title: The role of nitric oxide in the induction of caudal-type homeobox 2 through epidermal growth factor receptor in the development of Barrett's esophagus.
abstract: OBJECTIVE
  The high concentration of nitric oxide (NO) around the gastro-esophageal junction (GEJ) might play an important role in the development of Barrett's esophagus (BE), a precursor of Barrett's adenocarcimona. Although previous studies revealed that the expression of caudal-type homeobox 2 (CDX2), an important marker of BE, might be induced through Epidermal Growth Factor Receptor (EGFR), the roles of NO in this signal transduction remain unclear.
  
  
  METHODS
  First, we investigated the expressions of EGFR, CDX2 and nitrotyrosine by immunohistochemical study for BE and squamous epithelium of human specimens. Second, we studied the effect of peroxynitrite, peroxynitrite stimulator, SIN-1, or NO donor, NOC7, on the expression of phosphorylated EGFR and CDX2 in KYSE30, an EGFR-rich human esophageal squamous cell carcinoma cell-line. Specific inhibitors for EGFR, AG1478 and small interfering RNA for EGFR (EGFR-siRNA) were employed to elucidate the role of EGFR in the induction of CDX2.
  
  
  RESULTS
  The immunohistochemical study revealed that the expressions of EGFR, CDX2 and nitrotyrosine in BE were stronger than those in squamous epithelium with positive correlations. Exposure to peroxynitrite, SIN-1 or NOC7 induced EGFR phosphorylation and CDX2 expression in dose- and time-dependent manners. Both EGFR phosphorylation and CDX2 induction were significantly diminished by AG 1478 and EGFR-siRNA.
  
  
  CONCLUSIONS
  We revealed for the first time that extrinsic NO might directly induce CDX2 expression through EGFR phosphorylation. We suggested that NO had an important role in the development of BE from squamous epithelium around GEJ.
authors: Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan.
authors: Gen
authors: G
authors: Kusaka
authors: Kaname
authors: K
authors: Uno
authors: Katsunori
authors: K
authors: Iijima
authors: Hiroyuki
authors: H
authors: Endo
authors: Naoki
authors: N
authors: Asano
authors: Tomoyuki
authors: T
authors: Koike
authors: Akira
authors: A
authors: Imatani
authors: Tooru
authors: T
authors: Shimosegawa
mesh_terms: D001471:Barrett Esophagus / Q000378:metabolism / Q000473:pathology; D000071616:CDX2 Transcription Factor; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D004943:Esophagogastric Junction / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D010766:Phosphorylation; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D066246:ErbB Receptors