Comprehensive Multi-Omics Analysis Reveals Aberrant Metabolism of Epstein–Barr-Virus-Associated Gastric Carcinoma

Abstract

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.

The Better Survival of MSI Subtype Is Associated With the Oxidative Stress Related Pathways in Gastric Cancer

“…Meanwhile, some fatty acid biosynthesis related enzymes FASN and PLA2G4A decreased in EBVaGC and could lead to the worse survival. Similarly, EBV infection could make the metabolic reprogramming and it is the foundation of the poor clinical prognosis in GC patients (41). On the other hand, the discrepancy of tumor microenvironment was another controversial topic and may interpret the molecular mechanism.…”

Targeting the signaling in Epstein–Barr virus-associated diseases: mechanism, regulation, and clinical study

“…These findings may help explain the mechanism of EBVaGC tumorigenesis. 109 Furthermore, we know that in primary nasopharyngeal carcinoma, EBV-LMP1 induces lipid synthesis and lipid droplet formation. Lo et al 110 reported a novel function of LMP1 in promoting nascent lipogenesis.…”

Isolation and Metabolic Assessment of Cancer Cell Mitochondria

“…This platform showed comparable or better performance compared to an established in vitro gas chromatography–mass spectrometry (GC-MS) untargeted metabolomic analysis described in our previous study. 28 The chromatographic separation was achieved using an Amide XBridge HPLC (100 mm × 4.6 mm; 3.5 μm) plus a guard column (Waters, Milford, MA). The column temperature was held at 30 °C during the analysis.…”

“…Raw lipidomics data files (.d format) were converted to.abf format files by AbfConverter 4.0.0 (Reifycs), imported into MS-DIAL version 3.7.0, and processed as previously described. 28 Detailed parameters can be found in Table S3 .…”