• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Scientific Publications by FDA Staff

  • Print
  • Share
  • E-mail
-

Search Publications



Fields



Centers











Starting Date


Ending Date


Order by

Entry Details

Clin Transl Sci 2009 Aug;2(4):286-93

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

Gong L, Debruyne PR, Witek M, Nielsen K, Snook A, Lin JE, Bombonati A, Palazzo J, Schulz S, Waldman SA

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-kappaB transactivated the tissue-specific 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-specific differentiation program involving suppression of EGFR and AKT, activating the NF-kappaB-CDX2 axis. Induction of this axis provides the context for lineage-addicted tumorigenesis, in which autonomous activation of AKT corrupts adaptive intestinal NF-kappaB signaling, amplifying tumorigenic programs.


Category: Journal Article
PubMed ID: #20443907 DOI: 10.1111/j.1752-8062.2009.00131.x
Includes FDA Authors from Scientific Area(s): Drugs
Entry Created: 2013-01-11
Feedback
-
-