title: Fibroblast-derived HB-EGF promotes Cdx2 expression in esophageal squamous cells.
abstract: The molecular basis of attaining columnar phenotype in Barrett's esophagus is poorly understood. One hypothesis states that factors locally produced by cells of mesenchymal origin in chronic reflux esophagitis induce metaplastic transformation. This study was performed to elucidate the factors secreted from fibroblasts that cause columnar phenotype in adjacent squamous epithelium. Human fibroblast cells were exposed to acidified medium for 20 min, followed by medium neutralization for 2 h, and then total RNA was hybridized to Sentrix Human-6 Expression BeadChips. Furthermore, esophageal mucosal biopsy specimens from reflux esophagitis patients were examined for HB-EGF expression using immunohistochemistry. In addition, cells from the human esophageal squamous epithelial cell line HET1A were treated with recombinant HB-EGF, and changes in expressions of Cdx2 and columnar markers were analyzed. The gene expression profile revealed significant upregulation of a variety of growth factors and inflammatory chemokines in response to acid exposure. Among them, HB-EGF was upregulated more than 10-fold. Biopsy specimens from reflux esophagitis patients showed a strong expression of HB-EGF in fibroblast cells underlying the damaged epithelium. Furthermore, in vitro stimulation of HET1A cells with HB-EGF increased Cdx2 in dose-dependent manners. Functional analysis of human Cdx2 promoter also revealed its upregulation by HB-EGF stimulation, showing the role of potential responsive elements (AP-1 and NF-kappaB) for its transcriptional activation. Moreover, the columnar markers cytokeratin 7 and villin were also upregulated by HB-EGF stimulation. HB-EGF induces several genes characteristics of columnar phenotypes of esophageal squamous epithelium in a paracrine manner.
authors.affiliation: Department of Internal Medicine II, Shimane University School of Medicine, Izumo, Shimane, Japan.
authors.forename: Farzana B
authors.initials: FB
authors.lastname: Rahman
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kadowaki
authors.forename: Shunji
authors.initials: S
authors.lastname: Ishihara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tobita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imaoka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fukuhara
authors.forename: Md Monowar
authors.initials: MM
authors.lastname: Aziz
authors.forename: Kenji
authors.initials: K
authors.lastname: Furuta
authors.forename: Yuji
authors.initials: Y
authors.lastname: Amano
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kinoshita
mesh_terms: D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D004942:Esophagitis, Peptic / Q000378:metabolism; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005744:Gastric Acid / Q000502:physiology; D066257:Heparin-binding EGF-like Growth Factor; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008679:Metaplasia; D019899:Paracrine Communication
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D016207:Cytokines; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins