Abstract
435 Background: Patients with gastroesophageal reflux disease (GERD) with mixed gastric acid–bile acid reflux are at a high risk of developing reflux-induced esophageal cancer. Increased local production of prostaglandin E2 (PGE2) is etiologically associated with reflux-induced esophageal cancer pathogenesis; however, the underlying mechanism remains unclear. Our aim was to investigate the relationship between PGE2 production in esophageal cells and reflux fluids, particularly gastric acid. The effect of the Kampo medicine Hangeshashinto (HST), which reduced the incidence of reflux-induced esophageal cancer in rats (Surgery 2018), on PGE2 production was also examined. Methods: Esophageal squamous cell carcinoma were treated for 2 h with acidic culture condition (pH 3.5 – 6.5) and chenodeoxycholic acid (CDCA; 200, 400 μmol/L), followed by measurement of PGE2 production in the culture medium for the additional 6 h by enzyme-linked immunosorbent assay. Results: CDCA induced PGE2 production and significantly increased cyclooxygenase-2 (cox-2) expression. However, in weak acidic conditions (pH 4–5), a pH-specific and significant increase in PGE2 production with no increase in cox-2 expression was observed. cPLA2 inhibitor decreased the effect of weak acid stimulation, indicating that the mechanism underlying PGE2 production differs between weak acid and CDCA. In addition, HST significantly inhibited both weak acid- and CDCA-induced PGE2 production. Conclusions: The synergistic effect of bile acid-induced cox-2 expression and weak acid-induced arachidonic acid production via cPLA2 can cause excessive PGE2 production. Therefore, mixed reflux showing pH 4–5 could contribute to the high incidence of esophageal cancer, which might be prevented by HST treatment. Weak acid reflux around pH 4–5 has been observed in PPI-treated patients, who could exhibit excessive PGE2 production as well as increased risk of reflux-induced esophageal cancer.
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