Transcriptional regulation of transcription factor Cdx2 in intestinal mucosa

在慢性胃炎的发展过程中，胃粘膜细胞偏离胃分化的正常途径，向肠表型分化。许多流行病学研究发现肠上皮化生的形成与胃癌的发生有关。然而，迄今为止，还没有直接证据表明肠上皮化生是胃癌的前驱病变。我们定期检查我们以前产生的Cdx2转基因小鼠的肠粘膜化生。胃息肉的肠化生粘膜在所有的Cdx2转基因小鼠的胃检查。这些胃息肉包括浸润粘膜下层和固有肌层的膀胱型腺癌，偶尔扩散到浆膜下。p53和APC基因突变在腺癌中被识别。APC和p53基因突变参与肠上皮化生的胃癌发生，通过Cdx2转基因小鼠，携带ApcMin突变或p53缺陷，比单独Cdx2更早地发生胃息肉来验证。我们成功地证明了长期肠上皮化生诱导浸润性胃癌。提示肠上皮化生本身在胃癌的发生、发展中起重要作用。

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.