Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett's metaplasia

Gastroenterology. 2010 May;138(5):1810-22. doi: 10.1053/j.gastro.2010.01.048. Epub 2010 Feb 4.

Abstract

Background & aims: The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium.

Methods: Immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice.

Results: Marked up-regulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of Deleted in Malignant Brain Tumors 1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9, and columnar cytokeratins.

Conclusions: Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype.

Publication types

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

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Animals
  • Barrett Esophagus / etiology
  • Barrett Esophagus / metabolism*
  • Barrett Esophagus / pathology
  • Bile / metabolism
  • Bile Reflux / complications
  • Bile Reflux / metabolism
  • Bone Morphogenetic Protein 4 / metabolism
  • Cell Communication* / genetics
  • Cell Differentiation
  • Cell Line
  • Disease Models, Animal
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Esophageal Neoplasms / metabolism*
  • Esophageal Neoplasms / pathology
  • Esophagus / metabolism*
  • Esophagus / pathology
  • Gastroesophageal Reflux / complications
  • Gastroesophageal Reflux / metabolism
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Keratins / metabolism
  • Mesoderm / metabolism*
  • Mesoderm / pathology
  • Metaplasia
  • Mice
  • Mice, Transgenic
  • Patched Receptors
  • Patched-1 Receptor
  • Phenotype
  • Precancerous Conditions / etiology
  • Precancerous Conditions / metabolism*
  • Precancerous Conditions / pathology
  • RNA Interference
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • SOX9 Transcription Factor / metabolism
  • Signal Transduction* / genetics
  • Transfection

Substances

  • BMP4 protein, human
  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • DMBT1 protein, human
  • Hedgehog Proteins
  • PTCH1 protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • Receptors, Cell Surface
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Shh protein, mouse
  • Sox9 protein, mouse
  • Keratins