title: Bile acids induce Delta-like 1 expression via Cdx2-dependent pathway in the development of Barrett's esophagus.
abstract: Crosstalk between the Notch signaling pathway and Caudal-related homeobox 2 (Cdx2) has important roles in the development of Barrett's esophagus (BE). We investigated the expression and function of the Notch signaling ligand Delta-like 1 (Dll1) during the development of BE. We determined the expression levels of Dll1 and intracellular signaling molecules related to Notch signaling ((Notch1, Hairy/enhancer of split 1 (Hes1), and Atonal homolog 1 (ATOH1)) in human esophageal squamous and Barrett's epithelium samples. Next, those expression levels in esophageal squamous cells (Het-1A) and Barrett's esophageal cells (CP-A and BAR-T) following stimulation with either bile acids or gamma-secretase inhibitor were investigated. Finally, changes in those expression levels following transfection of a Cdx2 or Dll1 expression vector into Het-1A cells were examined. In addition, changes in those expression levels following knockdown of Cdx2 or Dll1 in CP-A cells were also examined. Dll1 was found to be upregulated and localized in the cell membrane and cytoplasm in BE. Bile acids enhanced cytoplasmic expression of Dll1 in CP-A cells, while cleaved Notch1 expression did not change, suggesting lack of a Dll1 agonistic effect on Notch signaling. Cells transfected with Cdx2 revealed significantly enhanced Dll1, while forced expression of Dll1 enhanced ATOH1, Cdx2, and MUC2 expression levels. Nevertheless, enhanced Dll1 did not induce Hes1 expression, suggesting that Dll1 may primarily function as an intracellular signaling molecule and not a Notch agonistic ligand in the canonical pathway. In addition, knockdown of Cdx2 completely abrogated any increase in Dll1 expression upon treatment with bile acids. Our results revealed a novel function of Dll1: facilitation of intestinal metaplasia in conjunction with Cdx2 expression. Furthermore, they suggest that intracellular induction of Dll1 expression in esophageal epithelial cells due to Cdx2 induction in response to bile acids has important roles in BE development.
authors.affiliation: Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.|Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Yuji
authors.identifier: http://orcid.org/0000-0002-1098-5726
authors.initials: Y
authors.lastname: Tamagawa
authors.affiliation: Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishimura
authors.affiliation: Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
authors.forename: Goichi
authors.initials: G
authors.lastname: Uno
authors.affiliation: Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Aimi
authors.affiliation: Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Oshima
authors.affiliation: Division of Gastrointestinal Endoscopy, Shimane University Hospital, Izumo, Shimane, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Yuki
authors.affiliation: Division of Gastrointestinal Endoscopy, Shimane University Hospital, Izumo, Shimane, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Ishihara
authors.affiliation: Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kinoshita
mesh_terms: D000368:Aged; D001471:Barrett Esophagus / Q000209:etiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D001647:Bile Acids and Salts / Q000494:pharmacology*; D000071616:CDX2 Transcription Factor; D002135:Calcium-Binding Proteins; D005260:Female; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008875:Middle Aged; D055262:Mucin-2 / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001647:Bile Acids and Salts; D000071616:CDX2 Transcription Factor; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D055262:Mucin-2; C500942:ATOH1 protein, human; C491270:CDX2 protein, human; C512941:DLK1 protein, human; C524625:MUC2 protein, human