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: 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.
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: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: Victoria G Weis; Josane F Sousa; Bonnie J LaFleur; Ki Taek Nam; Jared A Weis; Paul E Finke; Nadia A Ameen; James G Fox; James R Goldenring Journal: Gut Date: 2012-07-07 Impact factor: 23.059
Authors: Rita Nahta; Fahd Al-Mulla; Rabeah Al-Temaimi; Amedeo Amedei; Rafaela Andrade-Vieira; Sarah N Bay; Dustin G Brown; Gloria M Calaf; Robert C Castellino; Karine A Cohen-Solal; Annamaria Colacci; Nichola Cruickshanks; Paul Dent; Riccardo Di Fiore; Stefano Forte; Gary S Goldberg; Roslida A Hamid; Harini Krishnan; Dale W Laird; Ahmed Lasfar; Paola A Marignani; Lorenzo Memeo; Chiara Mondello; Christian C Naus; Richard Ponce-Cusi; Jayadev Raju; Debasish Roy; Rabindra Roy; Elizabeth P Ryan; Hosni K Salem; A Ivana Scovassi; Neetu Singh; Monica Vaccari; Renza Vento; Jan Vondráček; Mark Wade; Jordan Woodrick; William H Bisson Journal: Carcinogenesis Date: 2015-06 Impact factor: 4.944
Authors: Victoria G Weis; Christine P Petersen; Jason C Mills; Pamela L Tuma; Robert H Whitehead; James R Goldenring Journal: Am J Physiol Gastrointest Liver Physiol Date: 2014-09-04 Impact factor: 4.052