Search

Epstein–Barr virus (EBV) infection is associated with the occurrence and development of gastric cancer (GC). Methyl methanesulfonate and ultraviolet‐sensitive gene 81 (MUS81) is the catalytic component of a structure‐specific endonuclease and plays an important role in chromosomal stability. However, the link between EBV infection and MUS81 remains unclear. In the present study, we found that MUS81 expression was much lower in EBV‐associated GC cells than in EBV‐negative GC. MUS81 acts as an oncogene in GC by inducing the cell migration and proliferation. Western blot and luciferase reporter assays revealed that miR‐BART9‐5p directly targeted MUS81 and downregulated its expression. Additionally, overexpression of MUS81 in EBV‐positive GC cells inhibited the expression of EBV nuclear antigen 1 (EBNA1). EBNA1 is critical for the pathogenesis of EBV‐associated tumors and the maintenance of a stable copy number of the viral genomes. Altogether, these results indicated that the lowering MUS81 expression might be a mechanism by EBV to maintain its latent infection. [ABSTRACT FROM AUTHOR]

Epstein‐Barr virus (EBV) was the first tumor virus discovered in humans and can cause various types of tumors. Molecular classification suggests that EBV‐associated gastric cancer (EBVaGC) is a unique subtype of gastric cancer.EBV was also the first virus found to encode its own microRNAs. However, the functions of many miRNAs remain unknown. This study investigated the roles and targets of miR‐BART2‐5p (BART2‐5p) and miR‐BART11‐5p (BART11‐5p) in EBVaGC. The expression of RB and p21 in EBVaGC and EBV negative GC (EBVnGC) cells was evaluated by western blotting. Expression of BART2‐5p and BART11‐5p in EBVaGC cells was evaluated by droplet digital PCR. The effects of BART2‐5p or BART11‐5p and their potential mechanisms were further investigated using cell counting kit‐8, colony formation assay, flow cytometry analysis, and transwell assay. BART2‐5p and BART11‐5p were abundantly expressed and RB and p21 were downregulated in EBVaGC cells. BART2‐5p regulates RB and p21 expression by directly targeting them. BART11‐5p regulates RB expression by directly targeting RB. Both BART2‐5p and BART11‐5p promoted proliferation and migration of gastric cancer cells, while inhibiting apoptosis and promoting S‐phase arrest of the cell cycle. Thus, BART2‐5p and BART11‐5p play important roles in promoting proliferation and migration, and inhibiting apoptosis in EBVaGC by targeting RB and p21, thus providing new potential therapeutic targets for EBVaGC. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this study is to investigate the polymorphism and distribution characteristics of BALF2 gene in Epstein–Barr virus (EBV)-associated tumors (gastric cancer, nasopharyngeal carcinoma and lymphoma). Materials & methods: DNA sequences of 349 EBV-related samples were analyzed by nested PCR combined with DNA sequencing. Results: According to the phylogenetic tree, BALF2 was divided into six genotypes (BALF2-A–F). Statistically, the incidence of BALF2-E in nasopharyngeal carcinoma was higher than that in healthy people, and the incidence of BALF2-E in nasopharyngeal carcinoma in South China was higher than that in North China (p = 0.001). Conclusion:BALF2 variants in EBV-associated samples are not only tumor-specific, but also differ between northern and southern regions. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is a type IV herpesvirus that widely infects the vast majority of adults, and establishes a latent infection pattern in host cells to escape the clearance of immune system. The virus is intimately associated with the occurrence and progression of lymphomas and epithelial cell cancers. EBV latent membrane proteins (LMPs) can assist its immune escape by downregulating host immune response. Besides EBV, LMPs have important effects on the functions of exosomes and autophagy, which also help EBV to escape immune surveillance. These escape mechanisms may provide conditions for further development of EBV-associated tumors. In this article, we discussed the potential functions of EBV-encoded LMPs in promoting immune escape. [ABSTRACT FROM AUTHOR]

EBV is an important human tumor virus and is closely related to the occurrence of a variety of tumors, involving 10% of gastric cancer. In EBV-associated gastric carcinoma (EBVaGC), EBV expresses restrict viral genes including EBV nuclear antigen 1, EBV encoded small RNAs, Bam HI-A rightward transcripts, latent membrane protein 2A and miRNAs. The role of EBV in gastric carcinogenesis has received increasing attention and is considered to be another pathogenic factor in addition to Helicobacter pylori. A typical characteristic of EBVaGC is the extensive methylation of viral and host genome. Combined with other epigenetic mechanisms, EBV infection acts as an epigenetic driver of EBVaGC oncogenesis. In this review we discuss recent findings of EBV effect on host epigenetic alterations in EBVaGC and its role in oncogenic process. [ABSTRACT FROM AUTHOR]

BACKGROUND: Gap junction protein beta 2 gene (GJB2) encodes one of connexins- Connexin 26 (Cx26), which mainly expressed in epithelial cells. Cx26 is usually considered a channel to exchange information between cells, which plays a critical role in tumor cell proliferation. OBJECTIVE: We investigated GJB2 rs2274084 polymorphism in three types of tumors, including nasophoryngeal carcinoma (NPC), gastric cancer (GC) and lymphoma. METHODS: Proteinase K digestion and phenolchloroform purification and QIAamp DNA FFPE tissue kit was used for DNA extraction. The genotype of GJB2 gene rs2274084 was detected through Sequenom MassARRAY SNP technique. The Chi-square test and Fisher's exact test were used to compare the differences between two groups. RESULTS: The genotype frequency of GJB2 gene rs2274084 was significantly different between EBV-positive NPC and normal control (P < 0.05). However, for EBV-associated gastric cancer (EBVaGC), EBV-negative gastric cancer (EBVnGC) and lymphoma, no significant differences were found in comparison with the normal control. CONCLUSIONS: The mutation rate of TT genotype was a risk factor to the occurrence of EBV-positive NPC. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is an important DNA tumor virus that is associated with approximately 10% of gastric carcinomas and 99% of nasopharyngeal cancers (NPC). DNA methylation and microRNAs (miRNAs) are the most studied epigenetic mechanisms that can prompt disease susceptibility. This study aimed to detect the effect of EBV on Wnt inhibitory factor 1 (WIF1), Nemo-like kinase (NLK), and adenomatous polyposis coli (APC) gene methylation, and expression in gastric carcinoma and NPC. The WIF1, NLK, and APC gene mRNA expression levels were measured by real-time quantitative RT-PCR in four EBV-positive cell lines and four EBV-negative cell lines. Bisulfite genomic sequencing or methylation-specific PCR was used to detect the methylation status of the WIF1, NLK, and APC promoters. All cell lines were treated with 5-azacytidine (5-aza-dC), miR-BART19-3p mimics or an inhibitor, and analyzed by flow cytometry and MTT cell proliferation assays. The WIF1, NLK, and APC promoters were hypermethylated in all eight cell lines. 5-Aza-dC displayed a growth inhibitory effect on cells . After transfection with miR-BART19-3p mimics, the expression of WIF1, and APC decreased, and the cellular proliferation rate increased. After transfection with the miR-BART19-3p inhibitor, the expression levels were higher, and the cell growth was inhibited. In the NPC and GC cell lines, the promoters of WIF1, NLK, and APC are highly methylated, and the expression of these three genes is regulated by miR-BART19-3p. The activity of the Wnt pathway in EBV-associated tumors may be enhanced by miR-BART19-3p. [ABSTRACT FROM AUTHOR]

In order to study the mechanism of Epstein–Barr virus (EBV) infection in gastric carcinoma cells, we characterized the EBV infection in signet ring cell line HSC-39, derived from a human gastric carcinoma. HSC-39 cells were highly susceptible to cell-free EBV infection by Akata and P3HR-1 EBV strains. EBV nuclear antigen (EBNA) and EBV-encoded small RNA (EBER) were detected in the infected cells. Akata and P3HR-1 EBV-infected cell clones were isolated by a limiting dilution technique. The Akata and P3HR-1 EBV-infected clones differed from each other in morphology and growth patterns. Akata EBV-infected clones had lower growth rates than did P3HR-1 EBV-infected clones in both liquid and soft agar mediums. Both the infected HSC-39 cells and the clones expressed EBNA1 and EBER, but did not express EBNA2, latent membrane protein (LMP) 1 and LMP2A. The Q promoter (p), but not the Cp/Wp for EBNA transcription, was active in the infected HSC-39 cells and all clones. No lytic infection was observed in either infected parental cells or any clones. Uninfected HSC-39 cells did not express a principal EBV receptor CD21; however, Akata but not P3HR-1 EBV-infected clones expressed low levels of CD21 mRNA. These results demonstrate that the cellular phenotypes of HSC-39 cells are altered by EBV infection in strain-specific manner. We propose the HSC-39 cell line as a model target for the study of the mechanism and significance of EBV infection in gastric carcinoma. [Copyright &y& Elsevier]

• EBV can upregulate the PI3K/AKT pathway through its encoded EBER1 and LMP2A, thereby promoting the expression of YAP1 in EBVaGC cells. • YAP1 enhances the proliferation, migration, autophagy, S-phase accumulation, and anti-apoptotic ability of EBVaGC cells, which may play carcinogenic role in EBVaGC progression. • YAP1 also enhances EBV replication, and TPA and NaB induced EBV lytic reactivation, forming a bidirectional regulatory mechanism with EBV, further promoting the development of EBVaGC. This study aims to explore the role and regulatory mechanism of Yes-associated protein 1 (YAP1) in the development of Epstein-Barr virus-associated gastric cancer (EBVaGC). Here we showed that EBV can upregulate the expression and activity of YAP1 protein through its encoded latent products EBV-encoded small RNA 1 (EBER1) and latent membrane protein 2A (LMP2A), enhancing the malignant characteristics of EBVaGC cells. In addition, we also showed that overexpression of YAP1 induced the expression of EBV encoding latent and lytic phase genes and proteins in the epithelial cell line AGS-EBV infected with EBV, and increased the copy number of the EBV genome, while loss of YAP1 expression reduced the aforementioned indicators. Moreover, we found that YAP1 enhanced EBV lytic reactivation induced by two known activators, 12-O-tetradecanoylhorbol-13-acetate (TPA) and sodium butyrate (NaB). These results indicated a bidirectional regulatory mechanism between EBV and YAP1 proteins, providing new experimental evidence for further understanding the regulation of EBV infection patterns and carcinogenic mechanisms in gastric cancer. [ABSTRACT FROM AUTHOR]

• EBV can encode miRNAs and lncRNAs. • The host cell encoded miRNAs and lncRNAs are associated with EBV infection. • Non-coding RNAs can regulate EBV-associated epithelial cell tumors. Epstein-Barr virus (EBV) infection is highly prevalent in the population and is known to be associated with a variety of human tumors, such as nasopharyngeal carcinoma, gastric cancer, and lymphoma; however, the mechanisms of EBV carcinogenesis remain unclear. Recent studies have revealed that many non-coding RNAs participate in the regulation of proliferation, migration, invasion, and other processes in EBV-associated tumor, and the interaction between ncRNAs and the potential target genes has gradually become a research hotspot. Therefore, here, we discuss the expression and roles of ncRNAs in EBV-associated epithelial tumors. [ABSTRACT FROM AUTHOR]

Highlights • The relative expression of miR-BART16 is higher in EBVaGC tissues than cell lines. • Overexpression of miR-BART16 could reduce the LMP1 mRNA and protein levels. • Inhibition the endogenous miR-BART16 increases the LMP1 mRNA and protein level. • BART16 has a vital role on cell proliferation in EBV-associated gastric carcinoma. Abstract Epstein–Barr virus (EBV) is a ubiquitous oncogenic herpesvirus associated with various human tumors. Latent membrane protein (LMP) 1 is considered a key oncoprotein in some EBV-associated tumors, while it is absent in EBV-associated gastric carcinoma (EBVaGC). In the present study, we did not detect the mRNA or the protein expression of LMP1 in 10 EBVaGC tissue samples, but we found that miRNA-BART16 was more abundantly expressed in EBVaGC primary tissues than in cell lines. It has been reported that EBV-encoded miRNA-BART16 can target the 3′-untranslated regions of LMP1 and negatively regulate its expression. When a BART16 inhibitor or mimics were transfected into EBVaGC cell lines, both mRNA and protein levels were changed compared with those in controls. We further investigated the role of miRNA-BART16 in EBVaGC. According to the CCK8 assay, the proliferation of GT38 and GT39 cells increased after treatment with a miRNA-BART16 inhibitor. At the same time, the BART16 inhibitor caused increased accumulation of G2/M phase cells by bromodeoxyuridine and propidium iodide staining analysis. In addition, no obvious difference was observed in apoptosis after treatment with an inhibitor or mimics using annexin V staining. Our findings highlight the viral role of EBV-encoded miRNA-BART16 in regulating oncogenic LMP1 expression and a negative association with the proliferation of EBVaGC. [ABSTRACT FROM AUTHOR]

• EBV latent membrane protein 2A down-regulated AQP3 expression by inhibiting the activation of mTOR signaling pathway, and further inhibited autophagy and migration of gastric cancer cells. • AQP3 up-regulated the expression of 4E-BP1 and promoted its phosphorylation by activating the ERK signaling pathway. The effects of mTOR and ERK signaling on 4E-BP1 suggest that they have crosstalk in regulating 4E-BP1. Aquaporin 3(AQP3) is involved in epithelial-mesenchymal transformation of tumor cells and is closely related to the occurrence and development of tumors. However, the regulatory mechanism and function of AQP3 in EBV-associated gastric cancer (EBVaGC) are still poorly understood. This study aims to explore the regulatory effect of EBV on AQP3 and the cross talk of AQP3 with EIF4E-binding proteins 1(4E-BP1) in EBVaGC. The effect of LMP2A on the expression of AQP3 and 4E-BP1 was analyzed using real-time PCR and western blotting. The biological functions of AQP3 and 4E-BP1 in gastric cancer cells were detected by cell biological experiments. In addition, we examined the role of mTOR and ERK signaling pathways in the LMP2A/AQP3/4E-BP1 regulatory axis. We found that LMP2A could down-regulate AQP3 expression by inhibiting the activation of mTOR signaling pathway, and further promote autophagy and migration of gastric cancer cells. AQP3 up-regulated the expression of 4E-BP1 and its phosphorylated protein by activating ERK signaling pathway, thus promoting the autophagy and proliferation of gastric cancer cells. In conclusion, EBV-encoded LMP2A inhibits AQP3 expression, and further participates in cell proliferation, migration and autophagy through the mTOR/AQP3/ERK/4E-BP1 axis. [ABSTRACT FROM AUTHOR]