NMR‐based Tissue Metabolomic Analysis Clarifies Molecular Mechanisms of Gastric Carcinogenesis

NMR‐based Tissue Metabolomic Analysis Clarifies Molecular Mechanisms of Gastric Carcinogenesis:

Abstract

Gastric cancer (GC) is one of the deadliest cancers worldwide, and the progression of gastric carcinogenesis (GCG) covers multiple complicated pathological stages. Molecular mechanisms of GCG are still unclear. Here, we performed NMR‐based metabolomic analysis of aqueous metabolites extracted from gastric tissues in an established rat model of GCG. We showed that the metabolic profiles were clearly distinguished among five histologically classified groups: control (CON), gastritis (GS), low‐grade gastric dysplasia (LGD), high‐grade gastric dysplasia (HGD) and GC. Furthermore, we conducted metabolic pathway analysis based on identified significant metabolites, and revealed significantly disturbed metabolic pathways closely associated with the four pathological stages, including oxidation stress, choline phosphorylation, amino acid metabolism, Kreb's cycle and glycolysis. Three metabolic pathways were continually disturbed during the progression of GCG, including taurine and hypotaurine metabolism, glutamine and glutamate metabolism, alanine, aspartate and glutamate metabolism. Both the Kreb's cycle and glycine, serine and threonine metabolism were profoundly impaired in both the HGD and GC stages, potentially due to abnormal energy supply for tumor cell proliferation and growth. Furthermore, valine, leucine and isoleucine biosynthesis and glycolysis were significantly disturbed in the GC stage for more energy requirement of the rapid growth of tumor cells. Additionally, we identified potential gastric tissue biomarkers for metabolically discriminating the four pathological stages, which also showed good discriminant capabilities for their serum counterparts. This work sheds light on the molecular mechanisms of gastric carcinogenesis, and is of benefit to the exploration of potential biomarkers for clinically diagnosing and monitoring the progression of GCG.