To clarify the mechanism of the decrease of Shh in intestinal metaplastic mucosa

Shh（Sonic Hedgehog）是一种参与成人胃底腺分化的形态因子。在幽门螺杆菌相关的胃上皮肠化生变中，Shh表达减少，缺乏Shh的小鼠表现出胃粘膜的肠转化。同样，在Cdx2（尾型同源盒2）转基因小鼠的胃中，胃粘膜被肠化生粘膜所取代。本研究的目的是利用cdx2转基因小鼠研究：(i) Shh在cdx2转基因小鼠胃肠化生黏膜中的表达；（ii） Shh与Cdx2的关系。我们发现，与正常（野生型）小鼠胃相比，cdx2转基因小鼠胃肠化生粘膜中的Shh mRNA水平显著降低。这不是由于Shh启动子的超甲基化，而是我们发现Cdx2直接结合到Shh启动子的TATA盒区。Cdx2还能下调人胃癌细胞系AGS、MKN45和MKN74中Shh基因的转录。综上所述，Cdx2通过结合Cdx2转基因小鼠胃肠化生黏膜中未甲基化的Shh启动子来降低Shh的表达。

Shh(Sonic Hedgehog) is a morphogen involved in gastric fundic gland differentiation in the adult. Shh expression is reduced in Helicobacter pylori-associated intestinal metaplastic change of the gastric epithelium and mice that lack Shh show intestinal transformation of the gastric mucosa. Similarly, in the stomach of Cdx2(caudal-type homeobox 2)-transgenic mice, the gastric mucosa is replaced by intestinal metaplastic mucosa. The aim of the present study was to use Cdx2-transgenic mice to investigate :(i) Shh expression in the intestinal metaplastic mucosa of the Cdx2-transgenic mouse stomach ; and(ii) the relationship between Shh and Cdx2.We determined that Shh mRNA levels were dramatically reduced in the intestinal metaplastic mucosa of the Cdx2-transgenic mouse stomach compared with the normal(wild-type) mouse stomach. This was not due to hypermethylation of the Shh promoter, but instead we showed that Cdx2 directly bound to the TATA box region of the Shh promoter. Cdx2 also down-regulated transcription of the Shh gene in the human gastric carcinoma cell lines AGS, MKN45 and MKN74.In conclusion, Cdx2 reduced Shh expression by binding to the unmethylated Shh promoter in the intestinal metaplastic mucosa of Cdx2-transgenic mouse stomach.