GATA4 Forms a Positive Feedback Loop with CDX2 to Transactivate MUC2 in Bile Acids-Induced Gastric Intestinal Metaplasia

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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: GATA4 transcription factor; Intestinal metaplasia; NF-κB signaling; Transcriptional activation.

MeSH terms

  • Animals
  • Bile Acids and Salts* / metabolism
  • CDX2 Transcription Factor* / genetics
  • CDX2 Transcription Factor* / metabolism
  • Disease Models, Animal
  • Duodenogastric Reflux / genetics
  • Feedback, Physiological
  • GATA4 Transcription Factor* / genetics
  • GATA4 Transcription Factor* / metabolism
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / metabolism
  • Gastric Mucosa / pathology
  • Humans
  • Male
  • Metaplasia*
  • Mice
  • Mucin-2* / genetics
  • Mucin-2* / metabolism
  • Stomach Neoplasms / chemically induced
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Transcriptional Activation
  • Up-Regulation