Abstract
GATA4 promotes columnar epithelial cell fate during gastric development. When ectopically expressed in the developing mouse forestomach, the tissue emerges as columnar-like rather than stratified squamous with gene expression changes that parallel those observed in the pre-malignant squamous to columnar metaplasia known as Barrett’s esophagus (BE). GATA4 mRNA up-regulation and gene amplification occur in BE and its associated cancer, esophageal adenocarcinoma (EAC), and GATA4 gene amplification correlates with poor patient outcomes. Here, we explored the effect of ectopic expression of GATA4 in mature human esophageal squamous epithelial cells. We found that GATA4 expression in esophageal squamous epithelial cells compromised squamous cell marker gene expression and up-regulated expression of the canonical columnar cell cytokeratin KRT8. We observed GATA4 occupancy in the p63, KRT5, and KRT15 promoters, suggesting that GATA4 directly represses expression of squamous epithelial cell marker genes. Finally, we verified GATA4 protein expression in BE and EAC and found that exposure of esophageal squamous epithelial cells to acid and bile, known BE risk factors, induced GATA4 mRNA expression. We conclude that GATA4 suppresses expression of genes marking the stratified squamous epithelial cell lineage and that this repressive action by GATA4 may have implications in BE and EAC.
Highlights
GATA4 promotes columnar epithelial cell fate during gastric development
Columnar epithelial cell-associated transcription factors including CDX2, FOXA2, GATA4, GATA6, HNF4A, HNF1A, and SOX9 are aberrantly expressed in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) while stratified squamous cell-associated transcription factors including p63 and SOX2 are down-regulated in d isease[21,22,23,24,25,26,27,28,29,30]
Similar to what was observed between cell lines at the mRNA level, we found that GATA4 protein levels, as measured by immunoblot, were higher in NES-B10T cells transduced with the GATA4 expression construct compared with NES-B3T cells transduced; NES-B10T cells expressed an average of 3.3-fold more GATA4 protein than B3T clones (Fig. 1B)
Summary
GATA4 promotes columnar epithelial cell fate during gastric development. When ectopically expressed in the developing mouse forestomach, the tissue emerges as columnar-like rather than stratified squamous with gene expression changes that parallel those observed in the pre-malignant squamous to columnar metaplasia known as Barrett’s esophagus (BE). A population of unique transitional cells at the junction between the stratified squamous epithelium of the esophagus and simple columnar epithelium of the stomach has been identified as a potential source of BE c ells[20] These mechanisms are not mutually exclusive, and BE may emerge via multiple routes involving resident esophageal cells and cells from other tissue origins, including the transitional and cardiac zones. When ectopically expressed in the developing mouse forestomach, the tissue emerges as columnar-like rather than stratified squamous, and gene expression changes occurring in the abnormal GATA4-expressing mouse forestomach epithelium parallel those observed in B E34. Like other studies that have queried the function of BE-associated candidate transcription factors in esophageal cells, we expressed GATA4 in normal human adult esophageal squamous epithelial cells. We found exposure of human esophageal squamous epithelial cells to acid and bile, two key reflux components implicated in BE etiology, induced GATA4 mRNA expression
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