Figure 6 - uploaded by Teresa A Lehman
Content may be subject to copyright.
![Alternative splicing in the EBV BamH1 A region in EBVaGCs.
RNA-seq data from BR-4271, BR-4376, and BR-4298 and BR-4253 was analyzed using the TopHat aligner to obtain splice junction information. Samples with the type I strain of EBV, BR-4271, BR-4376, BR-4298, and BR-4253 were aligned to the type I genome, B95-8/Raji (Genbank accession number AJ507799). Junctions were visualized using Integrative Genomic Viewer (IGV) [88]. Thickness of red junction features correlates with the number of reads for the respective junction. The number of junction spanning reads for each junction is indicated below each olive green junction feature.](profile/Teresa-Lehman/publication/236741243/figure/fig1/AS:340789071761429@1458261854640/Alternative-splicing-in-the-EBV-BamH1-A-region-in-EBVaGCs-RNA-seq-data-from-BR-4271.png)
Alternative splicing in the EBV BamH1 A region in EBVaGCs. RNA-seq data from BR-4271, BR-4376, and BR-4298 and BR-4253 was analyzed using the TopHat aligner to obtain splice junction information. Samples with the type I strain of EBV, BR-4271, BR-4376, BR-4298, and BR-4253 were aligned to the type I genome, B95-8/Raji (Genbank accession number AJ507799). Junctions were visualized using Integrative Genomic Viewer (IGV) [88]. Thickness of red junction features correlates with the number of reads for the respective junction. The number of junction spanning reads for each junction is indicated below each olive green junction feature.
Source publication
Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we perfor...
Contexts in source publication
Context 1
... TopHat [21]. Consideration of the most abundant splice junction reads 266 indicates the predominance of sequential splicing from exons 1-2-3-4-5-6-7 ( Figure 6). 267 ...
Context 2
... there is significant evidence of intra-exonal splicing at exons 3 (3a to 3b), 268 5 (5a to 5b), and 7 (7a to 7b) ( Figure 6). Although splicing from exons 1 to 2 is the most 269 predominant 5' region splicing order, there is also good evidence of alternative splicing ...
Context 3
... also performed an additional clustering analysis using only the EBV genes across 308 the 12 EBVaGC. This analysis revealed that the 4 hiEBVaGC samples cluster distinctly 309 from the other EBVaGC samples ( Figure S6). This apparently distinct gene expression 310 pattern observed in the 4 hiEBVaGC samples raises the possibility that these samples Further, CTLs and NK cells are key producers of granzymes and perforin, which are 323 found to be elevated in the hiEBVaGC ( Figure 8A). ...
Citations
... than the next highest GC subtype (166). In EBVaGCs, the ratio of CD8+ to CD4+ T cells is 10:1, indicating increased cytotoxic antitumoral activity (167), with RNA-seq analysis of GCs showing that cytotoxic CD8+ T cell (CTL) signatures are strongly correlated with EBV viral load, which is expected given that viral antigens will be recognized as non-self by the host immune system (168). Though the level of infiltrating DCs is higher in EBVaGCs as compared to EBVnGCs (43, 165,167), few are CD1a+, resulting in tolerogenic responses of T cells against tumor cells (164) (169,170). ...
... Indeed, EBVaGCs display high mRNA levels for all MHC-I components, including heavy and light chains, as well as factors required for loading, in comparison to both normal control tissues or EBVnGCs (47). This is likely a consequence of higher IFN-g levels in EBVaGCs (168,198). Intratumoral IFN-g is produced by tumor-infiltrating lymphocytes and is a known inducer of transcription of the genes encoding MHC-I and components of the antigen loading complex (199). Interestingly, EBVaGCs were recently reported as exhibiting the highest IFN-g gene response signature of all the GC subtypes (200,201). ...
... As compared to EBVnGCs, a number of immunosuppressive genes are upregulated in the TME of EBVaGCs. One such gene is IDO1, a potent inhibitor of immune cells, allowing virus-associated tumors to persist in opposition to the increased local immune cell concentration (164,168). IDO1 functions by exhausting tryptophan within the TME, producing kynurenine in the process. Reduced environmental tryptophan results in reduced proliferation, immune cell function, and contributes to tumor escape and metastasis (211). ...
Epstein-Barr virus (EBV) is a pathogen known to cause a number of malignancies, often taking years for them to develop after primary infection. EBV-associated gastric cancer (EBVaGC) is one such malignancy, and is an immunologically, molecularly and pathologically distinct entity from EBV-negative gastric cancer (EBVnGC). In comparison with EBVnGCs, EBVaGCs overexpress a number of immune regulatory genes to help form an immunosuppressive tumor microenvironment (TME), have improved prognosis, and overall have an “immune-hot” phenotype. This review provides an overview of the histopathology, clinical features and clinical outcomes of EBVaGCs. We also summarize the differences between the TMEs of EBVaGCs and EBVnGCs, which includes significant differences in cell composition and immune infiltration. A list of available EBVaGC and EBVnGC gene expression datasets and computational tools are also provided within this review. Finally, an overview is provided of the various chemo- and immuno-therapeutics available in treating gastric cancers (GCs), with a focus on EBVaGCs.
... The discovery of LMP1 protein in gastric epithelial cells in individuals with gastric cancer indicated that the cellular reservoir for EBV maybe B lymphocytes invading the stomach's mucosal lymphoid tissue, allowing viral amplification (65)(66)(67)(68). This EBV movement indicates that the virus is switching between epithelial and B host cells. ...
... The discovery of LMP1 protein in gastric epithelial cells in individuals with gastric cancer indicated that the cellular reservoir for EBV maybe B lymphocytes invading the stomach's mucosal lymphoid tissue, allowing viral amplification (65)(66)(67)(68). This EBV movement indicates that the virus is switching between epithelial and B host cells. ...
Gastric cancer (GC) is a serious public health issue due to its frequency and severity. It is, for both sexes, one of the most common causes of cancer-related death and is a major contributor to the global burden of disease. Recent data show that Epstein-Barr virus (EBV) has been detected in different histopathological subtypes of gastric carcinoma and that EBV-associated gastric carcinoma (EBVaGC) represents about 10% of all cases. Moreover, the LMP1 protein characterizing the malignant transformation of cells in several cancer models seems to be very rarely expressed in this type of cancer. This study aimed to characterize EBVaGC in our population by detecting LMP1 in gastric carcinomas in about 30 selected patients. The results showed that in our population, nuclear staining predominates, showing that the antrum remains the most sampled site both for these pathologies and for LMP1 positivity (nuclear staining). In general, the LMP1 marking was negative for 22.58%, positive with a nuclear predominance at 64.52%, nuclear and cytoplasmic at 12.90%, and no positive marking for the cytoplasm. Results were not like the different studies on the expression of this oncogenic protein without EBVsCG, probably finding an explanation in the fact that our country is among the endemic regions for this herpes virus. In conclusion, the rate of LMP1 expression among gastric carcinomas does not seem similar to that observed in other countries. This study characterizing EBVaGC in Tizi-Ouzou, Algeria, reinforces the need for further studies to clarify the role of EBV (LMP1) and to explore its potential value as a predictive biomarker for the development of this type of cancer pathology.
... The discovery of LMP1 protein in gastric epithelial cells in individuals with gastric cancer indicated that the cellular reservoir for EBV maybe B lymphocytes invading the stomach's mucosal lymphoid tissue, allowing viral amplification (65)(66)(67)(68). This EBV movement indicates that the virus is switching between epithelial and B host cells. ...
We are looking into viral components that may contribute to breast cancer in order to find possible therapeutic targets. The Epstein-Barr virus (EBV), which has been found to cause nasopharyn-geal carcinoma and Burkitt lymphoma, is thought to play a role in breast cancer. Our series' patients had a median age of 49, with nearly half being under the age of 49. T2 tumors (two to five centimeters in size) make up the vast majority of our collection (60%). Six percent of our patients showed lymph node involvement, with roughly the same number in the N1 and N2 stages (41.17% each). Only 17.64% of people are at the N3 stage. SBR II tumors were the most common (90%). Only 20% of patients have HER2 overexpression, whereas 73.33% have ER expression. EBV was found in 23.33% of breast car-cinomas (7 cases/30) after oncoprotein LMP1 expression, but normal surrounding tissues tested negative. We discovered that overexpression of the HER2 protein is inversely related to the two HRs' expression. They have no relationship with EBV infection and, consequently, LMP1 expression. LMP1 expression was not shown to be linked with patient age, tumor grade, tumor size, or lymph node invasion. Introduction Breast cancer is the most commonly occurring cancer among women worldwide, and it is the leading cause of death for women in the poorest countries [1]. In developed countries, breast cancer is the second highest cause of death after lung cancer [2]. The disease is complex and multifaceted, arising when breast epithelial cells lose control over their development. Despite progress in treatment, breast cancer remains a significant public health concern globally. To identify new therapeutic targets, it is critical to discover prognostic and predictive markers, such as hormone receptors (HR) and the HER2 oncogene. Steroid hormones, including estrogen and progesterone, can have a significant impact on breast tissue and lead to hormone-sensitive or hormone-dependent cancers. HER2 overexpression is a common genetic alteration in this disease, and monoclonal antibodies targeting this receptor have emerged as an effective therapeutic approach. Various factors, including age, histological type, tumor size, lymph node invasion, and histoprog-nostic grade according to Scarff, Bloom, and Richardson (SBR), as well as the expression of hormone receptors or HER2 overexpression, are known predictors of breast cancer and provide crucial information for treatment and prognosis. Additionally, viral infections are believed to be associated with
... This is evidenced by the impaired function of cytotoxic T lymphocytes (CTLs) and natural killer cells in EBVaGC. Elevated levels of IFN-g depletes tryptophan and suppresses tryptophan sensitive cytotoxic T lymphocytes (CTLs) and natural killer cells (234). Additionally, LMP2A mutations on exons 1-8 (30) and PD-L1 upregulation in both EBVaGC and NPC (235-237) limit CTL detection and promote differentiation of CD4+ cells into Treg cells (238). ...
... Additionally, LMP2A mutations on exons 1-8 (30) and PD-L1 upregulation in both EBVaGC and NPC (235-237) limit CTL detection and promote differentiation of CD4+ cells into Treg cells (238). Other molecules contributing to immunosuppression include CCL22 which increases Treg recruitment, and indoleamine 2,3dioxygenase (IDO1) (234,239,240). Antigen processing in EBVaGC is also inhibited by EBNA1 repeats and early lytic gene BNLF1a (234,241), perpetuating immune evasion. ...
... Other molecules contributing to immunosuppression include CCL22 which increases Treg recruitment, and indoleamine 2,3dioxygenase (IDO1) (234,239,240). Antigen processing in EBVaGC is also inhibited by EBNA1 repeats and early lytic gene BNLF1a (234,241), perpetuating immune evasion. ...
Epstein-Barr virus (EBV), one of the most common human viruses, has been associated with both lymphoid and epithelial cancers. Undifferentiated nasopharyngeal carcinoma (NPC), EBV associated gastric cancer (EBVaGC) and lymphoepithelioma-like carcinoma (LELC) are amongst the few common epithelial cancers that EBV has been associated with. The pathogenesis of EBV-associated NPC has been well described, however, the same cannot be said for primary pulmonary LELC (PPLELC) owing to the rarity of the cancer. In this review, we outline the pathogenesis of EBV-associated NPC and EBVaGCs and their recent advances. By drawing on similarities between NPC and PPLELC, we then also postulated the pathogenesis of PPLELC. A deeper understanding about the pathogenesis of EBV enables us to postulate the pathogenesis of other EBV associated cancers such as PPLELC.
... Lytically infected cells could release growth factors and immunosuppressive cytokines capable of signaling through many different signaling pathways, leading to tumor growth enhancement [53]. Besides the contribution of the lytic cycle itself to the development of EBV-induced cancers, numerous studies have showed that specific lytic proteins can promote oncogenesis [114][115][116]. The two EBV immediate early transcriptional activators, BZLF1 and BRLF1, can synergistically induce expression of multiple early lytic genes involved in viral DNA amplification, late gene expression, and virion production [38,117]. ...
... EBV-GCs also display viral latency II program, similar to that of NPC [56]. However, LMP1 is absent in some cases, while BART miRNAs are highly expressed [116]. The precise contribution of EBV to the development of EBV-GC is unknown, but it is shown that EBV-GC development is also linked to several other pathogenic factors, including genetic susceptible background, dietary habits, and metal dust environmental cofactors exposure [170]. ...
Epstein–Barr virus (EBV) is the first identified human oncogenic virus that can establish asymptomatic life-long persistence. It is associated with a large spectrum of diseases, including benign diseases, a number of lymphoid malignancies, and epithelial cancers. EBV can also transform quiescent B lymphocytes into lymphoblastoid cell lines (LCLs) in vitro. Although EBV molecular biology and EBV-related diseases have been continuously investigated for nearly 60 years, the mechanism of viral-mediated transformation, as well as the precise role of EBV in promoting these diseases, remain a major challenge yet to be completely explored. This review will highlight the history of EBV and current advances in EBV-associated diseases, focusing on how this virus provides a paradigm for exploiting the many insights identified through interplay between EBV and its host during oncogenesis, and other related non-malignant disorders.
... In EBVaGC, the latent infection type of EBV is between type I and type II, mainly expressing Epstein-Barr nuclear antigen 1 (EBNA1), EBV-encoded small RNAs (EBERs) and BamHI-A rightward transcripts BARTs [5]. Furthermore, latent membrane protein 2A (LMP2A) expression could be detected in 40% of EBVaGC cases [6]. ...
This study aimed to investigate the association of Epstein-Barr virus (EBV) with nuclear respiratory factor 1 (NRF1) and the biological function of NRF1 in EBV-associated gastric cancer (EBVaGC). Western blot and qRT-PCR were used to assess the effect of latent membrane protein 2A (LMP2A) on NRF1 expression after transfection with LMP2A plasmid or siLMP2A. The effects of NRF1 on the migration and apoptosis ability of GC cells were investigated by transwell assay and flow cytometry apoptosis analysis in vitro, respectively. In addition, we determined the regulatory role of NRF1 in EBV latent infection by western blot and droplet digital PCR (ddPCR). LMP2A upregulated NRF1 expression by activating the NF-κB pathway. Moreover, NRF1 upregulated the expression of N-Cadherin and ZEB1 to promote cell migration. NRF1 promoted the expression of Bcl-2 to increase the anti-apoptotic ability of cells. In addition, NRF1 maintained latent infection of EBV by promoting the expression of the latent protein Epstein-Barr nuclear antigen 1 (EBNA1) and inhibiting the expression of the lytic proteins. Our data indicated the role of NRF1 in EBVaGC progression and the maintenance of EBV latent infection. This provided a new theoretical basis for further NRF1-based anti-cancer therapy.
... The tumor microenvironment has been implicated in the pathogenesis of EBV-associated nasopharyngeal carcinoma (62) and upregulation of genes in the interferon-gamma pathway has been discovered in EBV-associated gastric cancer (63). ...
Epstein-Barr virus (EBV)-associated smooth muscle tumors (EBV-SMTs) are rare smooth muscle neoplasms exclusively associated with immunosuppression, such as in patients with HIV/AIDS, posttransplant, and congenital immunodeficiency. However, the genomic landscape of EBV-SMTs is poorly understood. Leiomyosarcomas harbor genomic instability and multiple recurrent DNA copy number alterations, whereas leiomyomas lack such changes. Thus, this study aimed to fill this knowledge gap by characterizing copy number alterations in EBV-SMTs and correlating this information with clinicopathologic characteristics. Our study investigated and compared the pathologic characteristics and copy number profiles of 9 EBV-SMTs (from 7 patients with AIDS after transplantation), 6 leiomyomas, and 7 leiomyosarcomas, using chromosomal microarray platforms. Our results showed a lower copy number alteration burden in EBV-SMTs and leiomyoma than in leiomyosarcoma. This contrast in the molecular profile between EBV-SMTs and leiomyosarcoma is concordant with the different clinical behaviors and pathologic characteristics exhibited by these tumors. Despite having an overall copy number alteration profile closer to leiomyoma, recurrent copy number gain of oncogenes, such as RUNX1, CCND2, and ETS2, was found in EBV-SMTs. Epigenetic alterations may play an important role in tumorigenesis as recurrent copy number gains were found in histone deacetylases. A gene enrichment analysis also demonstrated enrichment of genes involved in the host response to viral infection, suggesting that the tumor immune microenvironment may play an important role in EBV-SMT tumorigenesis.
... Several studies reported the expression of lytic EBV genes in gastric tumor tissue (n = 25), including the IE genes BZRF1 and BRLF1 [146,147]. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), Strong et al. [148] conducted a quantitative and global assessment of EBV gene expression in gastric carcinomas and examined EBV-associated cellular pathway alterations. They found that in addition to LMP1 and LMP2, IE genes, BZLF1 and BRLF1, were also expressed but no progression beyond E gene expression occurred, thus suggesting abortive-lytic replication in vivo. ...
Simple Summary
In this review, we summarize the current knowledge concerning the potential roles of “abortive-lytic” replication of EBV in establishing the latent state and its contribution to the tumor microenvironment (TME) and oncogenesis. Particular emphasis is given to discussing how EBV deoxyuridine triphosphate nucleotidohydrolase (dUTPase), an early protein encoded by BLLF3 which possesses novel immunomodulatory properties, may contribute to these processes.
Abstract
There is increasing evidence that put into question the classical dogma that the Epstein–Barr virus (EBV) exists in cells as either a lytic virus in which new progeny is produced or in a latent state in which no progeny is produced. Notably, a third state has now been described, known as the abortive-lytic phase, which is characterized by the expression of some immediate early (IE) and early (E) genes, but no new virus progeny is produced. While the function of these IE and E gene products is not well understood, several recent studies support the concept they may contribute to tumor promotion by altering the tumor microenvironment (TME). The mechanisms by which these viral gene products may contribute to tumorigenesis remain unclear; however, it has been proposed that some of them promote cellular growth, immune evasion, and/or inhibit apoptosis. One of these EBV early gene products is the deoxyuridine triphosphate nucleotidohydrolase (dUTPase) encoded by BLLF3, which not only contributes to the establishment of latency through the production of activin A and IL-21, but it may also alter the TME, thus promoting oncogenesis.
... Eventually, EBV-infected gastric epithelial cells begin clonal growth, and gene mutations in EBV-infected cells lead to carcinogenesis [144]. EBV-associated gastric carcinoma is molecularly characterized by frequent mutations in phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit α (PIK3CA) [124] and ATrich interaction domain 1A (ARID1A) [125], rare TP53 mutations [124], and the overexpression of interferon-γ [149] and programmed death ligand 1 (PD-L1) [124,150]. ...
The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.
