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Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a unique type of gastric carcinomas that promoter hypermethylation of tumor-related genes is extremely frequent to be found. Aquaporin 3 (AQP3) is a small membrane transport protein that plays a crucial role in cancer progression and metastasis. However, there is no experimental study on the expression of AQP3 in EBVaGC and the regulation mechanism of EBV on AQP3. In this study, the loss of AQP3 was contributed by the hypermethylation status of AQP3 promoter in EBVaGC which was caused by elevated expression of DNMT3a. In addition, stable and transient transfection system in SGC7901 showed that viral latent membrane protein 2A (LMP2A) activated phosphorylated ERK and up-regulated DNMT3a. Taken together, LMP2A induced the phosphorylation of ERK, which activated DNMT3a transcription and caused AQP3 expression loss through CpG island methylation of AQP3 promoter in EBVaGC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background/aims: Aquaporins are widely expressed in a variety of cancers and were found to play an important role in cell migration, angiogenesis, tumor formation, and tumor development. Thus, they have been proposed as a potential biomarker for some cancers. Accordingly, we analyzed the association between a single-nucleotide polymorphism locus of aquaporin 3 (rs2231231) and Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (EBVaNPC), lymphoma (EBVaL), and gastric carcinoma in China., Methods: Sequenom MassARRAY technique and polymerase chain reaction sequencing were used to test the genotype of 393 cases of patients with cancer and 148 normal control (NC) samples. A χ2 test or correction for continuity or the likelihood ratio was used for statistical analysis, and two-sided p values < 0.05 were considered a statistically significant difference., Results: We found that the genotype distributions were significantly different between either the EBVaNPC group and the NC group or the EBVaL case group and the NC group. However, no statistical associations between rs2231231 and gastric carcinoma was observed in the current study., Conclusions: The AQP3 gene polymorphism is associated with a susceptibility to EBVaNPC and EBVaL, and the homozygous AA genotype is more frequently observed in individuals who develop EBVaNPC and EBVaL., (© 2018 S. Karger AG, Basel.)

• 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]