Linked Life Data

20443907

Source:http://linkedlifedata.com/resource/pubmed/id/20443907

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2010-5-6
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1752-8062
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
2
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
286-93
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:20443907-Adenocarcinoma, pubmed-meshheading:20443907-Bile Acids and Salts, pubmed-meshheading:20443907-Biopsy, pubmed-meshheading:20443907-Cell Line, Tumor, pubmed-meshheading:20443907-Cell Lineage, pubmed-meshheading:20443907-Deoxycholic Acid, pubmed-meshheading:20443907-Esophageal Neoplasms, pubmed-meshheading:20443907-Guanylate Cyclase, pubmed-meshheading:20443907-Humans, pubmed-meshheading:20443907-Ligands, pubmed-meshheading:20443907-NF-kappa B, pubmed-meshheading:20443907-Phosphorylation, pubmed-meshheading:20443907-Proto-Oncogene Proteins c-akt, pubmed-meshheading:20443907-Receptor, Epidermal Growth Factor, pubmed-meshheading:20443907-Receptors, Guanylate Cyclase-Coupled, pubmed-meshheading:20443907-Receptors, Peptide, pubmed-meshheading:20443907-Stomach Neoplasms
pubmed:year
2009
pubmed:articleTitle
Bile acids initiate lineage-addicted gastroesophageal tumorigenesis by suppressing the EGF receptor-AKT axis.
pubmed:affiliation
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural