Hedgehog Signaling Regulates FOXA2 in Esophageal Embryogenesis and Barrett's Metaplasia

J Clin Invest. 2014 Sep;124(9):3767-80. doi: 10.1172/JCI66603. Epub 2014 Aug 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Barrett Esophagus / etiology*
  • Barrett Esophagus / metabolism
  • Esophagus / embryology*
  • Female
  • Hedgehog Proteins / physiology*
  • Hepatocyte Nuclear Factor 3-beta / analysis
  • Hepatocyte Nuclear Factor 3-beta / genetics
  • Hepatocyte Nuclear Factor 3-beta / physiology*
  • Kruppel-Like Transcription Factors
  • Mice
  • Mice, Inbred C57BL
  • Mucin-2 / genetics
  • Mucoproteins / genetics
  • SOX9 Transcription Factor / physiology
  • Signal Transduction / physiology*
  • Zinc Finger Protein GLI1

Substances

  • Agr2 protein, mouse
  • Foxa2 protein, mouse
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Muc2 protein, mouse
  • Mucin-2
  • Mucoproteins
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Zinc Finger Protein GLI1
  • Hepatocyte Nuclear Factor 3-beta