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

Gen Kusaka, Kaname Uno, Katsunori Iijima, Hiroyuki Endo, Naoki Asano, Tomoyuki Koike, Akira Imatani, Tooru Shimosegawa

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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. Material and 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.

Original languageEnglish
Pages (from-to)1148-1158
Number of pages11
JournalScandinavian journal of gastroenterology
Volume47
Issue number10
DOIs
Publication statusPublished - 2012 Oct

Keywords

  • Barrett's esophagus
  • CDX2
  • EGFR
  • Esophageal squamous epithelium
  • Nitric oxide

ASJC Scopus subject areas

  • Gastroenterology

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