Evidence of lytic infection of Epstein-Barr virus (EBV) in EBV-positive gastric carcinoma

2002 ◽  
Vol 66 (3) ◽  
pp. 351-359 ◽  
Author(s):  
Yoshiko Hoshikawa ◽  
Yukio Satoh ◽  
Masanao Murakami ◽  
Michio Maeta ◽  
Nobuaki Kaibara ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Epstein Barr Virus ◽  
Lytic Infection ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals A Screen for Epstein-Barr Virus Proteins That Inhibit the DNA Damage Response Reveals a Novel Histone Binding Protein

2018 ◽  
Vol 92 (14) ◽  
Author(s):  
Ting-Hin Ho ◽  
Justine Sitz ◽  
Qingtang Shen ◽  
Ariane Leblanc-Lacroix ◽  
Eric I. Campos ◽  
...  
Keyword(s):  
Dna Damage ◽  
Gastric Carcinoma ◽  
Dna Damage Response ◽  
Epstein Barr Virus ◽  
Lytic Infection ◽  
Genome Integrity ◽  
Barr Virus ◽  
Ebv Infection ◽  
Damage Response ◽  
Epstein Barr

ABSTRACTTo replicate and persist in human cells, linear double-stranded DNA (dsDNA) viruses, such as Epstein-Barr virus (EBV), must overcome the host DNA damage response (DDR) that is triggered by the viral genomes. Since this response is necessary to maintain cellular genome integrity, its inhibition by EBV is likely an important factor in the development of cancers associated with EBV infection, including gastric carcinoma. Here we present the first extensive screen of EBV proteins that inhibit dsDNA break signaling. We identify the BKRF4 tegument protein as a DDR inhibitor that interferes with histone ubiquitylation at dsDNA breaks and recruitment of the RNF168 histone ubiquitin ligase. We further show that BKRF4 binds directly to histones through an acidic domain that targets BKRF4 to cellular chromatin and is sufficient to inhibit dsDNA break signaling. BKRF4 transcripts were detected in EBV-positive gastric carcinoma cells (AGS-EBV), and these increased in lytic infection. Silencing of BKRF4 in both latent and lytic AGS-EBV cells (but not in EBV-negative AGS cells) resulted in increased dsDNA break signaling, confirming a role for BKRF4 in DDR inhibition in the context of EBV infection and suggesting that BKRF4 is expressed in latent cells. BKRF4 was also found to be consistently expressed in EBV-positive gastric tumors in the absence of a full lytic infection. The results suggest that BKRF4 plays a role in inhibiting the cellular DDR in latent and lytic EBV infection and that the resulting accumulation of DNA damage might contribute to development of gastric carcinoma.IMPORTANCEEpstein-Barr virus (EBV) infects most people worldwide and is causatively associated with several types of cancer, including ∼10% of gastric carcinomas. EBV encodes ∼80 proteins, many of which are believed to manipulate cellular regulatory pathways but are poorly characterized. The DNA damage response (DDR) is one such pathway that is critical for maintaining genome integrity and preventing cancer-associated mutations. In this study, a screen for EBV proteins that inhibit the DDR identified BKRF4 as a DDR inhibitor that binds histones and blocks their ubiquitylation at the DNA damage sites. We also present evidence that BKRF4 is expressed in both latent and lytic forms of EBV infection, where it downregulates the DDR, as well as in EBV-positive gastric tumors. The results suggest that BKRF4 could contribute to the development of gastric carcinoma through its ability to inhibit the DDR.

scholarly journals Epstein-Barr virus-associated gastric carcinoma in Brazil: comparison between in situ hybridization and polymerase chain reaction detection

2012 ◽  
Vol 43 (1) ◽  
pp. 393-404 ◽  
Author(s):  
Marcos Antonio Pereira de Lima ◽  
Márcia Valéria Pitombeira Ferreira ◽  
Marcos Aurélio Pessoa Barros ◽  
Maria Inês de Moura Campos Pardini ◽  
Adriana Camargo Ferrasi ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
In Situ Hybridization ◽  
Gastric Carcinoma ◽  
Epstein Barr Virus ◽  
Polymerase Chain Reaction Detection ◽  
Chain Reaction ◽  
Barr Virus ◽  
Polymerase Chain ◽  
Epstein Barr

Phenotype analysis by MUC2, MUC5AC, MUC6, and CD10 expression in Epstein-Barr virus-associated gastric carcinoma

2006 ◽  
Vol 41 (8) ◽  
pp. 733-739 ◽  
Author(s):  
Rita Rani Barua ◽  
Hiroshi Uozaki ◽  
Ja-Mun Chong ◽  
Tetsuo Ushiku ◽  
Rumi Hino ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Phenotype Analysis ◽  
Cd10 Expression ◽  
Epstein Barr

scholarly journals Cytolytic Epstein-Barr Virus Reactivation Therapy for EBV-Associated Gastric Carcinoma

2020 ◽  
pp. 1-10
Author(s):  
Jaap M. Middeldorp ◽  
Zlata Novalić ◽  
Sandra A.W.M. Verkuijlen ◽  
Astrid E. Greijer ◽  
Jaap M. Middeldorp
Keyword(s):  
Gastric Carcinoma ◽  
Mouse Model ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Drug Combinations ◽  
Model Systems ◽  
Virus Reactivation ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Epstein Barr

Background: Epstein-Barr virus associated gastric carcinoma (EBVaGC) is considered a distinct GC disease entity, with the virus persisting in a latent phase. Treatment with Epirubicin, Capecitabine and Cisplatin (ECC combination) showed survival benefit in patients with GC in clinical trials (MAGIC study and CRITICS study) when compared to chemotherapy with Capecitabine and Cisplatin (GCb/Cis). Current treatment protocols for GC do not consider virus involvement. Methods: In this study, we tested a CytoLytic Virus Activation (CLVA) strategy consisting of the ECC combination or GCb/Cis together with the HDAC inhibitor Valproic acid (VPA) to define whether EBV reactivation and subsequent antiviral treatment with Ganciclovir (GCV) could be used as virus-targeted therapy for EBVaGC. Drug combinations with VPA and GCV were evaluated in multiple cell lines and in an EBVaGC mouse model based on human naturally EBV-infected SNU-719 cells. Results: EBV reactivation was demonstrated by lytic mRNA transcripts and proteins in treated cells, and the virus-reactivating capacity of different CLVA drug combinations was compared in C666.1, AGS-BX1 and SNU-719 cell lines. In an EBVaGC mouse model, GCb/Cis with VPA and GCV strongly reduced tumor volume and showed the highest potential for EBV-reactivation. Upon a single round of CLVA treatment, EBV DNA levels in circulation decreased, and loss of EBV-positive cells in treated tumors was observed. In vivo EBV-reactivation was revealed by the presence of lytic gene transcripts and proteins in tumor tissues 6 days after treatment. Conclusion: In EBVaGC model systems, CLVA treatment showed a more potent virus reactivation and killing of tumor cells when compared to standard chemotherapy alone, suggesting that addition of VPA plus GCV to the ECC or GCb/Cis combination should be considered in future clinical studies.

scholarly journals Efficacy of Immune Checkpoint Inhibitors in Metastatic Epstein-Barr Virus Associated Gastric Cancer (EBVaGC): A Case Series and Review of Literature

2021 ◽  
Author(s):  
Shimeng Liang ◽  
Weibing Leng ◽  
Dan Jiang ◽  
Ming Liu ◽  
Dan Cao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Carcinoma ◽  
Immune Checkpoint Inhibitors ◽  
Epstein Barr Virus ◽  
Checkpoint Inhibitors ◽  
Case Series ◽  
Metastatic Gastric Cancer ◽  
Pooled Analysis ◽  
Barr Virus ◽  
Epstein Barr

Abstract Background Immunotherapy has revolutionized the treatment of malignant tumors. However, limited clinical data are available to report the efficacy of immune checkpoint inhibitors (ICIs) on Epstein-Barr virus-associated gastric carcinoma. Methods In this study, we report a case series of five patients with metastatic Epstein-Barr virus-associated gastric carcinoma who were treated with ICIs and to perform a pooled analysis of published cases to investigate the efficacy of ICIs in Epstein-Barr virus-associated gastric carcinoma patients. Results Between 2018 and 2020, five metastatic gastric cancer patients with EBV positivity who received PD-1 antibodies treatment were included in the analysis at the authors’ institution. Furthermore, we performed a pooled analysis of the contemporary literature. In our case series, two patients experienced partial response (PR); one patient achieved complete response (CR), whereas two patients had progression disease (PD), resulting an ORR of 60%. In the pooled analysis of all 36 patients, ORR was 48.6% (17/35). For the first line and later lines, it was 75% (3/4) and 45.2% (14/31) respectively. The ORR was 46.7% (14/30) for ICIs monotherapy and improved to 60% (3/5) by combination with chemotherapy. Conclusions These results demonstrated that an EBV-positive status was a reliable biomarker for immunotherapy in metastatic gastric cancer, especially for monotherapy. Immunotherapy combined with chemotherapy may be a better strategy, warranting further large-scale clinical trials for validation.

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