Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.
Sci Rep. 2021 Feb 5;11(1):3206. doi: 10.1038/s41598-021-82557-x.
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.
GATA4 在胃发育过程中促进柱状上皮细胞命运。当在发育中的小鼠前胃中异位表达时，组织呈现出柱状而不是分层鳞状，其基因表达变化与称为 Barrett 食管 (BE) 的恶性前鳞状到柱状化生中观察到的变化相似。GATA4 mRNA 上调和基因扩增发生在 BE 及其相关的癌症食管腺癌 (EAC) 中，并且 GATA4 基因扩增与患者预后不良相关。在这里，我们探讨了异位表达 GATA4 在成熟人食管鳞状上皮细胞中的作用。我们发现，食管鳞状上皮细胞中 GATA4 的表达损害了鳞状细胞标记基因的表达，并上调了经典柱状细胞细胞角蛋白 KRT8 的表达。我们观察到 GATA4 在 p63、KRT5 和 KRT15 启动子上的占据，表明 GATA4 直接抑制鳞状上皮细胞标记基因的表达。最后，我们在 BE 和 EAC 中验证了 GATA4 蛋白的表达，并发现已知 BE 风险因素的胃酸和胆汁暴露诱导了食管鳞状上皮细胞中 GATA4 mRNA 的表达。我们得出结论，GATA4 抑制了标记分层鳞状上皮细胞谱系的基因的表达，并且 GATA4 的这种抑制作用可能对 BE 和 EAC 具有影响。
