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GATA4 blocks squamous epithelial cell gene expression in human esophageal squamous cells. Sci Rep 2021 02 05;11(1):3206

Date

02/07/2021

Pubmed ID

33547361

Pubmed Central ID

PMC7864948

DOI

10.1038/s41598-021-82557-x

Scopus ID

2-s2.0-85100555273   3 Citations

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.

Author List

Stavniichuk R, DeLaForest A, Thompson CA, Miller J, Souza RF, Battle MA

Authors

Michele A. Battle PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
James Adam Miller MD, MPH Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Barrett Esophagus
Cell Line
Cell Line, Tumor
Epithelial Cells
Esophageal Neoplasms
GATA4 Transcription Factor
Gene Amplification
Gene Expression Regulation, Neoplastic
Humans
Promoter Regions, Genetic
RNA, Messenger