Loss of Runx3 Is a Key Event in Inducing Precancerous State of the Stomach

BACKGROUND & AIMS: RUNX3 is a tumor suppressor originally identified in gastric cancer. The mutation R122C in RUNX3 promotes gastric carcinogenesis by unclear mechanisms. We investigated how Runx3-deficiency contributes to distinct changes in the gastric epithelium that precede neoplasia. METHODS: Runx3-deficient (Runx3(-/-)) and wild-type BALB/c adult mice were subjected to histological analyses. Gastric cancer formation after administration of N-methyl-N-nitrosourea was evaluated. Runx3(-/-) and Runx3(-/-) gastric epithelial cell lines were used to investigate the molecular basis underlying Runx3 function. RESULTS: The gastric epithelia in Runx3(-/-) adult mice was hyperplastic, with loss of chief cells and development of mucin 6- and trefoil factor-2-expressing metaplasia. The gastric epithelium of Runx3(-/-) mice had an intestinal phenotype that expressed Cdx2. After addition of N-methyl-N-nitrosourea, Runx3- mice, unlike wild-type mice, consistently developed adenocarcinomas, indicating that Runx3-deficiency leads to premalignant changes in the gastric epithelia. RUNX3, but not the RUNX3 mutant R122C, repressed Cdx2 expression by attenuation of oncogenic beta(symbol)- catenin and Tcfs. CONCLUSIONS: Runx3deficiency leads to a precancerous state in the gastric epithelia of mice, characterized by loss of chief cells but not parietal cells; inflammation did not appear to be involved.