Fig. 6

Gastrin suppressed GC growth in vivo and in vitro through AE2 up-regulation. a Gastrin induced inhibition of tumor cell proliferation. SGC7901 xenograft-bearing nude mice were treated with 0.9 % NaCl or gastrin. Tumor growth rates were determined by calculating the percentage of change in tumor volume (T) compared with initial tumor volume (T0). *p < 0.05, compared with control group (n = 10). b Gastrin increased AE2 abundance in tumor extracts. The ratio of AE2 protein abundance to that of β-actin was normalized to a value of 1.0 for the 0.9 % NaCl group. *p < 0.05, compared with 0.9 % NaCl group (n = 10). A representative immunoblot is presented below. c Gastrin induced up-regulation of AE2 protein expression and down-regulation of cyclin D1 protein expression. The ratio of AE2 and cyclin D1 protein abundance to that of β-actin was normalized to a value of 1.0 for the SGC7901 group (n = 3), *p < 0.05, compared with the SGC7901 group. d Cellular acidification occurred in SGC7901 cells after incubation with 10⁻⁷ M gastrin for 24 h. Data are representative of experiments performed three times in triplicate, *p < 0.05, compared with untreated SGC7901 cells. e Model for gastrin-induced inhibition of GC through up-regulation of AE2 levels, which were decreased by AE1/p16. In GC cells, intracellular retention of AE1 and cytoplasmic sequestration of p16 lead to increased AE2 ubiquitin-dependent degradation, as well as reduced total and plasmalemmal abundance of AE2. The resulting reduction in AE2-mediated anion exchange activity may result in cellular alkalinization, leading to increased cyclin D1 expression. Gastrin up-regulates AE2 expression by blocking formation of the AE1/p16 complex. Enhanced AE2-mediated Cl⁻/HCO₃ ⁻ exchange activity acidifies GC cells that in turn retards cell growth