Transcriptional regulation of transcription factor Cdx2 in intestinal mucosa

在慢性胃炎的发展过程中，胃粘膜细胞偏离正常的胃分化途径，向肠表型转变。许多流行病学研究发现肠化生的形成与胃癌的发展之间存在关联。然而，目前尚无直接证据表明肠化生是胃癌的前兆病变。我们定期检查我们之前产生的cdx2转基因小鼠的肠化生黏膜。在cdx2转基因小鼠的所有胃中，胃息肉都是由肠化生粘膜形成的。这些胃息肉由肠型腺癌组成，侵入粘膜下层和固有肌层，偶尔扩散到浆膜下。在腺癌中发现p53和APC基因突变。通过携带ApcMin突变或p53缺失的Cdx2转基因小鼠，证实APC和p53基因突变参与肠化生的胃癌发生，其发生胃息肉的时间远早于单独Cdx2。我们成功地证明了长期肠化生诱导浸润性胃癌。这些结果表明，肠化生本身在胃癌的发生和发展中起着重要的作用。

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.