scholarly journals Andrographolide Inhibits Lytic Reactivation of Epstein–Barr Virus by Modulating Transcription Factors in Gastric Cancer

2021 ◽  
Vol 9 (12) ◽  
pp. 2561
Author(s):  
Praphatson Malat ◽  
Tipaya Ekalaksananan ◽  
Chukkris Heawchaiyaphum ◽  
Supawadee Suebsasana ◽  
Sittiruk Roytrakul ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Transcription Factors ◽  
Protein Expression ◽  
Epstein Barr Virus ◽  
Expression Patterns ◽  
Chemical Constituent ◽  
Barr Virus ◽  
Lytic Reactivation ◽  
Epstein Barr ◽  
Apoptosis Related Protein

Andrographolide is the principal bioactive chemical constituent of Andrographis paniculata and exhibits activity against several viruses, including Epstein–Barr virus (EBV). However, the particular mechanism by which andrographolide exerts an anti-EBV effect in EBV-associated gastric cancer (EBVaGC) cells remains unclear. We investigated the molecular mechanism by which andrographolide inhibits lytic reactivation of EBV in EBVaGC cells (AGS-EBV cell line) using proteomics and bioinformatics approaches. An andrographolide treatment altered EBV protein-expression patterns in AGS-EBV cells by suppressing the expression of EBV lytic protein. Interestingly cellular transcription factors (TFs), activators for EBV lytic reactivation, such as MEF2D and SP1, were significantly abolished in AGS-EBV cells treated with andrographolide and sodium butyrate (NaB) compared with NaB-treated cells. In contrast, the suppressors of EBV lytic reactivation, such as EZH2 and HDAC6, were significantly up-regulated in cells treated with both andrographolide and NaB compared with NaB treatment alone. In addition, bioinformatics predicted that HDAC6 could interact directly with MEF2D and SP1. Furthermore, andrographolide significantly induced cell cytotoxicity and apoptosis of AGS-EBV cells by induction of apoptosis-related protein expression. Our results suggest that andrographolide inhibits EBV lytic reactivation by inhibition of host TFs, partially through the interaction of HDAC6 with TFs, and induces apoptosis of EBVaGC cells.

scholarly journals Identification of differential proteomics in Epstein-Barr virus-associated gastric cancer and related functional analysis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zeyang Wang ◽  
Zhi Lv ◽  
Qian Xu ◽  
Liping Sun ◽  
Yuan Yuan
Keyword(s):  
Gastric Cancer ◽  
Functional Analysis ◽  
Protein Expression ◽  
Epstein Barr Virus ◽  
Protein Profile ◽  
Expression Patterns ◽  
Clinicopathological Parameters ◽  
Differential Proteomics ◽  
Barr Virus ◽  
Epstein Barr

Abstract Background Epstein-Barr virus-associated gastric cancer (EBVaGC) is the most common EBV-related malignancy. A comprehensive research for the protein expression patterns in EBVaGC established by high-throughput assay remains lacking. In the present study, the protein profile in EBVaGC tissue was explored and related functional analysis was performed. Methods Epstein-Barr virus-encoded RNA (EBER) in situ hybridization (ISH) was applied to EBV detection in GC cases. Data-independent acquisition (DIA) mass spectrometry (MS) was performed for proteomics assay of EBVaGC. Functional analysis of identified proteins was conducted with bioinformatics methods. Immunohistochemistry (IHC) staining was employed to detect protein expression in tissue. Results The proteomics study for EBVaGC was conducted with 7 pairs of GC cases. A total of 137 differentially expressed proteins in EBV-positive GC group were identified compared with EBV-negative GC group. A PPI network was constructed for all of them, and several proteins with relatively high interaction degrees could be the hub genes in EBVaGC. Gene enrichment analysis showed they might be involved in the biological pathways related to energy and biochemical metabolism. Combined with GEO datasets, a highly associated protein (GBP5) with EBVaGC was screened out and validated with IHC staining. Further analyses demonstrated that GBP5 protein might be associated with clinicopathological parameters and EBV infection in GC. Conclusions The newly identified proteins with significant differences and potential central roles could be applied as diagnostic markers of EBVaGC. Our study would provide research clues for EBVaGC pathogenesis as well as novel targets for the molecular-targeted therapy of EBVaGC.

scholarly journals The Transcriptomic Landscape of Gastric Cancer: Insights into Epstein-Barr Virus Infected and Microsatellite Unstable Tumors

2018 ◽  
Vol 19 (7) ◽  
pp. 2079 ◽  
Author(s):  
Irene Gullo ◽  
Joana Carvalho ◽  
Diana Martins ◽  
Diana Lemos ◽  
Ana Monteiro ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Protein Expression ◽  
Epstein Barr Virus ◽  
Molecular Subtype ◽  
Expression Patterns ◽  
Therapeutic Implications ◽  
Barr Virus ◽  
Epstein Barr ◽  
Nanostring Technology ◽  
L1 Protein

Background: Epstein-Barr Virus (EBV) positive and microsatellite unstable (MSI-high) gastric cancer (GC) are molecular subgroups with distinctive molecular profiles. We explored the transcriptomic differences between EBV+ and MSI-high GCs, and the expression of current GC immunotherapy targets such as PD-1, PD-L1, CTLA4 and Dies1/VISTA. Methods: Using Nanostring Technology and comparative bioinformatics, we analyzed the expression of 499 genes in 46 GCs, classified either as EBV positive (EBER in situ hybridization) or MSI-high (PCR/fragment analysis). PD-L1 protein expression was assessed by immunohistochemistry. Results: From the 46 GCs, 27 tested MSI-high/EBV−, 15 tested MSS/EBV+ and four tested MSS/EBV−. The Nanostring CodeSet could segregate GCs according to MSI and, to a lesser extent, EBV status. Functional annotation of differentially expressed genes associated MSI-high/EBV− GCs with mitotic activity and MSS/EBV+ GCs with immune response. PD-L1 protein expression, evaluated in stromal immune cells, was lower in MSI-high/EBV− GCs. High mRNA expression of PD-1, CTLA4 and Dies1/VISTA and distinctive PD-1/PD-L1 co-expression patterns (PD-1high/PD-L1low, PD-1high/PDL1high) were associated with MSS/EBV+ molecular subtype and gastric cancer with lymphoid stroma (GCLS) morphological features. Conclusions: EBV+ and MSI-high GCs present distinct transcriptomic profiles. GCLS/EBV+ cases frequently present co-expression of multiple immunotherapy targets, a finding with putative therapeutic implications.

scholarly journals Cellular Differentiation Regulator BLIMP1 Induces Epstein-Barr Virus Lytic Reactivation in Epithelial and B Cells by Activating Transcription from both the R and Z Promoters

2014 ◽  
Vol 89 (3) ◽  
pp. 1731-1743 ◽  
Author(s):  
Jessica A. Reusch ◽  
Dhananjay M. Nawandar ◽  
Kenneth L. Wright ◽  
Shannon C. Kenney ◽  
Janet E. Mertz
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Cell Types ◽  
Lytic Replication ◽  
Barr Virus ◽  
Lytic Reactivation ◽  
Epstein Barr ◽  
Cellular Transcription

ABSTRACTEpstein-Barr virus (EBV) maintains a lifelong latent infection within a subset of its host's memory B cells, while lytic EBV replication takes place in plasma cells and differentiated epithelial cells. Therefore, cellular transcription factors, such as BLIMP1, that are key mediators of differentiation likely contribute to the EBV latent-to-lytic switch. Previous reports showed that ectopic BLIMP1 expression induces reactivation in some EBV-positive (EBV+) B-cell lines and transcription from Zp, with all Z+cells in oral hairy leukoplakia being BLIMP1+. Here, we examined BLIMP1's role in inducing EBV lytic gene expression in numerous EBV+epithelial and B-cell lines and activating transcription from Rp. BLIMP1 addition was sufficient to induce reactivation in latently infected epithelial cells derived from gastric cancers, nasopharyngeal carcinomas, and normal oral keratinocytes (NOK) as well as some, but not all B-cell lines. BLIMP1 strongly induced transcription from Rp as well as Zp, with there being three or more synergistically acting BLIMP1-responsive elements (BRE) within Rp. BLIMP1's DNA-binding domain was required for reactivation, but BLIMP1 did not directly bind the nucleotide (nt) −660 Rp BRE. siRNA knockdown of BLIMP1 inhibited 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced lytic reactivation in NOK-Akata cells, cells that can be reactivated by R, but not Z. Thus, we conclude that BLIMP1 expression is both necessary and sufficient to induce EBV lytic replication in many (possibly all) EBV+epithelial-cell types, but in only a subset of EBV+B-cell types; it does so, at least in part, by strongly activating expression of both EBV immediately early genes,BZLF1andBRLF1.IMPORTANCEThis study is the first one to show that the cellular transcription factor BLIMP1, a key player in both epithelial and B-cell differentiation, induces reactivation of the oncogenic herpesvirus Epstein-Barr virus (EBV) out of latency into lytic replication in a variety of cancerous epithelial cell types as well as in some, but not all, B-cell types that contain this virus in a dormant state. The mechanism by which BLIMP1 does so involves strongly turning on expression of both of the immediate early genes of the virus, probably by directly acting upon the promoters as part of protein complexes or indirectly by altering the expression or activities of some cellular transcription factors and signaling pathways. The fact that EBV+cancers usually contain mostly undifferentiated cells may be due in part to these cells dying from lytic EBV infection when they differentiate and express wild-type BLIMP1.

Relationship of intratumoural protein expression patterns to age and Epstein-Barr virus status in classical Hodgkin lymphoma

2014 ◽  
Vol 95 (2) ◽  
pp. 137-149 ◽  
Author(s):  
Maja Ludvigsen ◽  
Peter Kamper ◽  
Stephen J. Hamilton-Dutroit ◽  
Knud Bendix ◽  
Michael B. Møller ◽  
...  
Keyword(s):  
Protein Expression ◽  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Expression Patterns ◽  
Classical Hodgkin Lymphoma ◽  
Barr Virus ◽  
Epstein Barr ◽  
Relationship Of

scholarly journals Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through ATM Methylation

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4252
Author(s):  
Sun Hee Lee ◽  
Su Jin Choi ◽  
Wonhyeok Choi ◽  
Subin Cho ◽  
Miyeon Cho ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Gastric Carcinoma ◽  
Epstein Barr Virus ◽  
Cisplatin Resistance ◽  
Dna Demethylation ◽  
Barr Virus ◽  
Lytic Reactivation ◽  
Atm Gene ◽  
Epstein Barr

Epstein–Barr-virus-associated gastric carcinoma (EBVaGC), first reported in 1992, currently accounts for 10% of all gastric carcinoma worldwide. EBVaGC has unique DNA hypermethylation phenotypes that allow for higher proportions of DNA methylation than any other gastric cancer. CpG islands in the gene promoter region are one of the major regions in which DNA methylation controls gene transcription. Despite cisplatin-based chemotherapy being one of the standard treatment regimens for advanced gastric cancer, including EBVaGC, cisplatin alone or in combination with 5-fluorouracil has been limited by its less potent anticancer activity and the occurrence of cisplatin resistance. Accordingly, the current study evaluated the anticancer activities of a combination of cisplatin and 5-Azacytidine (5-AZA) against EBVaGC. Our findings showed that cisplatin upregulated the DNMT3A gene, whereas shRNA-targeted removal of DNMT3A mRNA contributed to cisplatin-mediated EBV lytic reactivation. Moreover, the removal of DNMT3A mRNA upregulated the ATM gene through DNA demethylation on the ATM promoter. Furthermore, CRISPR/Cas9-targeted removal of the ATM gene resulted in significantly reduced cell susceptibility and EBV lytic reactivation by a combination of cisplatin and DNMT3A inhibitor 5-AZA. Finally, 5-AZA exhibited a synergistic effect with cisplatin in anti-EBV and anti-EBVaGC activities by increasing drug susceptibility and EBV lytic reactivation. The aforementioned results suggest that cisplatin combined with DNA methylation inhibitors could be a novel therapeutic approach for EBVaGC.

scholarly journals Intratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jieti Wang ◽  
Ruochen Li ◽  
Yifan Cao ◽  
Yun Gu ◽  
Hanji Fang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
T Cells ◽  
Epstein Barr Virus ◽  
Effector Memory ◽  
Feature Identification ◽  
Barr Virus ◽  
T Cell Infiltration ◽  
Epstein Barr ◽  
Gastric Cancer Patients

AbstractStudies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein–Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies.

scholarly journals PARP1 restricts Epstein Barr Virus lytic reactivation by binding the BZLF1 promoter

Virology ◽  
2017 ◽  
Vol 507 ◽  
pp. 220-230 ◽  
Author(s):  
Lena N. Lupey-Green ◽  
Stephanie A. Moquin ◽  
Kayla A. Martin ◽  
Shane M. McDevitt ◽  
Michael Hulse ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Barr Virus ◽  
Lytic Reactivation ◽  
Epstein Barr ◽  
Bzlf1 Promoter
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