Development of Epstein-Barr virus-associated gastric cancer: Infection, inflammation, and oncogenesis.

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) cells originate from a single-cell clone infected with EBV. However, more than 95% of patients with gastric cancer have a history of Helicobacter pylori (H. pylori) infection, and H. pylori is a major causative agent of gastric cancer. Therefore, it has long been argued that H. pylori infection may affect the development of EBVaGC, a subtype of gastric cancer. Atrophic gastrointestinal inflammation, a symptom of H. pylori infection, is observed in the gastric mucosa of EBVaGC. Therefore, it remains unclear whether H. pylori infection is a cofactor for gastric carcinogenesis caused by EBV infection or whether H. pylori and EBV infections act independently on gastric cancer formation. It has been reported that EBV infection assists in the onco-genesis of gastric cancer caused by H. pylori infection. In contrast, several studies have reported that H. pylori infection accelerates tumorigenesis initiated by EBV infection. By reviewing both clinical epidemiological and experimental data, we reorganized the role of H. pylori and EBV infections in gastric cancer formation.

Gastric epithelial attachment of Helicobacter pylori induces EphA2 and NMHC-IIA receptors for Epstein-Barr virus.

Epstein-Barr virus (EBV)-associated gastric cancer belongs to 1 of the 4 subtypes of gastric cancer and accounts for 10% of total gastric cancers. However, most cases of gastric cancer have a history of Helicobacter pylori infection. Therefore, we investigated the possibility that H. pylori infection promotes the development of EBV-associated gastric cancer. H. pylori was exposed to principal EBV receptor, CD21, negative gastric epithelial cells, and then infected with EBV recombinant expressing enhanced green fluorescent protein. Changes in EBV infectivity due to prior H. pylori exposure were analyzed using flow cytometry. The treatment of gastric epithelial cells with H. pylori increased the efficiency of EBV infection. An increase was also observed when CagA-deficient, VacA-deficient, and FlaA-deficient H. pylori strains were used, but not when cag pathogenicity island-deficient H. pylori was used. The treatment of epithelial cells with H. pylori induced the expression of accessory EBV receptors, EphA2 and NMHC-IIA, and increased the efficiency of EBV infection depending on their expression levels. When gastric epithelial cells were treated with EPHA2 or NMHC-IIA siRNA, EBV infection via H. pylori attachment was decreased. The adhesion of H. pylori induced the expression of accessory EBV receptors in gastric epithelial cells and increased the efficiency of EBV infection.

Epstein-Barr Virus Infection of Pseudostratified Nasopharyngeal Epithelium Disrupts Epithelial Integrity.

Epstein-Barr virus (EBV) is a human oncogenic virus that causes several types of tumor, such as Burkitt's lymphoma and nasopharyngeal carcinoma (NPC). NPC tumor cells are clonal expansions of latently EBV-infected epithelial cells. However, the mechanisms by which EBV transforms the nasopharyngeal epithelium is hampered, because of the lack of good in vitro model to pursue oncogenic process. Our primary nasopharyngeal epithelial cell cultures developed pseudostratified epithelium at the air-liquid interface, which was susceptible to EBV infection. Using the highly sensitive RNA in situ hybridization technique, we detected viral infection in diverse cell types, including ciliated cells, goblet cells, and basal cells. EBV-encoded small RNA-positive cells were more frequently detected in the suprabasal layer than in the basal layer. We established the most physiologically relevant EBV infection model of nasopharyngeal epithelial cells. This model will advance our understanding of EBV pathogenesis in the development of NPC.

Application of Biopsy Samples Used for Helicobacter pylori Urease Test to Predict Epstein-Barr Virus-Associated Cancer.

Persistent gastric mucosal damage caused by Helicobacter pylori infection is a major risk factor for gastric cancer (GC). The Epstein-Barr virus (EBV) is also associated with GC. Most patients with EBV-associated GC are infected with H. pylori in East Asia. However, very few reports have described where and when both H. pylori and EBV infect the gastric mucosa. To clarify this, old biopsy samples used for the rapid urease test (RUT) were applied to count EBV genomic DNA (gDNA) copies using DNA probe quantitative polymerase chain reaction. DNA extracted from the gastric biopsy samples of 58 patients with atrophic gastritis was used to analyze the correlation between the degree of atrophic gastritis and the copy number of EBV gDNA. EBV was detected in 44 cases (75.9%), with viral copy numbers ranging from 12.6 to 4754.6. A significant correlation was found between patients with more than 900 copies of EBV gDNA and those with a more severe grade of atrophic gastritis (p = 0.041). This study shows that EBV can be detected in RUT samples in a manner that reduces patient burden.

Corrigendum: Role of Viral and Host microRNAs in Immune Regulation of Epstein-Barr Virus-Associated Diseases.

[This corrects the article DOI: 10.3389/fimmu.2020.00367.].

Role of Viral and Host microRNAs in Immune Regulation of Epstein-Barr Virus-Associated Diseases.

Epstein-Barr virus (EBV) is an oncogenic human herpes virus that was discovered in 1964. Viral non-coding RNAs, such as BamHI-A rightward fragment-derived microRNAs (BART miRNAs) or BamHI-H rightward fragment 1-derived miRNAs (BHRF1 miRNA) in EBV-infected cells have been recently reported. Host miRNAs are also upregulated upon EBV infection. Viral and host miRNAs are important in maintaining viral infection and evasion of host immunity. Although miRNAs in EBV-infected cells often promote cell proliferation by targeting apoptosis or cell cycle, this review focuses on the regulation of the recognition of the host immune system. This review firstly describes the location and organization of two clusters of viral miRNAs, then describes evasion from host immune surveillance systems by modulating viral gene expression or inhibiting innate and acquired immunity by viral miRNAs as well as host miRNAs. Another topic is the enigmatic depletion of viral miRNAs in several types of EBV-infected tumor cells. Finally, this review introduces the strong correlation of nasopharyngeal cancer cases with a newly identified single nucleotide polymorphism that enhances BART miRNA promoter activity.