Direct repression of Sonic Hedgehog expression in the stomach by Cdx2 leads to intestinal transformation

摘要

pShh (Sonic Hedgehog) is a morphogen involved in gastric fundic gland differentiation in the adult. Shh expression is reduced in iHelicobacter pylori/i-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) iShh/i expression in the intestinal metaplastic mucosa of the Cdx2-transgenic mouse stomach; and (ii) the relationship between Shh and Cdx2. We determined that iShh/i 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 iShh/i promoter, but instead we showed that Cdx2 directly bound to the TATA box region of the iShh/i promoter. Cdx2 also down-regulated transcription of the iShh/i gene in the human gastric carcinoma cell lines AGS, MKN45 and MKN74. In conclusion, Cdx2 reduced iShh/i expression by binding to the unmethylated iShh/i promoter in the intestinal metaplastic mucosa of Cdx2-transgenic mouse stomach./p