Bile acids initiate lineage-addicted gastroesophageal tumorigenesis by suppressing the EGF receptor-AKT axis

Li Gong, Philip R. Debruyne, Matthew Witek, Karl Nielsen, Adam Snook, Jieru E. Lin, Alessandro Bombonati, Juan Palazzo, Stephanie Schulz, Scott A. Waldman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

While bile acids are a risk factor for tumorigenesis induced by reflux disease, the mechanisms by which they contribute to neoplasia remain undefined. Here, we reveal that in gastroesophageal junction (GEJ) cells bile acids activate a tissue-specific developmental program defining the intestinal epithelial cell phenotype characterizing GEJ metaplasia. Deoxycholic acid (DCA) inhibited phosphorylation of EGF receptors (EGFRs) suppressing the proto-oncogene AKT. Suppression of EGFRs and AKT by DCA actuated an intestine-specific cascade in which NF-κB transactivated the tissue-specifi c transcription factor CDX2. In turn, CDX2 orchestrated a lineage-specific differentiation program encompassing genes characterizing intestinal epithelial cells. Conversely, progression from metaplasia to invasive carcinoma in patients, universally associated with autonomous activation of EGFRs and/ or AKT, was coupled with loss of this intestinal program. Thus, bile acids induce intestinal metaplasia at the GEJ by activating the lineage-specifi c differentiation program involving suppression of EGFR and AKT, activating the NF-κB-CDX2 axis. Induction of this axis provides the context for lineage-addicted tumorigenesis, in which autonomous activation of AKT corrupts adaptive intestinal NF-κB signaling, amplifying tumorigenic programs.

Original languageEnglish
Pages (from-to)286-293
Number of pages8
JournalClinical and Translational Science
Volume2
Issue number4
DOIs
Publication statusPublished - 2009
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • General Pharmacology, Toxicology and Pharmaceutics

Keywords

  • Bile acids
  • CDX2
  • Deoxycholic acid
  • EGFR phosphorylation
  • Esophageal adenocarcinoma
  • Gastric adenocarcinoma
  • Gastroesophageal junction
  • GUCY2C
  • Intestinal metaplasia
  • Lineage-addicted tumorigenesis
  • Neoplastic transformation
  • NF-κB

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