Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) account for about 10% of gastric cancers globally, with higher prevalence in East Asia and Latin America. These cancers develop through a "gastritis-infection-cancer sequence" and are characterized by unique molecular signatures, including CpG island methylator phenotype and mutations in ARID1A and PIK3CA genes. EBVaGCs typically present in the proximal stomach with diffuse-type histology and dense lymphocytic infiltration. Key viral proteins EBNA1 and LMP2A drive oncogenesis by altering cellular processes and immune responses. The IFN-γ signature and extensive epigenetic modifications contribute to their distinct profile. Despite often presenting at advanced stages, EBVaGCs generally have a more favorable prognosis. EBV employs sophisticated strategies to evade immune detection, utilizing latent proteins and noncoding RNAs. Paradoxically, despite an immune-hot environment, EBVaGCs demonstrate effective immune evasion, partly due to the expression of immune checkpoint molecules like PD-L1 and LAG3. Treatment approaches vary based on disease stage, from endoscopic resection for early-stage cancers to systemic therapies for advanced cases. Immunotherapy, particularly PD-1/PD-L1 inhibitors, shows promising results. Emerging research suggests combining these with LAG3 inhibitors may enhance efficacy. Ongoing research and advanced genomic techniques continue to reveal new insights, paving the way for personalized therapies and novel diagnostic approaches.

Natural killer/T-cell lymphoma (NKTL) is a rare malignancy of mature natural killer/T-cells, predominantly found in Asian and South/Central American populations, with limited studies conducted in Europe and the United States.

The aim of this study is to present an overview of the incidence rate, demographic and clinical characteristics, treatment options, overall survival (OS), and factors influencing OS of NKTL in the United States.

We used data from the Surveillance, Epidemiology, and End Results 17 database to analyze NKTL cases recorded between 2000 and 2020. In a cohort of 1162 patients with NKTL, we calculated the incidence rates and performed statistical analyses to evaluate OS, the effect of radiotherapy and chemotherapy on survival, and lymphoma-specific survival.

The mean annual incidence rate of NKTL in the United States was 0.067 per 100,000, with higher rates observed in men compared to women, and an increase noted with age. However, there has been no significant rise in incidence over recent years. Significant racial disparities were observed, with higher incidence rates in non-Hispanic Asian or Pacific Islanders and Hispanic people. The median survival time for patients with NKTL was 21 months, with a 5-year OS rate of 39.5%, which has shown improvement in recent years. Key independent prognostic factors impacting patient survival included age at diagnosis, clinical stage, nasal type presentation, presence of systemic symptoms, and treatment modality. Patients receiving combined radiotherapy and chemotherapy exhibited the best outcomes, with a median OS of 138 months and a 5-year OS rate of 58%. This survival benefit remained consistent even in patients with stage I/localized nasal type lymphoma, achieving a 5-year OS rate of 73.3%.

The incidence of NKTL has remained stable in recent years. Patients with the nasal type generally experience better survival outcomes. The use of combined radiotherapy and chemotherapy appears to enhance survival, though further validation through prospective multicenter clinical trials is necessary.

Epstein-Barr virus (EBV) and herpes simplex virus-1 (HSV-1) are members of the Herpesviridae family and cause various human malignancies and acute infections. Despite their clinical significance, effective treatments remain limited. Here, we report the broad-spectrum antiviral activity of Ganoderma microsporum immunomodulatory protein (GMI), a safe dietary ingredient known for its immunomodulatory, anti-tumor, and antiviral properties. GMI effectively blocks EBV infection in epithelial cells in a dose-dependent manner by targeting both viral and host cells. Notably, GMI displays antiviral activity across multiple EBV strains in epithelial cell infection and represses EBV infection in primary B cells. Mechanistically, GMI interacts with the EBV fusion glycoprotein gB and the host epithelial receptor EphA2 to disrupt viral fusion. Given the structural conservation of gB among herpesviruses, GMI was tested against HSV-1. Remarkably, GMI effectively blocks HSV-1 infection by targeting viral binding and fusion, as well as interacting with HSV-1 gB. In silico modeling suggests that GMI may interact with EBV and HSV-1 gB domain I, contributing to its antiviral activity. Our findings provide the first evidence that GMI suppresses both EBV and HSV-1 infections by targeting the conserved gB-mediated fusion process, suggesting its potential as an antiviral against herpesviruses that rely on fusion-mediated entry.

Epstein-Barr virus (EBV) was the first DNA virus identified to be tightly associated with multiple human tumors. It promotes malignant progression of tumors - including related lymphomas, nasopharyngeal carcinoma, and gastric adenocarcinoma - in part by evading surveillance and attack by the host immune system. In this article we review the main molecular mechanisms by which EBV-encoded proteins and RNAs interact with key molecules of the host immune system to inhibit Toll-like receptor (TLR)-nuclear factor κB (NF-κB), retinoic acid-inducible gene I (RIG-I), and interferon (IFN) signaling pathways, affect antigen presentation, prevent the cytotoxic effects of CD8+ effector cells, regulate the tumor microenvironment (TME) and cell metastasis and invasion, and inhibit cell apoptosis. These interactions not only contribute to the persistence of the virus but also provide potential targets for developing new immunotherapy strategies.

Epstein-Barr virus (EBV), the first human virus identified with oncogenic properties, encodes a class of microRNAs known as miR-BART (BamHI-A rightward transcript microRNAs). This study investigates the pivotal role of EBV-miR-BART14-3p in the progression of gastric cancer, particularly focusing on its effects on epithelial-mesenchymal transition (EMT), cell proliferation, and migration. EBV-associated gastric cancer (EBVaGC) is distinguished by unique genomic and epigenomic characteristics, with EBV miRNAs significantly influencing tumor biology by regulating gene expression. Our research demonstrates that EBV-miR-BART14-3p facilitates gastric cancer cell migration and invasion by targeting the tumor suppressor gene LACTB, which in turn activates the Phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, a critical driver of EMT. The suppression of LACTB in EBVaGC highlights its crucial role in inhibiting tumor progression. These findings position EBV-miR-BART14-3p as a key player in gastric cancer development and underscore its potential as both a prognostic biomarker and a therapeutic target for EBVaGC.

Gastric cancer remains a significant health burden globally, especially prevalent in Asian and European regions. Despite a notable decline in incidence in the United States and Western Europe over recent decades, the disease's persistence underscores the urgency for advanced research in its pathogenesis and treatment strategies. Central to this pursuit is the exploration of the mitogen-activated protein kinase (MAPK) pathway, a pivotal cellular mechanism implicated in the complex processes of gastric cancer development, including cellular proliferation, invasion, migration, and metastasis. The MAPK or extracellular signal-regulated kinase pathway serves as a crucial conduit for transmitting extracellular signals to elicit intracellular responses, with its signaling cascades subject to alterations due to genetic and epigenetic variations across various diseases, prominently cancer. This review delves into the intricate role of the MAPK signaling pathway in the pathogenesis of gastric cancer, drawing upon the most recent and critical studies that shed light on MAPK pathway alterations as a gateway to the disease. It highlights the pathway's involvement in Helicobacter pylori-mediated gastric carcinogenesis and the tumorigenic processes induced by the Epstein-Barr virus, showcasing the substantial influence of miRNAs and lncRNAs in modulating gastric cancer's biological properties through their interaction with the MAPK pathway. Furthermore, the review extends into the therapeutic arena, discussing the promising impacts of herbal medicines, MAPK pathway inhibitors, and immunosuppressants on mitigating gastric cancer's progression. Through an exhaustive examination of the MAPK pathway's multifaceted role in gastric cancer, from molecular crosstalks to therapeutic prospects, this review aspires to contribute to the ongoing efforts in understanding and combating this global health challenge, paving the way for novel therapeutic interventions and improved patient outcomes.

Uterine sarcoma (US) is a rare malignant tumor that has various pathological types and high heterogeneity in the female reproductive system. Its subtle early symptoms, frequent recurrence, and resistance to radiation and chemotherapy make the prognosis for US patients very poor. Therefore, understanding the molecular mechanisms underlying tumorigenesis and progression is essential for an accurate diagnosis and targeted therapy to improve patient outcomes. Recent advancements in high-throughput molecular sequencing have allowed for a deeper understanding of diseases through multi-omics technologies. In this review, the latest progress and future potential of multi-omics technologies in US research is examined, and their roles in biomarker discovery and their application in the precise diagnosis and treatment of US are highlighted.

Increased mutational burden and EBV load have been revealed from normal tissues to Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs). BPLF1, encoded by EBV, is a lytic cycle protein with deubiquitinating activity has been found to participate in disrupting repair of DNA damage. We first confirmed that BPLF1 gene in gastric cancer (GC) significantly increased the DNA double strand breaks (DSBs). Ubiquitination mass spectrometry identified histones as BPLF1 interactors and potential substrates, and co-immunoprecipitation and in vitro experiments verified that BPLF1 regulates H2Bub by targeting Rad6. Over-expressing Rad6 restored H2Bub but partially reduced γ-H2AX, suggesting that other downstream DNA repair processes were affected. mRNA expression of BRCA2 were significantly down-regulated by next-generation sequencing after over-expression of BPLF1, and over-expression of p65 facilitated the repair of DSBs. We demonstrated BPLF1 may lead to the accumulation of DSBs by two pathways, reducing H2B ubiquitination (H2Bub) and blocking homologous recombination which may provide new ideas for the treatment of gastric cancer.

Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon-γ (IFN-γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine-2,3-dioxygenase (IDO)- kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan-to-phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV-positive GC continuously secreted IFN-γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV-positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV-positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti-tumor immunotherapy.

Helicobacter pylori (H. pylori) infection is critical in the development and occurrence of gastric cancer. H. pylori secretes gamma-glutamyl transferase (GGT), which affects energy metabolism and histone methylation in mesenchymal stem cells. However, its effect on human gastric epithelial cells remains unclear. This study aimed to investigate the effects of GGT on energy metabolism and histone methylation in gastric epithelial cells and determine its role in the development and progression of H. pylori-induced gastric cancer.

A GGT knockout H. pylori strain and mouse gastric cancer model were constructed, and alpha-ketoglutarate (α-KG) was added. The underlying mechanism was investigated using proteomics, immunohistochemistry, Western blotting, and other experimental assays.

H. pylori can colonize the host's stomach and destroy the gastric epithelium. GGT secreted by H. pylori decreased the concentration of glutamine in the stomach and increased H3K9me3 and H3K27me3 expression, which promoted the proliferation and migration of gastric epithelial cells. Additionally, α-KG reversed this effect. GGT increased the tumorigenic ability of nude mice. GGT, secreted by H. pylori, promoted the expression of ribosomal protein L15 (RPL15), while GGT knockout and supplementation with α-KG and trimethylation inhibitors reduced RPL15 expression and Wnt signaling pathway expression.

H. pylori secreted GGT decreased the expression of glutamine and α-KG in gastric epithelial cells, increased the expression of histones H3K9me3 and H3K27me3, and activated the Wnt signaling pathway through RPL15 expression, ultimately changing the biological characteristics of the gastric epithelium and promoting the occurrence of gastric cancer. Altered energy metabolism and histone hypermethylation are important factors involved in this process.

Angiogenesis is one of the characteristics of malignant tumors, and persistent generation of abnormal tumor blood vessels is an important factor contributing to tumor treatment resistance. Epstein-Barr virus (EBV) is a highly prevalent DNA oncogenic virus that is associated with the development of various epithelial malignancies. However, the relationship between EBV infection and tumor vascular abnormalities as well as its underlying mechanisms is still unclear. In this study, we found that compared to EBV-uninfected tumors, EBV-infected tumors were more angiogenic, but the neovascularization was mostly immature vessels without pericyte attachment in both clinical patient tumor samples and mouse xenograft models; These immature vessels exhibited aberrant functionality, characterized by poor blood perfusion and increased vascular permeability. The vascular abnormalities caused by EBV infection exacerbated tumor hypoxia and was responsible for accelerated tumor growth. Mechanistically, EBV infection upregulated ANXA3-HIF-1α-VEGF pathway. Silencing the ANXA3 gene or neutralizing ANXA3 with an antibody can diminish vascular abnormalities, thereby increasing immune cell infiltration and alleviating treatment resistance. Finally, a new therapy combining ANXA3 blockade and NK cell + PD1 antibody significantly inhibited the growth of EBV-infected xenografts in mice. In conclusion, our study identified a previously unrecognized role for EBV infection in tumor vascular abnormalities and revealed its underlying mechanism that upregulated the ANXA3-HIF-1α-VEGF pathway. ANXA3 is a potential therapeutic target for EBV-infected tumors and ANXA3 blockade to improve vascular conditions, in combination with NK cell + PD1 antibody therapy, holds promise as an effective treatment strategy for EBV-associated epithelial malignancies.

Recent research has unveiled fascinating insights into the intricate mechanisms governing tumor evolution. These studies have illuminated how tumors adapt and proliferate by exploiting various factors, including immune evasion, resistance to therapeutic drugs, genetic mutations, and their ability to adapt to different environments. Furthermore, investigations into tumor heterogeneity and chromosomal aberrations have revealed the profound complexity that underlies the evolution of cancer. Emerging findings have also underscored the role of viral influences in the development and progression of cancer, introducing an additional layer of complexity to the field of oncology. Tumor evolution is a dynamic and complex process influenced by various factors, including immune evasion, drug resistance, tumor heterogeneity, and viral influences. Understanding these elements is indispensable for developing more effective treatments and advancing cancer therapies. A holistic approach to studying and addressing tumor evolution is crucial in the ongoing battle against cancer. The main goal of this comprehensive review is to explore the intricate relationship between tumor evolution and critical aspects of cancer biology. By delving into this complex interplay, we aim to provide a profound understanding of how tumors evolve, adapt, and respond to treatment strategies. This review underscores the pivotal importance of comprehending tumor evolution in shaping effective approaches to cancer treatment.

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.

As an oncovirus, EBV is associated with multiple cancers, including solid tumors and hematological malignancies. EBV methylation plays an important role in regulating tumor occurrence. However, the EBV methylation profiles in EBV-associated tumor tissues are poorly understood.

In this study, EBV methylation capture sequencing was conducted in several different tumor tissue samples, including NPC, EBVaGC, lung LELC and parotid LELC. Besides, EBV capture sequencing and following qMSP were performed on nasopharyngeal brushing samples from NPC and nasal NKTCL patients. Our results showed that the EBV genome among different types of tumors displayed specific methylation patterns. Among the four types of tumors from epithelial origin (NPC, EBVaGC, lung LELC and parotid LELC), the most significant differences were found between EBVaGC and the others. For example, in EBVaGC, all CpG sites within 1,44,189-1,45,136 bp of the EBV genome sequence on gene RPMS1 were hyper-methylated compared to the others. Differently, significant differences of EBV CpG sites, particularly those located on gene BILF2, were observed between NPC and nasal NKTCL patients in nasopharyngeal brushing samples. Further, the methylated level of BILF2 was further detected using qMSP, and a diagnostic model distinguishing NPC and nasal NKTCL was established. The AUC of the model was 0.9801 (95% CI 0.9524-1.0000), with the sensitivity and specificity of 98.81% (95% CI 93.63-99.94%) and 76.92% (95% CI 49.74-91.82%), respectively.

Our study reveals more clues for further understanding the pathogenesis of EBV, and provides a possibility for distinguishing EBV-related tumor by detecting specific EBV CpG sites.

Gastric cancer (GC), the fifth most common cancer globally, remains the leading cause of cancer deaths worldwide. Inflammation-induced tumorigenesis is the predominant process in GC development; therefore, systematic research in this area should improve understanding of the biological mechanisms that initiate GC development and promote cancer hallmarks. Here, we summarize biological knowledge regarding gastric inflammation-induced tumorigenesis, and characterize the multi-omics data and systems biology methods for investigating GC development. Of note, we highlight pioneering studies in multi-omics data and state-of-the-art network-based algorithms used for dissecting the features of gastric inflammation-induced tumorigenesis, and we propose translational applications in early GC warning biomarkers and precise treatment strategies. This review offers integrative insights for GC research, with the goal of paving the way to novel paradigms for GC precision oncology and prevention.

Long INterspersed Element 1 (LINE-1 or L1) acts as a major remodeling force in genome regulation and evolution. Accumulating evidence shows that virus infection impacts L1 expression, potentially impacting host antiviral response and diseases. The underlying regulation mechanism is unclear. Epstein-Barr virus (EBV), a double-stranded DNA virus linked to B-cell and epithelial malignancies, is known to have viral-host genome interaction, resulting in transcriptional rewiring in EBV-associated gastric cancer (EBVaGC). By analyzing publicly available datasets from the Gene Expression Omnibus (GEO), we found that EBVaGC has L1 transcriptional repression compared with EBV-negative gastric cancer (EBVnGC). More specifically, retrotransposition-associated young and full-length L1s (FL-L1s) were among the most repressed L1s. Epigenetic alterations, especially increased H3K9me3, were observed on FL-L1s. H3K9me3 deposition was potentially attributed to increased TASOR expression, a key component of the human silencing hub (HUSH) complex for H3K9 trimethylation. The 4C- and HiC-seq data indicated that the viral DNA interacted in the proximity of the TASOR enhancer, strengthening the loop formation between the TASOR enhancer and its promoter. These results indicated that EBV infection is associated with increased H3K9me3 deposition, leading to L1 repression. This study uncovers a regulation mechanism of L1 expression by chromatin topology remodeling associated with viral-host genome interaction in EBVaGC.

Viral-associated cancers are a distinct group of malignancies with a unique pathogenesis and epidemiology. Liquid biopsy is a minimally invasive way to identify tumor-associated abnormalities in blood derivatives, such as plasma, to guide the diagnosis, prognosis, and treatment of patients with cancer. Liquid biopsy encompasses a multitude of circulating analytes with the most extensively studied being cell-free DNA (cfDNA). In recent decades, substantial advances have been made toward the study of circulating tumor DNA in nonviral-associated cancers. Many of these observations have been translated to the clinic to improve the outcomes of patients with cancer. The study of cfDNA in viral-associated cancers is rapidly evolving and reveals tremendous potential for clinical applications. This review provides an overview of the pathogenesis of viral-associated malignancies, the current state of cfDNA analysis in oncology, the current state of cfDNA analysis in viral-associated cancers, and perspectives for the future of liquid biopsies in viral-associated cancers.

Epstein-Barr virus (EBV) associated gastric carcinoma (EBVaGC) is a subtype of gastric cancer with distinct histological and molecular features. The study aimed to assess the EBV DNA copy number and the prevalence of EBVaGC in gastric cancer samples taken from Iranian patients. The next aim was to assess whether the DNA and microRNAs EBV are present in plasma. EBV load was analyzed in 68 gastric cancer biopsies and compared with the results of EBV-encoded small RNA in situ hybridization (EBER-ISH) test in these patients. After the detection of 6 EBV miRNAs in gastric tissue by stem-loop RT-PCR, plasma samples were evaluated for the viral load and EBV miRNAs. Four gastric cancer cases were EBER -ISH positive (5.8%), with a significantly higher viral load than the remaining cases, 47,781 vs. 1909 copies/μg of tissue DNA. Here, was also found a significant difference in plasma EBV load between EBER-positive and EBER-negative cases. Although EBV miRNAs were detectable in all the EBER-positive tumors, the test did not detect any of these miRNAs among the plasma samples tested. Our data indicate that the prevalence of EBVaGC among Iranian patients with gastric cancer is lower than the global prevalence and although none of the EBV miRNAs were detected in plasma, evaluation of EBV microRNAs in tumor tissue, especially miR-BART7-3p, may constitute useful biomarkers for diagnosis of EBVaGC.

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer (GC) distinguished by the presence of the EBV genome and limited viral gene expression within malignant epithelial cells. EBV infection is generally thought to be a relatively late event following atrophic gastritis in carcinogenesis, which implies the heterogeneity of EBVaGC. To facilitate the study of the role of EBV in EBVaGC, we established two EBV-positive GC cell lines (AGS-EBV and HGC27-EBV) with an epitheliotropic EBV strain M81 and characterized viral and cellular gene expression profiles in comparison to SNU719, a naturally derived EBV-positive GC cell line. Like SNU719, AGS-EBV and HGC27-EBV stably maintained their EBV genomes and expressed EBV-encoded small RNAs and nuclear antigen EBNA1. Comprehensive analysis of the expression of EBV-encoded miRNAs within the BamHI-A region rightward transcript region, and the transcripts of EBV latent and lytic genes in cell lines, as well as xenografts, reveals that AGS-EBV and HGC27-EBV cells undergo distinct viral expression profiles. A very small fraction of AGS-EBV and SNU719 cells can spontaneously produce infectious progeny virions, while HGC27-EBV does not. AGS-EBV (both M81 and Akata) cells largely mimic SNU719 cells in viral gene expression profiles, and altered cellular functions and pathways perturbed by EBV infection. Phylogenetic analysis of the EBV genome shows both M81 and Akata EBV strains are closely related to clinical EBVaGC isolates. Taken together, these two newly established EBV-positive GC cell lines can serve as models to further investigate the role of EBV in different contexts of gastric carcinogenesis and identify novel therapeutics against EBVaGC.

(1) Abnormally increased expression of claudin-6 in gastric cancer is considered a prognostic marker of the chromosomal unstable molecular subtype. However, a detailed molecular profile analysis of differentially expressed genes and affected pathways associated with claudin-6 increased (Cldn6^high) expression has not been assessed. (2) The TCGA Stomach Adenocarcinoma Pan-Cancer Atlas Data was evaluated using Cytoscape's Gene Mania, MCODE, and Cytohubba bioinformatic software. (3) 96.88% of Cldn6^high gastric cancer tumors belonging to the chromosomal unstable molecular subtype are associated with a worse prognosis. Cldn6expression coincided with higher mutations in TP53, MIEN1, STARD3, PGAP3, and CCNE1 genes compared to Cldn6^low expression. In Cldn6^high cancers, 1316 genes were highly expressed. Cholesterol metabolism was the most affected pathway as APOA1, APOA2, APOH, APOC2, APOC3, APOB-100, LDL receptor-related protein 1/2, Sterol O-acyltransferase, STARD3, MAGEA-2, -3, -4, -6, -9B, and -12 genes were overexpressed in Cldn6^high gastric cancers; interestingly, APOA2 and MAGEA9b were identified as top hub genes. Functional enrichment of DEGs linked HNF-4α and HNF-1α genes as highly expressed in Cldn6^high gastric cancer. (4) Our results suggest that APOA2 and MAGEA9b could be considered as prognostic markers for Cldn6^high gastric cancers.