Department of Gastroenterology, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University School of Medicine, Chongqing, China.
Department of Gastroenterology, Bishan Hospital of Chongqing, Bishan Hospital of Chongqing Medical University, Chongqing, China.
Gut Liver. 2024 May 15;18(3):414-425. doi: 10.5009/gnl220394. Epub 2023 Mar 2.
BACKGROUND/AIMS: Gastric intestinal metaplasia (GIM), a common precancerous lesion of gastric cancer, can be caused by bile acid reflux. GATA binding protein 4 (GATA4) is an intestinal transcription factor involved in the progression of gastric cancer. However, the expression and regulation of GATA4 in GIM has not been clarified.
The expression of GATA4 in bile acid-induced cell models and human specimens was examined. The transcriptional regulation of GATA4 was investigated by chromatin immunoprecipitation and luciferase reporter gene analysis. An animal model of duodenogastric reflux was used to confirm the regulation of GATA4 and its target genes by bile acids.
GATA4 expression was elevated in bile acid-induced GIM and human specimens. GATA4 bound to the promoter of mucin 2 (MUC2) and stimulate its transcription. GATA4 and MUC2 expression was positively correlated in GIM tissues. Nuclear transcription factor-κB activation was required for the upregulation of GATA4 and MUC2 in bile acid-induced GIM cell models. GATA4 and caudal-related homeobox 2 (CDX2) reciprocally transactivated each other to drive the transcription of MUC2. In chenodeoxycholic acid-treated mice, MUC2, CDX2, GATA4, p50, and p65 expression levels were increased in the gastric mucosa.
GATA4 is upregulated and can form a positive feedback loop with CDX2 to transactivate MUC2 in GIM. NF-κB signaling is involved in the upregulation of GATA4 by chenodeoxycholic acid.
背景/目的：胃肠上皮化生（GIM）是胃癌的常见癌前病变，可由胆汁酸反流引起。GATA 结合蛋白 4（GATA4）是一种参与胃癌进展的肠转录因子。然而，GATA4 在 GIM 中的表达和调节尚未阐明。
检测胆汁酸诱导的细胞模型和人类标本中 GATA4 的表达。通过染色质免疫沉淀和荧光素酶报告基因分析研究 GATA4 的转录调节。使用十二指肠胃反流动物模型来确认胆汁酸对 GATA4 及其靶基因的调节作用。
GATA4 在胆汁酸诱导的 GIM 和人类标本中表达上调。GATA4 结合到粘蛋白 2（MUC2）的启动子上并刺激其转录。GATA4 和 MUC2 在 GIM 组织中的表达呈正相关。核转录因子-κB 的激活是胆汁酸诱导的 GIM 细胞模型中 GATA4 和 MUC2 上调所必需的。GATA4 和尾相关同源盒 2（CDX2）相互反式激活彼此以驱动 MUC2 的转录。在鹅去氧胆酸处理的小鼠中，胃黏膜中 MUC2、CDX2、GATA4、p50 和 p65 的表达水平增加。
GATA4 上调，并与 CDX2 形成正反馈回路以转激活 GIM 中的 MUC2。NF-κB 信号通路参与鹅去氧胆酸上调 GATA4。
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