title: Bile acids initiate lineage-addicted gastroesophageal tumorigenesis by suppressing the EGF receptor-AKT axis.
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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Gong
authors.forename: Philip R
authors.initials: PR
authors.lastname: Debruyne
authors.forename: Matthew
authors.initials: M
authors.lastname: Witek
authors.forename: Karl
authors.initials: K
authors.lastname: Nielsen
authors.forename: Adam
authors.initials: A
authors.lastname: Snook
authors.forename: Jieru E
authors.initials: JE
authors.lastname: Lin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bombonati
authors.forename: Juan
authors.initials: J
authors.lastname: Palazzo
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schulz
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D001647:Bile Acids and Salts / Q000737:chemistry* / Q000378:metabolism; D001706:Biopsy; D045744:Cell Line, Tumor; D019070:Cell Lineage; D003840:Deoxycholic Acid / Q000737:chemistry; D066246:ErbB Receptors / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000473:pathology*; D006162:Guanylate Cyclase / Q000737:chemistry; D006801:Humans; D008024:Ligands; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000737:chemistry; D013274:Stomach Neoplasms / Q000473:pathology*
chemical_list: D001647:Bile Acids and Salts; D008024:Ligands; C000715470:MAS1 protein, human; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; D018000:Receptors, Peptide; D003840:Deoxycholic Acid; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled