title: Loss of Runx3 is a key event in inducing precancerous state of the stomach.
abstract: OBJECTIVE
  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
  Runx3-deficiency 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.
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Ito
authors.forename: Linda Shyue Huey
authors.initials: LS
authors.lastname: Chuang
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ito
authors.forename: Ti Ling
authors.initials: TL
authors.lastname: Chang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukamachi
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009374:Neoplasms, Experimental; D011230:Precancerous Conditions; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D004273:DNA, Neoplasm; C493730:Runx3 protein, mouse