We retrospectively analyzed the 5mC content of 42 patients with intestinal metaplasia (a precancerous lesion of GC) treated with a COX-2 specific inhibitor Rofecoxib or placebo for 2 years, revealing that the COX-2 inhibitor significantly down-regulated 5mC levels (N=42, P=0.009).
Using a monoclonal antibody (PAb1801), nuclear p53 was detected in 22 of 45 (49%) cases of gastric carcinoma, and no staining for p53 was demonstrated in the adjacent normal epithelium, including areas of intestinal metaplasia.
In patients with chronic gastritis, antral mucosa with high p53AIP1 expression tended to have severe intestinal metaplasia.No mutation was found at p53 codon-46.
Methylation of the Cdx2 promoter was not observed in intestinal metaplasia, while hypermethylation of part of its promoter was observed in hot dipped and IMC.
Conversely, ectopic CDX2 expression in the stomach of transgenic mice promotes intestinal metaplasia, and CDX2 expression often is seen in intestinal metaplasia in stomach and esophagus.
These data indicate that MUC2 mucin is expressed in gastric regenerative epithelium in addition to intestinal metaplasia and intestinal type adenocarcinoma.
Molecular alterations involving microsatellites D5S82 and the CA repeat inside the retinoblastoma gene were more frequent in nonintestinal metaplasia whereas those involving the p53 locus took place in columnar intestinal metaplasia and in low-grade dysplasia.
Concerning about the origin of p63/p40 and CDX2, it was suggested that the tumor cells were not derived from ectopic squamous epithelium but from intestinal metaplasia.
Barrett's metaplasia was also associated with a specific MUC gene expression pattern, since the gastric apomucin mRNAs, MUC5AC and MUC6, were expressed in gastric metaplasia, and the intestinal apomucin mRNAs, MUC3, MUC4 and mostly MUC2, in intestinal metaplasia.
The following on molecular mechanisms of Barrett's esophagus and adenocarcinoma contains commentaries on the mechanism of bile and gastric acid induced damage; the roles of BMP-4 and CDX-2 in the development of intestinal metaplasia; the transcription factors driving intestinalization in Barrett's esophagus; the contribution of bone marrow to metaplasia and adenocarcinoma; activation and inactivation of transcription factors; and a novel study design targeting molecular pathways in Barrett's esophagus.
In gastric tumors, and in early preneoplastic lesions such as intestinal metaplasia, the glycosylation pattern detected in normal stomach is lost and, intestinal mucins, MUC2 and MUC4, can be ectopically detected in the gastric epithelium.
In conclusion, these functionally interacting events drive CDX1 expression and contribute to intestinal metaplasia, epithelial dedifferentiation, and carcinogenesis in the human stomach.
CDX2 is a crucial factor in the development of pre-cancerous lesions such as Barrett's esophagus or intestinal metaplasia in the stomach, and its tumor suppressive role has been investigated in colorectal cancers.
Previous studies indicated that SOX2, the key transcription factor in gastric differentiation, was downregulated during IM development while CDX2, the pivotal intestine-specific transcription factor was upregulated significantly.
We have studied the effect of H. pylori infection on apoptosis of the antral epithelium in the presence/absence of intestinal metaplasia and the expression of the p53 oncoprotein.
Histologically, 52 of the 130 enrolled patients showed intestinal metaplasia type I (IM) (90.4% of these were also HP positive), 47 had HP-related gastritis and 31 were normal. p53 cytosol levels were significantly higher in patients with IM or HP-related gastritis than in normal patients (p = 0.0137 and p = 0.0411, respectively).
The COX-2 1195 G-carrier genotype was also significantly (p = 0.038) associated with the score of endoscopic intestinal metaplasia based on Kyoto classification.
These patterns of expression have shown that CDX2 is important for the initiation of intestinal metaplasia in the gastric mucosa, but the role of CDX2 in established gastric cancer remains unclear.