MUC6 is normally observed in the mucous neck cells and pyloric glands of the stomach, and Brunner's glands of the duodenum. Pseudopyloric glands, which express MUC6 protein, develop in mucosae affected by gastritis and are regenerative in nature, as in the case of wound healing of the mucosa, replacing glands of the corpus. We have reported that MUC6 and PDX1 expression, which are normally observed in the pyloric glands of the stomach, were found in not only pseudopyloric glands but also gastric carcinomas of the corpus, suggesting that pseudopyloric glands may reflect a condition associated with gastric carcinogenesis. To clarify the development of pseudopyloric glands, we examined the mechanism underlying regulation of MUC6 expression. We isolated the 5′flanking region of the MUC6 gene (5′-MUC6), and determined its transcription start site. There were a TATA box at -35 to -29 bp, a putative NFκB consensus sequence at -173 to -164 bp, and putative Sp family binding sites at -530 to -521 bp and -847 to -838 bp in the 5′-MUC6. The luciferase activity of 5′-MUC6 gradually decreased with deletion of these sites. NFκB inhibitory factor IκB decreased the luciferase activity, and forced expression of NFκB induced MUC6 transcription. An inhibitor of Sp family binding, mithramycin A, suppressed MUC6 transcripts, and Sp1 and Sp3 overexpression up-regulated them. Binding of Sp family members to their putative sites was confirmed by electrophoretic mobility shift assays. Our results suggest that MUC6 transcription is regulated by NFκB and Sp family members. Furthermore, these evidences suggest a pathway from inflammation to NFκB induction, MUC6 expression, and finally the development of pseudopyloric glands and gastric carcinogenesis.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]