Abstract
Gastric cancer (GC) is one of the most malignant tumors with a poor prognosis. Alterations in metabolic pathways are inextricably linked to GC progression. However, the underlying molecular mechanisms remain elusive. We performed NMR-based metabolomic analysis of sera derived from a rat model of gastric carcinogenesis, revealed significantly altered metabolic pathways correlated with the progression of gastric carcinogenesis. Rats were histologically classified into four pathological groups (gastritis, GS; low-grade gastric dysplasia, LGD; high-grade gastric dysplasia, HGD; GC) and the normal control group (CON). The metabolic profiles of the five groups were clearly distinguished from each other. Furthermore, significant inter-metabolite correlations were extracted and used to reconstruct perturbed metabolic networks associated with the four pathological stages compared with the normal stage. Then, significantly altered metabolic pathways were identified by pathway analysis. Our results showed that oxidative stress-related metabolic pathways, choline phosphorylation and fatty acid degradation were continually disturbed during gastric carcinogenesis. Moreover, amino acid metabolism was perturbed dramatically in gastric dysplasia and GC. The GC stage showed more changed metabolite levels and more altered metabolic pathways. Two activated pathways (glycolysis; glycine, serine and threonine metabolism) substantially contributed to the metabolic alterations in GC. These results lay the basis for addressing the molecular mechanisms underlying gastric carcinogenesis and extend our understanding of GC progression.
Highlights
Gastric cancer (GC), one of the most prevalent and deadly forms of cancers worldwide, is common in East Asia, especially in Japan and China [1]
We performed NMR-based metabolomic analysis of sera derived from a rat model of gastric carcinogenesis, revealed significantly altered metabolic pathways correlated with the progression of gastric carcinogenesis
For few works have been reported to clarify the globe metabolic alterations associated with GC progression, and reveal the underlying molecular mechanisms
Summary
Gastric cancer (GC), one of the most prevalent and deadly forms of cancers worldwide, is common in East Asia, especially in Japan and China [1]. Ikeda et al performed metabolic profiling on sera derived from GC patients with gas chromatography-mass spectrometry (GC-MS), and found that both 3-hydropropionic acid and pyruvate made significant contributions to discriminate the metabolic profile of GC patients from that of healthy subjects [6]. These works showed that the levels of some metabolites were changed in both gastric tumors and infected organisms. Yu et al analyzed metabolic alterations in the GC and precancerous stages (chronic superficial gastritis, chronic atrophic gastritis, intestinal metaplasia and gastric dysplasia) with GC-MS [7]. They found that the metabolic phenotype of chronic superficial gastritis was distinctly distinguished from that of GC, while intestinal metaplasia shared similar metabolic phenotype with GC
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