Transcriptional regulation of transcription factor Cdx2 in intestinal mucosa

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In the progression of chronic gastritis, gastric mucosal cells deviate from the normal pathway of gastric differentiation to an intestinal phenotype. Many epidemiological studies have found an association between the formation of intestinal metaplasia and the development of gastric carcinoma. However, there is no direct evidence which shows intestinal metaplasia is a precursor lesion of gastric carcinoma to date. We periodically examined the intestinal metaplastic mucosa of Cdx2-transgenic mice we have previously generated. Gastric polyps developed from intestinal metaplastic mucosa in all stomachs of Cdx2-transgenic mice examined. These gastric polyps consisted of intestinal-type adenocarcinoma that invaded the submucosa and muscularis propria, and occasionally spread into the subserosa. p53 and APC gene mutations were recognized in the adenocarcinomas. The participation of APC and p53 gene mutations in gastric carcinogenesis from the intestinal metaplasia was verified by the Cdx2-transgenic mice, carrying ApcMin mutation or p53 deficiency, that developed gastric polyps much earlier than Cdx2 alone. We successfully demonstrated that long-term intestinal metaplasia induces invasive gastric carcinoma. These results indicate that intestinal metaplasia itself plays a significant role in the genesis and progression of gastric carcinoma.