The metabolic landscape of Epstein–Barr-virus-associated gastric cancer (EBVaGC) remains to be elucidated. In this study, we used transcriptomics, metabolomics, and lipidomics to comprehensively investigate aberrant metabolism in EBVaGC. Specifically, we conducted gene expression analyses using microarray-based data from gastric adenocarcinoma epithelial cell lines and tissue samples from patients with clinically advanced gastric carcinoma. We also conducted complementary metabolomics and lipidomics using various mass spectrometry platforms. We found a significant downregulation of genes related to metabolic pathways, especially the metabolism of amino acids, lipids, and carbohydrates. The effect of dysregulated metabolic genes was confirmed in a survival analysis of 3951 gastric cancer patients. We found 57 upregulated metabolites and 31 metabolites that were downregulated in EBVaGC compared with EBV-negative gastric cancer. Sixty-nine lipids, mainly ether-linked phospholipids and triacylglycerols, were downregulated, whereas 45 lipids, mainly phospholipids, were upregulated. In total, 15 metabolisms related to polar metabolites and 15 lipid-associated pathways were involved in alteration of metabolites by EBV in gastric cancer. In this work, we have described the metabolic landscape of EBVaGC at the multi-omics level. These findings could help elucidate the mechanism of EBVaGC oncogenesis.

Integrating sex as an important biological variable is imperative to enhance the accuracy and reproducibility of cell-based studies, which provide basic information for subsequent preclinical and clinical study designs. Recently, international funding agencies and renowned journals have been attempting to integrate sex as a variable in every research step. To understand what progress has been made in reporting of cell sex in the articles published in AJP-Cell Physiology since the analysis in 2013, we examined the sex notation of the cells in relevant articles published in the same journal in 2018. Of the 107 articles reporting cell experiments, 53 reported the sex of the cells, 18 used both male and female cells, 23 used male cells only, and 12 used female cells only. Sex omission was more frequent when cell lines were used than when primary cells were used. In the articles describing experiments performed using rodent primary cells, more than half of the studies used only male cells. Our results showed an overall improvement in sex reporting for cells in AJP-Cell Physiology articles from 2013 (25%) to 2018 (50%). However, sex omission and male bias were often found still. Furthermore, the obtained results were rarely analyzed by sex even when both male and female cells were used in the experiments. To boost sex considerate research implementation in basic biomedical studies, cooperative efforts of the research community, funders, and publishers are urged.

Although Epstein-Barr virus (EBV) is known to encode over 40 different miRNAs of its own, the roles of most EBV miRNAs remain unknown. Disabled homolog 2 (DAB2) is a putative tumor suppressor, but its role in gastric carcinoma (GC), especially in EBV-associated GC, needs to be clarified. Our qRT-PCR and mRNA microarray results showed that DAB2 expression was down-regulated in EBV-positive GC cells compared to EBV-negative cells. Four BART miRNAs that might target DAB2 were predicted, and we found, using a luciferase reporter assay, that miR-BART1-3p directly targeted the 3'-UTR of DAB2. The miR-BART1-3p transfection decreased DAB2 expression at both mRNA and protein levels, while transfection of an inhibitor of miR-BART1-3p, miR-BART1-3p(i), increased DAB2 expression. In addition, miR-BART1-3p as well as siDAB2 increased migration and decreased apoptosis. Meanwhile, miR-BART1-3p(i) or pcDNA3.1-DAB2 transfection decreased migration and increased apoptosis in EBV-infected GC cells. Furthermore, decreased migration by miR-BART1-3p(i) was abrogated by co-transfected siDAB2, while decreased migration by miR-BART1-3p(i) was further suppressed by a co-transfected DAB2 over-expression vector. Our data suggest that miR-BART1-3p plays an important role in the tumorigenesis of EBV-associated GC by directly targeting DAB2.