RRC ID 31028
Author Wang DH, Tiwari A, Kim ME, Clemons NJ, Regmi NL, Hodges WA, Berman DM, Montgomery EA, Watkins DN, Zhang X, Zhang Q, Jie C, Spechler SJ, Souza RF.
Title Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett's metaplasia.
Journal J Clin Invest
Abstract Metaplasia can result when injury reactivates latent developmental signaling pathways that determine cell phenotype. Barrett's esophagus is a squamous-to-columnar epithelial metaplasia caused by reflux esophagitis. Hedgehog (Hh) signaling is active in columnar-lined, embryonic esophagus and inactive in squamous-lined, adult esophagus. We showed previously that Hh signaling is reactivated in Barrett's metaplasia and overexpression of Sonic hedgehog (SHH) in mouse esophageal squamous epithelium leads to a columnar phenotype. Here, our objective was to identify Hh target genes involved in Barrett's pathogenesis. By microarray analysis, we found that the transcription factor Foxa2 is more highly expressed in murine embryonic esophagus compared with postnatal esophagus. Conditional activation of Shh in mouse esophageal epithelium induced FOXA2, while FOXA2 expression was reduced in Shh knockout embryos, establishing Foxa2 as an esophageal Hh target gene. Evaluation of patient samples revealed FOXA2 expression in Barrett's metaplasia, dysplasia, and adenocarcinoma but not in esophageal squamous epithelium or squamous cell carcinoma. In esophageal squamous cell lines, Hh signaling upregulated FOXA2, which induced expression of MUC2, an intestinal mucin found in Barrett's esophagus, and the MUC2-processing protein AGR2. Together, these data indicate that Hh signaling induces expression of genes that determine an intestinal phenotype in esophageal squamous epithelial cells and may contribute to the development of Barrett's metaplasia.
Volume 124(9)
Pages 3767-80
Published 2014-9-1
DOI 10.1172/JCI66603
PII 66603
Description ヒトバレット食道表皮細胞を用いGli1トランスクリプションアクチベーターがGli結合領域を活性化するか調べるために8×3′Gli-BS-delta51-LucIIが使用されました。 また、ネガティブコントロールとして8xm3′Gli-BS-delta51-LucIIが使用されました。
PMID 25083987
PMC PMC4151220
MeSH Animals Barrett Esophagus / etiology* Barrett Esophagus / metabolism Esophagus / embryology* Female Hedgehog Proteins / physiology* Hepatocyte Nuclear Factor 3-beta / analysis Hepatocyte Nuclear Factor 3-beta / genetics Hepatocyte Nuclear Factor 3-beta / physiology* Kruppel-Like Transcription Factors Mice Mice, Inbred C57BL Mucin-2 / genetics Mucoproteins / genetics SOX9 Transcription Factor / physiology Signal Transduction / physiology* Zinc Finger Protein GLI1
IF 12.282
Times Cited 51
WOS Category MEDICINE, RESEARCH & EXPERIMENTAL
Resource
DNA material 8x3'Gli-BS-delta51-LucII (RDB08061) 8xm3'Gli-BS-delta51-LucII (RDB08062).