Cdx2 ectopic expression induced gastric intestinal metaplasia in transgenic mice
Cdx2 ectopic expression induced gastric intestinal metaplasia in transgenic mice
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DOI：
10.1053/gast.2002.31902
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发表时间：
2002-03-01
期刊：
影响因子：
29.4
通讯作者：
Kaestner, KH
中科院分区：
文献类型：
--
作者：
Silberg, DG;Sullivan, J;Kaestner, KH
背景与目的：人肠型胃癌常伴肠化生。肠化生中发生转分化的遗传事件尚不清楚。Cdx2是一种通常只表达于肠道的转录因子，在胃肠化生中被检测到。Cdx2诱导肠上皮细胞的体外分化因此，我们试图确定Cdx2激活与肠化生之间是否存在因果关系。方法：利用Foxa3 （Hnf3gamma）顺式调控元件在转基因小鼠胃黏膜中直接表达Cdx2。分析转基因小鼠的组织学和基因表达变化。结果。Foxa3/Cdx2小鼠胃粘膜的组织学检查显示存在阿利新蓝阳性肠型杯状细胞，这是肠化生的标志。此外，Cdx2还能诱导肠道特异性基因的表达。结论：单在胃中表达Cdx2足以诱导小鼠肠化生。这些小鼠是研究促进肠化生的分子机制的有力工具。此外，由于人类胃癌通常发生在肠化生之前，本文描述的表型强烈提示CdX2参与了导致胃粘膜肠瘤变的起始过程。
Background & Aims: Intestinal-type gastric cancer is often preceded by intestinal metaplasia in humans. The genetic events responsible for the transdifferentiation that occurs in intestinal metaplasia are not well understood. Cdx2, a transcription factor whose expression is normally limited to the Intestine, has been detected in gastric intestinal metaplasia. Cdx2 induces differentiation of intestinal epithelial cells in vitro; therefore, we sought to establish whether a causal relationship exists between Cdx2 activation and intestinal metaplasia. Methods: Cdx2 expression was directed to the gastric mucosa In transgenic mice using cis-regulatory elements of Foxa3 (Hnf3gamma). Transgenic mice were analyzed for histologic and gene expression changes. Results. Histologic examination of the gastric mucosa of the Foxa3/Cdx2 mice revealed the presence of alcian blue-positive intestinal-type goblet cells, a hallmark of intestinal metaplasia. In addition, Cdx2 induced the expression of intestine-specific genes. Conclusions: Gastric expression of Cdx2 alone was sufficient to induce intestinal metaplasia in mice. These mice represent a powerful tool to investigate the molecular mechanisms that promote intestinal metaplasia. Moreover, as gastric cancer in humans is often preceded by intestinal metaplasia, the phenotype described here strongly suggests involvement of CdX2 in the initiation of the process leading to intestinal neoplasia of the gastric mucosa.