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Our aim was to investigate the molecular mechanisms responsible for the regulation of aberrant MUC2 mucin gene transcription and expression in intestinal metaplasia and gastric carcinoma. We showed that the CDX2 intestinal homeobox gene is directly involved in transcriptional regulation of the MUC2 gene in gastric cells and that site-specific hypomethylation in two AP-2 binding sites is related to MUC2 mucin expression in gastric carcinomas. The involvement of the intestine-specific homeobox proteins CDX1 and CDX2 in intestine development, and their role in transcription of several intestinal genes, strongly support their role in aberrant intestinal differentiation of intestinal metaplasia and gastric carcinoma. In fact, our group has shown that CDX1 and CDX2 are aberrantly expressed in intestinal metaplasia and in a subset of gastric carcinomas, and their expression is closely associated with the expression of MUC2. In the present study, we demonstrate that CDX2 is directly involved in the transcriptional regulation of the MUC2 gene in gastric (and intestinal) carcinoma cells. In gastric cells, CDX2 binds to two cognate ciselements in the MUC2 proximal promoter and regulates the activity of the promoter of MUC2 in a cell-specific manner. It has been demonstrated that regulation of mucin genes of the 11p15.5 cluster, including MUC2, is controlled by promoter methylation. In order to assess if the observed de novo expression of the intestinal mucin MUC2 in intestinal metaplasia and gastric cancer is associated with changes in MUC2 promoter methylation, we analyzed the methylation levels of nine CpG sites immediately upstream of the transcription start site using human samples of normal gastric mucosa and mucinous gastric carcinoma. We have shown that de novo MUC2 expression in mucinous gastric carcinoma correlates with site-specific hypomethylation of MUC2 promoter, at two specific CpG sites, included in two putative binding sites for activating protein-2 (AP-2). This observation and the fact that binding of this transcription factor is known to be affected by methylation prompted us to establish the role of methylation of these AP-2 binding sites in the regulation of MUC2 gene expression in gastric cells. We have shown that AP-2 transcription factor binds to these two cis-elements on MUC2 proximal promoter and that its binding to one of the sites is prevented by CpG methylation.

Regulation of MUC2 Mucin Gene Expression in Gastric Carcinoma And Gastric Carcinoma Cell Lines: Role of Methylation and Putative Transcription Factors