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Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett's metaplasia

Abstract

Metaplasia can result when injury reactivates latent developmental signaling pathways that determine cell phenotype. Barrett's esophagus is a squamous-to-columnar epithelial metaplasia caused by reflux esophagitis. Hedgehog (Hh) signaling is active in columnar-lined, embryonic esophagus and inactive in squamous-lined, adult esophagus. We showed previously that Hh signaling is reactivated in Barrett's metaplasia and overexpression of Sonic hedgehog (SHH) in mouse esophageal squamous epithelium leads to a columnar phenotype. Here, our objective was to identify Hh target genes involved in Barrett's pathogenesis. By microarray analysis, we found that the transcription factor Foxa2 is more highly expressed in murine embryonic esophagus compared with postnatal esophagus. Conditional activation of Shh in mouse esophageal epithelium induced FOXA2, while FOXA2 expression was reduced in Shh knockout embryos, establishing Foxa2 as an esophageal Hh target gene. Evaluation of patient samples revealed FOXA2 expression in Barrett's metaplasia, dysplasia, and adenocarcinoma but not in esophageal squamous epithelium or squamous cell carcinoma. In esophageal squamous cell lines, Hh signaling upregulated FOXA2, which induced expression of MUC2, an intestinal mucin found in Barrett's esophagus, and the MUC2-processing protein AGR2. Together, these data indicate that Hh signaling induces expression of genes that determine an intestinal phenotype in esophageal squamous epithelial cells and may contribute to the development of Barrett's metaplasia.

Type Journal
ISBN 1558-8238 (Electronic) 0021-9738 (Linking)
Authors Wang, D. H.; Tiwari, A.; Kim, M. E.; Clemons, N. J.; Regmi, N. L.; Hodges, W. A.; Berman, D. M.; Montgomery, E. A.; Watkins, D. N.; Zhang, X.; Zhang, Q.; Jie, C.; Spechler, S. J.; Souza, R. F.;
Garvan Authors Prof Neil Watkins
Publisher Name J CLIN INVEST
Published Date 2014-01-01 00:00:00
Published Volume 124
Published Issue 9
Published Pages 3767-80
URL http://www.ncbi.nlm.nih.gov/pubmed/25083987
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?12713_13005/2014-Wang-J Clin Invest.pdf