ASTE1 frameshift mutation triggers the immune response in Epstein-Barr virus-associated gastric cancer.
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ABSTRACT:
SUBMITTER: Huang B
PROVIDER: S-EPMC8727626 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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ASTE1 frameshift mutation triggers the immune response in Epstein-Barr virus-associated gastric cancer.
Huang Binhao B Li Qin Q Geng Qirong Q Lao Jiawen J Guo Jing J Huang Shenglin S Xu Dazhi D
Signal transduction and targeted therapy 20220105 1
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Project description:Epstein-Barr virus associated gastric cancer (EBVaGC) comprises approximately 10% of gastric carcinomas. Multiple factors contribute to tumorigenesis, including EBV driven hypermethylation of tumor suppressor genes, inflammatory changes in gastric mucosa, host immune evasion by EBV and changes in cell cycle pathways. The unique molecular characteristics of EBVaGC, such as programmed death ligand 1 (PD-L1) overexpression, highlight the potential for using EBV as a biomarker for response to immunotherapy. Few studies have reported benefit from immunotherapy in EBV positive cancers, and clinical trials investigating the impact of checkpoint inhibitors in EBVaGC are currently underway. This review provides the most recent updates on molecular pathophysiology, epidemiology, clinical features and treatment advances pertaining to EBVaGC.
| S-EPMC5964025 | biostudies-literature
Project description:BackgroundEpstein-Barr virus-associated gastric carcinoma (EBVaGC) is a subset of gastric cancers linked to EBV infection. While the role of male hormones in cancers such as prostate, breast, and ovarian cancers is well-studied, their impact on EBVaGC remains less understood. This study aims to examine the effect of dihydrotestosterone (DHT) on EBVaGC, particularly focusing on its influence on the immune response.MethodsThe study utilized the SNU719 EBVaGC cell line. Cells were treated with DHT to assess androgen receptor (AR) expression and the activation of signaling pathways, including NF-κB. The expression of MHC class I polypeptide-related sequence A (MICA) and its interaction with the NKG2D receptor on NK and T cells was evaluated. Cytotoxicity assays were conducted to determine DHT's effect on NK and T cell-mediated cytotoxicity, and proinflammatory cytokine gene expression was analyzed.ResultsDHT significantly increased AR expression in EBVaGC cells and activated the NF-κB pathway, which led to increased transcription of target genes such as MICA and EBNA1. These changes enhanced the interaction with receptors on NK and T cells, thereby boosting their cytotoxicity against EBVaGC cells. Importantly, DHT did not upregulate proinflammatory cytokine genes.ConclusionDHT enhances the immune response against EBVaGC by upregulating MICA and activating NK and T cells. These findings suggest potential therapeutic strategies targeting androgen signaling to improve anti-tumor immunity in EBVaGC.
| S-EPMC11429822 | biostudies-literature
Project description:BackgroundEpstein-Barr virus (EBV) is a highly prevalent human herpesvirus capable of infecting the central nervous system and establishing persistent infection.MethodsWe employed solid phase immunoassay techniques to measure immunoglobulin G (IgG) class antibodies to EBV virions and defined proteins in 432 individuals with schizophrenia and 311 individuals without a history of a psychiatric disorder. Western blot testing was performed to document reactivity to specific EBV proteins. Polygenic risk for schizophrenia was calculated from genome sequencing arrays. Levels of antibodies between the groups were compared by multivariate analyses incorporating clinical, genetic, and demographic measures.ResultsIndividuals with schizophrenia had marked elevations in the levels of antibodies to EBV virions as compared to the control population. Further analyses indicated increased levels of reactivity to EBV-viral capsid antibody (VCA) but not to EBV nuclear antigen-1 (EBNA-1) or to other human herpesviruses. Western blot analysis confirmed increased reactivity to VCA proteins in the group of individuals with schizophrenia and documented a lack of increased levels of antibodies to EBNA-1. Genetic analyses indicated an additive effect of increased levels of antibodies to EBV virions and genetic susceptibility to schizophrenia, with individuals with elevated levels of both type of markers having a greater than 8.5-fold odds of a schizophrenia diagnosis.ConclusionsIndividuals with schizophrenia have increased levels of antibodies to some but not all EBV proteins indicating an aberrant response to EBV infection. This aberrant response may contribute to the immunopathology of schizophrenia and related disorders.
| S-EPMC6737467 | biostudies-literature
Project description:Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all EBV-associated malignancies, and play a critical role in the onset, progression, and/or maintenance of these tumors. Based on the signature changes at amino acid residue 487, EBNA1 is classified into five distinct subtypes: P-ala, P-thr, V-leu, V-val and V-pro. In the present study, the sequence variations of EBNA1 in EBV-associated gastric carcinoma (EBVaGC) and throat washing (TW) samples of healthy EBV carriers in Guangzhou, southern China, where nasopharyngeal carcinoma (NPC) is endemic, were analyzed by PCR and DNA sequencing. V-val subtype was the most predominant (53.6%, 15/28) in EBVaGC, followed by P-ala (42.9%, 12/28) and V-leu (32.1%, 9/28) subtypes. In TWs of healthy EBV carriers, V-val subtype was also predominant (85.7%, 18/21). The sequence variations of EBNA1 in EBVaGC were similar to those in TW of healthy EBV carriers (p>0.05), suggesting that the EBV strains in EBVaGC might originate from the viral strains prevalent within the background population. The predominance of V-val subtype in EBVaGC in Guangzhou was similar to that in EBVaGC in northern China and Japan, but was different from that in EBVaGC in America, suggesting that the variations of EBNA1 in EBVaGC represent geographic-associated polymorphisms rather than tumor-specific mutations. In addition, the EBNA1 variations in EBVaGC in gastric remnant carcinoma were also determined. V-leu subtype was detected in all 4 (100%) cases, although 2 cases occurred as mixed infection with P-ala subtype. This is different from the predominant V-val subtype in EBVaGC in conventional gastric carcinoma, suggesting that V-leu might be a subtype that adapts particularly well to the microenvironment within the gastric stump and enters the remnant gastric mucosa epithelia easily. This, to our best knowledge, is the first investigation of EBNA1 polymorphisms in EBVaGC from endemic area of NPC.
| S-EPMC3506544 | biostudies-literature
Project description:Cancer stem cells (CSCs) play a decisive role in the development and progression of cancer. To investigate CSCs in Epstein-Barr virus (EBV)-associated carcinoma (EBVaGC), we screened previously reported stem cell markers of gastric cancer in EBV-infected gastric cancer cell lines (TMK1 and NUGC3) and identified CD44v6v9 double positive cells as candidate CSCs. CD44v6/v9+/+ cells were sorted from EBVaGC cell line (SNU719) cells and EBV-infected TMK1 cells and these cell populations showed high spheroid-forming ability and tumor formation in SCID mice compared with the respective CD44v6/v9-/- cells. Sphere-forming ability was dependent on the nuclear factor-κB (NF-κB) signaling pathway, which was confirmed by decrease of sphere formation ability under BAY 11-7082. Small interfering RNA knockdown of latent membrane protein 2A (LMP2A), one of the latent gene products of EBV infection, decreased spheroid formation in SNU719 cells. Transfection of the LMP2A gene increased the sphere-forming ability of TMK1 cells, which was mediated through NF-κB signaling. Together, these results indicate that CD44v6v9+/+ cells are CSCs in EBVaGC that are maintained through the LMP2A/NF-κB pathway. Future studies should investigate CD44v6/v9+/+ cells in normal and neoplastic gastric epithelium to prevent and treat this specific subtype of gastric cancer infected with EBV.
| S-EPMC7385383 | biostudies-literature
Project description:The comprehensive DNA methylation status of gastric cancer cells obtained from an advanced Epstein-Barr virus-associated gastric cancer case, in which complete response to S-1 plus cisplatin chemotherapy was achieved, was analyzed with DNA methylation microarray (Illumina Infinium MethylationEPIC BeadChip). DNA was extracted from metastatic lesion (lymph node).
2019-06-08 | GSE132406 | GEO
Project description:BackgroundGastric carcinomas (GC) are aggressive malignancies, and only ~15% of patients respond to anti-programmed cell death (ligand) 1 (PD-(L)1) monotherapy. However, Epstein-Barr virus (EBV)-associated GCs (~5-10% of GCs) often harbor PD-L1 and PD-L2 chromosomal amplifications and robust CD8+ T cell infiltrates, and respond at a high rate to anti-PD-1. The current study compares the tumor immune microenvironments (TiMEs) of EBV+ versus EBV(-) GCs.MethodsOver 1000 cases of primary invasive GCs were screened to identify 25 treatment-naïve specimens for study (11 EBV+, 14 EBV(-)). Quantitative immunohistochemistry (IHC) was conducted for markers of immune cell subsets and co-regulatory molecules. Gene expression profiling (GEP) was performed on RNAs isolated from macrodissected areas of CD3+ T cell infiltrates abutting PD-L1+ stromal/tumor cells, using multiplex quantitative reverse transcriptase PCR for a panel of 122 candidate immune-related genes.ResultsIHC revealed that 17/25 GCs contained PD-L1+ stromal cells, with no significant difference between EBV+/- specimens; however, only 3/25 specimens (all EBV+) contained PD-L1+ tumor cells. CD8+ T cell densities were higher in EBV+ versus EBV(-) tumors (p=0.044). With GEP normalized to the pan-leukocyte marker PTPRC/CD45, EBV+ GCs overexpressed ITGAE (CD103, marking intraepithelial T cells and a dendritic cell subset) and the interferon-inducible genes CXCL9 and IDO1. In contrast, EBV(-) tumors overexpressed several functionally-related gene groups associated with myeloid cells (CD163, IL1A, NOS2, RIGI), immunosuppressive cytokines/chemokines (CXCL2, CXCR4, IL10, IL32), coinhibitory molecules (HAVCR2/TIM-3 and VSIR/VISTA), and adenosine pathway components (ENTPD1/ CD39 and NT5E/CD73). Notably, compared with EBV+ GCs, EBV(-) GCs also overexpressed components of the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway associated with cancer-promoting inflammation, including PTGS2/COX-2 (most highly upregulated gene, 32-fold, p=0.005); prostaglandin receptors PTGER1 (EP1; up 21-fold, p=0.015) and PTGER4 (EP4; up twofold, p=0.022); and the major COX-2-inducing cytokine IL1B (up 11-fold, p=0.019). Consistent with these findings, COX-2 protein expression trended higher in EBV(-) versus EBV+ GCs (p=0.068).ConclusionsWhile certain markers of immunosuppression are found in the GC TiME regardless of EBV status, EBV(-) GCs, which are much more common than EBV+ GCs, overexpress components of the COX-2/PGE2 pathway. These findings provide novel insights into the immune microenvironments of EBV+ and EBV(-) GC, and offer potential targets to overcome resistance to anti-PD-(L)1 therapies.
| S-EPMC11580252 | biostudies-literature
Project description:BackgroundAn atypical immune response to Epstein-Barr virus (EBV) infection has been associated with several complex diseases including schizophrenia. The etiology of MDD is unclear; host immune response to EBV infection could play a role.MethodsWe utilized solid phase immunoassays and western blots to measure antibodies to EBV virions, specific viral proteins, and 5 other herpesviruses in 87 individuals with MDD and 312 control individuals.ResultsIndividuals with MDD had significantly reduced levels of reactivity to EBV Nuclear Antigen-1. Quantitative levels of antibodies to EBV virions and Viral Capsid Antigen did not differ between groups. Individuals with decreased levels of anti-Nuclear Antigen-1, or elevated levels of anti-virion had increased odds of being in the MDD group. The odds of MDD were elevated in individuals who had the combination of high levels of anti-virion and low levels of anti-Nuclear Antigen-1 (OR =13.6). Western blot analysis corroborated decreased reactivity to Nuclear Antigen-1 in the MDD group and revealed altered levels of antibodies to other EBV proteins. There was a trend towards decreased levels of antibodies to varicella virus in the group of individuals with MDD.LimitationsThe MDD sample size was relatively small. There could be unmeasured factors that account for the association between MDD and the immune response to EBV.ConclusionsIndividuals with MDD have altered levels and patterns of antibodies to EBV antigens. This atypical response could contribute to the immunopathology of MDD. Therapeutic interventions available for treatment of EBV infection could potentially be of benefit in MDD.
| S-EPMC7025817 | biostudies-literature
Project description:Epstein-Barr virus (EBV), originally discovered through its association with Burkitt lymphoma, is now aetiologically linked to a remarkably wide range of lymphoproliferative lesions and malignant lymphomas of B-, T- and NK-cell origin. Some occur as rare accidents of virus persistence in the B lymphoid system, while others arise as a result of viral entry into unnatural target cells. The early finding that EBV is a potent B-cell growth transforming agent hinted at a simple oncogenic mechanism by which this virus could promote lymphomagenesis. In reality, the pathogenesis of EBV-associated lymphomas involves a complex interplay between different patterns of viral gene expression and cellular genetic changes. Here we review recent developments in our understanding of EBV-associated lymphomagenesis in both the immunocompetent and immunocompromised host.This article is part of the themed issue 'Human oncogenic viruses'.
| S-EPMC5597738 | biostudies-literature
Project description:BackgroundRecent whole-genome sequencing identified four molecular subtypes of gastric cancer (GC), of which the subgroup of Epstein-Barr virus-associated GC (EBVaGC) showed a significant enrichment of PIK3CA mutations. We here aimed to validate independently the enrichment of PIK3CA mutations in EBVaGC of a Central European GC cohort, to correlate EBV status with clinico-pathological patient characteristics and to test for a major issue of GC, intratumoral heterogeneity.Patients and methodsIn a first step, 484 GCs were screened for EBV and PIK3CA hot spot mutations of exon 9/20 using EBER in situ hybridization and pyrosequencing, respectively. Secondly, an extended sequencing of PIK3CA also utilizing next generation sequencing was carried out in all EBVaGCs and 96 corresponding lymph node metastases.ResultsTwenty-two GCs were EBER-positive, all being of latency type I. Intratumoral heterogeneity of EBER-positivity was found in 18% of EBVaGCs. Twenty-three GCs held PIK3CA mutations in hot spot regions of exon 9 or 20, being significantly more common in EBVaGCs (P < 0.001). Subsequent extended sequencing of PIK3CA of EBVaGCs showed that 14% harvested three to five different PIK3CA genotypes (including wildtype) in the same primary tumor, albeit in histologically and spatially distinct tumor areas, and that intratumoral heterogeneity of PIK3CA was also present in the corresponding lymph node metastases.ConclusionsOur findings unravel issues of tumor heterogeneity and illustrate that the assessment of the EBV status in tissue biopsies might carry the risk of sampling errors, which may significantly hamper adequate molecular tumor classification in a more clinical setting. Moreover, this is the first report of intratumoral heterogeneity of PIK3CA mutations in GC, and our findings lead to the conclusion that PIK3CA mutant and -wildtype tumor subclones are skilled to metastasize independently to different regional lymph nodes.
| S-EPMC5406766 | biostudies-literature