Meijuan Luo, LiTing Liu, Qiu-Yan Chen, Lin-Quan Tang, and Hai-Qiang Mai. "Incidence and trend of Epstein-Barr virus-related cancer: A surveillance, epidemiology, and end results program based study." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 10575. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.10575.
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10575 Background: Epstein-Barr virus (EBV) infection was highly prevalent, as was found in more than 90% of the adults globally. EBV infection has been found to be related with several types of cancer and classified as group 1 carcinogen by the International Agency for Research on Cancer. The association between EBV infection and malignancy was observed in Burkitt lymphoma (BL), Hodgkin lymphoma (HL), extranodal natural killer (NK)/T-cell lymphoma (NNKTL), gastric cancer (GC) and nasopharyngeal cancer (NPC). In this study, we aimed to analyze the incidence and the trend of incidence of these virus-related cancer and to identify whether the trend was similar between them. Methods: This was a retrospective analysis based on the data from Surveillance, Epidemiology, and End Results (18 registries, 2000-2017), which totally included 71,415 patients. EBV-related cancers were defined as BL, HL, NNKTL, GC and NPC. Age-adjusted incidence rates were displayed as per 100,000 persons. In terms of incidence trend, we calculated the average annual percent change (AAPC). AAPC was considered significantly different from 0 when the P-value was smaller than 0.05. The impact of the epidemiological and clinical characteristics on the incidence trend was estimated, with cancer type, histology, age, sex and race considered. Results: Incidence rates of EBV-related cancers were 6.68 per 100,000 persons in 2000 and 5.80 in 2017, of which the AAPC was -0.8 (95%CI, -1.1 - -0.5, P-value < 0.001). (Table) Similar with EBV-related cancer as a whole, the APCCs of BL, HL and GC were statistically significantly smaller than 0, except that the APCCs of NNKTL and NPC were statistically significantly larger than 0 and not statistically significantly different from 0 respectively. The incidence of EBV-related cancer also decreased in mixed cellularity classical HL, nodular sclerosis classical HL, adenocarcinoma of GC, signet ring cell carcinoma in GC, undifferentiated carcinoma of NPC, squamous cell carcinoma of NPC, patients diagnosed at the age of 20-39 years old and 60-79 years old, male patients and race as white, black or Asian, but increased in classical HL, NOS, nodular lymphocyte predominant HL and non-keratinizing carcinoma of NPC. Conclusions: Incidence of EBV-related cancer decreased during 2000 and 2017, which was consistent in BL, HL and GC.[Table: see text]
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Kim, Young-Bae, Hoon Hur, and Dakeun Lee. "Frequent EBV positivity in conventional adenocarcinomas occurring simultaneously with EBV-associated gastric cancers." Pathology 48, no. 6 (October 2016): 616–18. http://dx.doi.org/10.1016/j.pathol.2016.05.012.
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Lutzky, Viviana P., Denis J. Moss, David Chin, William B. Coman, Peter G. Parsons, and Glen M. Boyle. "Biomarkers for Cancers of the Head and Neck." Clinical medicine. Ear, nose and throat 1 (January 2008): CMENT.S1051. http://dx.doi.org/10.4137/cment.s1051.
Full textAbstract:
Head and neck cancer is a broad term used to describe malignancies that arise in the nasal and oral cavities, pharynx and larynx, as well as the paranasal sinuses. Head and neck squamous cell carcinoma (HNSCC) affects the squamous epithelium of the oral cavity, tongue and oropharynx, excluding the nasopharynx. Recent advances in molecular technology, including gene expression and proteomic profiling appear to offer the potential for the development of specific biomarkers including diagnostic tools which may act as an aid to guide therapy for this malignancy. The other human head and neck cancer included in this review, nasopharyngeal carcinoma (NPC) is a malignancy derived from the undifferentiated epithelium of the nasopharyngeal cavity, and is considered here as a separate entity because its strong association with Epstein-Barr virus (EBV) presents the opportunity for the development of virus related and unrelated biomarkers. In particular, IgA antibodies to EBV and high levels of EBV DNA in serum samples of NPC patients have been recorded. This review aims to summarize some current and also potential new biomarkers that could be used for screening, diagnosis, monitoring and prognostic prediction for cancers of the head and neck, including NPC and HNSCC.