Generation of intestinal metaplasia by ectopic expression of Cdx1 and Cdx2

为了阐明胃和食管粘膜转分化为被认为是癌前状态的肠化生的机制，我们在壁细胞中建立了表达Cdx-1或Cdx-2同源盒基因的小鼠模型。在表达cdx的小鼠中，胃底黏膜逐渐转化为肠黏膜，具有吸收型、杯状、肠内分泌和Paneth细胞系。相比之下，Cdx-2在胃黏膜表达引起的肠化生表现为吸收细胞、杯状细胞和肠内分泌细胞，但缺乏Paneth细胞谱系。这两种小鼠模型的肠化生在粘膜结构上有所不同。Cdx-1转基因小鼠肠窝到绒毛的规则有序结构丧失，Paneth细胞分散在绒毛顶端。在Cdx-2小鼠中，在腺体底部发现类似于不完全肠化生的假幽门腺样部分。在两种小鼠模型中，粘膜增殖加速导致增生，后期出现息肉样形成。我们目前正在分析Cdx-1和Cdx-2异位表达引起的基因表达改变。在人类胃和食管粘膜中，我们已经证实Cdx-2的表达先于肠化生的表型改变，暗示其作为触发因素的作用。

In an attempt to elucidate the mechanism of transdifferentiation of gastric and esophageal mucosa to intestinal metaplasia that is considered to be a precancerous state, we have generated mice models expressing either Cdx-1 or Cdx-2 homeobox gene in the parietal cells. In the Cdx-lexpressing mice, gastric fundic mucosa was gradually converted to intestinal mucosa with absorptive, goblet, entero-endocrine and Paneth cell lineage. By contrast, intestinal metaplasia developed by Cdx-2 expression in the gastric mucosa exhibit absorptive, goblet and entero-endocrine cells but lacked Paneth cell lineage. The intestinal metaplasia of these two mice models differs in terms of mucosal architecture. The regular and orderly architecture of intestinal pit to villus was lost and Paneth cells were dispersed in the tip portion of the villi in the Cdx-1 transgenic mice. In Cdx-2 mice, the psuedopyloric gland like portion was found in the base of the gland similar to the incomplete intestinal metaplasia. In both mice models, mucosal proliferation was accelerated resulting in hyperplasia and polyp-like formation was noted at the later stage. We are currently analyzing the alteration of the gene expression induced by the ectopic expression of Cdx-1 and Cdx-2. In human gastric and esophageal mucosa, we have confirmed that Cdx-2 expression precedes the phenotypic change to intestinal metaplasia, implicating its role as a trigger.