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 language | English |
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Pages (from-to) | 286-293 |
Number of pages | 8 |
Journal | Clinical and Translational Science |
Volume | 2 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2009 |
Externally published | Yes |
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