Sa1839 Atonal Homolog 1 (ATOH1) Upregulates Gastric-and Intestinal-Type Protein Expression in Esophageal Squamous Cells, and Increases Proliferation in Barrett's Cells: Potential Roles for ATOH1 in Barrett's Pathogenesis and Carcinogenesis

Abstract

in response to DCA treatment. 14% of the K14-Cdx2 mice treated with DCA developed two nodules each at the SCJ, whereas none of the K14-Cdx2 mice receiving water alone developed nodules. In contrast, 70% of the IL-1β mice, and an equal number of Cdx2/IL1β mice developed nodular disease at the SCJ after DCA treatment. All DCA treatmentassociated nodules were histologically consistent with metaplasia. However overall the double-transgenic mice had half as many nodules as IL-1β mice. Cdx2 did not affect IL-1β mRNA levels in the double transgenic mice, nor was the inflammation associated with IL1β expression reduced in the Cdx2/IL-1β mice compared to IL-1β mice, as determined by CD45R+ cell infiltration in the esophagi and forestomach. Moreover, cell proliferation rates were not altered by Cdx2 expression, as EdU incorporation was not significantly different. Lastly, the morphologic appearance of the nodules in all three lines, K14-Cdx2, L2-IL-1β, and K14-Cdx2/L2-IL-1β mice was similar, with abundant alcian blue expressing goblet cells detected, along with expression of other markers of intestinalization. Further molecular characterization of the metaplastic nodules by cDNA microarray profiling is underway. Conclusion: Ectopic expression of Cdx2 in the IL-1Beta mouse model for BE reduces the nodular intestinal metaplasia disease burden. These studies raise new questions as to the specific role of inflammation and intestinal transcription factors in the development of Barrett's esophagus in humans.