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BACKGROUND: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a common malignant tumor associated with EBV infection. Insulin-like growth factor 2 (IGF2) is an imprinted gene and a key protein that regulates growth, especially during normal fetal development. Loss of imprinting (LOI), is a common epigenetic anomaly in a variety of human cancers. However, the promoter methylation, imprinting status and function of IGF2 gene in GC are unclear. OBJECTIVE: To explore the role of IGF2 in the occurrence and development of gastric cancer. METHODS: The biological function of IGF2 in gastric cancer was investigated by Transwell, wound healing, CCK-8 and flow cytometry assays. IGF2 imprinting status and gene promoter methylation in gastric cancer tissues were detected by PCR-RFLP and BGS. RESULTS: The results showed that the expression of IGF2 was higher in GC tissues than adjacent tissues. IGF2 gene promoter methylation and LOI were significantly higher in EBVaGC tissues than in EBV-negative gastric cancer (EBVnGC) tissues. The high expression of IGF2 in gastric cancer can promote the migration and proliferation of gastric cancer cells. CONCLUSION: Our data suggest that IGF2 is involved in the occurrence and development of gastric cancer. Targeting IGF2 may be a potential therapeutic target for gastric cancer. [ABSTRACT FROM AUTHOR]

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]

Gastric cancer (GC) is a malignant tumor that seriously affects human health and Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a molecular subtype of GC. This study aims to determine the relationship between the methylation status of the TMEM130 gene and GC, and to explore the influence of EBV infection. qRT-PCR was conducted to investigate the transcriptional expression of TMEM130 in GC. BSP and MSP assays were used to detect the methylation level of the TMEM130 promoter. The cell migration ability was detected by Transwell and western blot after transfection of TMEM130 plasmids in GC cells. The transcriptional expression of TMEM130 decreased in GC with hypermethylation of the promoter region. The DNA methyltransferase inhibitor could increase the mRNA expression of TMEM130. Moreover, hypermethylation of the TMEM130 promoter in GC tissues was associated with EBV infection. Overexpression of TMEM130 in GC cell lines suppresses cell migration ability. This study was the first to research the expression and function of TMEM130 and found that TMEM130 gene hypermethylation might contribute to GC migration and EBV infection as a cause of hypermethylation of the TMEM130 gene. TMEM130 is a promising biomarker for the diagnosis of GC. [ABSTRACT FROM AUTHOR]

• 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]

• 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]

Epstein-Barr virus (EBV) infection is closely related to gastric carcinoma (GC). In this study, we identified a set of DEGs (different expression genes) between EBVaGC (EBV-associated gastric carcinoma) and EBVnGC (EBV-negative gastric carcinoma) through multiple bioinformatics analysis using the data from GEO (Gene Expression Omnibus) dataset GSE51575, and identified ten hub genes (CXCL10, C3, CXCL9, CXCL11, SST, ICAM1, CHRM2, NPY, GBP5 and GBP1). Therefore, we performed relevant survival analysis and immune infiltration analysis, then verified the mRNA expression in GC cell lines and TCGA database. CXCL11 was finally selected to be a potential biomarker for a better prognosis and tumor infiltrating. This may provide a new view about immune therapy for EBVaGC. [ABSTRACT FROM AUTHOR]

• Epstein-Barr virus regulates the expression pattern of FOXO1, FOXO3 and FOXO4. • PI3K/AKT was activated in EBVaGC. • LMP1 and LMP2A increased the expression of FOXO1and FOXO3 in EBVaGC. Epstein-Barr virus (EBV) infection is associated with the development of gastric cancer (GC). Forkhead box class O (FOXO) transcription factors play important roles in tumor suppression. This study aims to investigate the interplay between EBV and FOXOs in EBV-associated GC (EBVaGC). The results showed that EBV infection of GC cells led to the downregulation of FOXO1 by the inhibition of its mRNA and protein expression. FOXO3 protein is repressed by EBV infection. FOXO4 mRNA is upregulated in EBV-positive cell lines, while its protein expression is downregulated. FOXO1, FOXO3 and FOXO4 proteins are upregulated following PI3K inhibition in GT39 cells, confirming that they are partially suppressed by the PI3K/AKT pathway. However, the upregulation of FOXO1 and FOXO3 by single transfection with LMP1 or LMP2A implies that the dysregulation of FOXOs in EBVaGC is affected by various EBV latent genes and that PI3K/AKT signaling is not the only mechanism of FOXO regulation. [ABSTRACT FROM AUTHOR]