Abnormal arginine synthesis confers worse prognosis in patients with middle third gastric cancer

Abstract

Background: Gastric cancer at different locations has distinct prognoses and biological behaviors, but the specific mechanism is unclear. Methods: Non-targeted metabolomics was performed to examine the differential metabolite phenotypes that may be associated with the effects of tumor location on the prognosis of gastric cancer. And silencing of the rate-limiting enzyme to evaluate the effect of abnormal changes in metabolic pathway on the functional biological assaysof gastric cancer cells HGC-27 and MKN28. Results: In a retrospective study of 94 gastric cancer patients, the average survival time of patients with gastric cancer in the middle third of the stomach was significantly lower than that of patients with gastric cancer in other locations (p< 0.05). The middle third location was also found to be an independent risk factor for poor prognosis (HR = 2.723, 95%CI 1.334-5.520), which was closely associated with larger tumors in this location. Non-targeted metabolomic analysis showed that the differential metabolites affected 16 signaling pathways including arginine synthesis, retrograde endocannabinoid signaling, arginine biosynthesis, and alanine and aspartate and glutamate metabolism between gastric cancer and normal tissue, as well as between tumors located in the middle third of the stomach and other locations. Argininosuccinate synthase 1 (ASS1), the rate-limiting enzyme of the arginine biosynthesis pathway, catalyzes the production of argininosuccinic acid. Here, knockdown of ASS1 significantly inhibited the proliferation, colony formation, and migration/invasion of gastric cancer cells, and promoted apoptosis. Conclusions: Our study suggests that abnormal arginine synthesis may lead to larger tumor size and worse prognosis in gastric cancer located in the middle third position of the stomach. These findings may provide the basis for the stratification and targeted treatment of gastric cancer in different locations.