Math1/Atoh1 Contributes to Intestinalization of Esophageal Keratinocytes by Inducing the Expression of Muc2 and Keratin-20

Abstract

Esophageal intestinal metaplasia, also known as Barrett's esophagus, is the replacement of the normal epithelium with one that resembles the intestine morphologically. Generally, this includes intestinal mucin-secreting goblet cells. Barrett's esophagus is an important risk factor for adenocarcinoma development. In-vitro models for Barrett's esophagus have not, to date, focused on the induction of goblet cells in Barrett's epithelium. To explore the contribution of Math1/Atoh1 to induction of Barrett's esophagus and intestinal mucin-secreting goblet cells from normal human esophageal epithelium. We explored the level and pattern of Math1/Atoh1 mRNA and protein expression in human Barrett's esophagus. Then, using retroviral-mediated gene expression, we induced Math1 mRNA and protein expression in a human esophageal keratinocyte cell line. We evaluated the effects of this ectopic Math1 expression on cell proliferation and gene expression patterns in cells cultured under two-dimensional and three-dimensional tissue-engineering conditions. Math1/Atoh1 mRNA and protein are detected in human Barrett's esophagus specimens, but the mRNA levels vary substantially. In the keratinocyte expression studies, we observed that Math1/Atoh1 ectopic expression significantly reduced cell proliferation and altered cell morphology. Moreover, Math1/Atoh1 expression is associated with a more intestinalized gene expression pattern that is distinct from that reported in after studies using other intestinal transcription factors. Most significantly, we observe the induction of the Barrett's esophagus markers Mucin-2 and Keratin-20 with Math1/Atoh1 expression. We conclude that ectopic Math1/Atoh1 expression makes unique contributions to intestinalization of the esophageal epithelium in Barrett's esophagus.