MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia

Abstract

Background and aimsGastric intestinal metaplasia (IM) is common in the gastric epithelium of patients with chronic atrophic gastritis. CDX2 activation in IM is driven by reflux of bile acids and following chronic inflammation. But the mechanism underlying how bile acids activate CDX2 in gastric epithelium has not been fully explored.MethodsWe performed microRNA (miRNA) and messenger RNA (mRNA) profiling using microarray in cells treated with bile acids. Data integration of the miRNA/mRNA profiles with gene ontology (GO) analysis and bioinformatics was performed to detect potential miRNA-mRNA regulatory circuits. Transfection of gastric cancer cell lines with miRNA mimics and inhibitors was used to evaluate their effects on the expression of candidate targets and functions. Immunohistochemistry and in situhybridisation were used to detect the expression of selected miRNAs and their targets in IM tissue microarrays.ResultsWe demonstrate a bile acids-triggered pathway involving upregulation of miR-92a-1–5p and suppression of its target FOXD1 in gastric cells. We first found that miR-92a-1–5p was increased in IM tissues and induced by bile acids. Moreover, miR-92a-1–5p was found to activate CDX2 and downstream intestinal markers by targeting FOXD1/FOXJ1 axis and modulating activation of nuclear factor kappa B (NF-κB) pathway. Furthermore, these effects were found to be clinical relevant, as high miR-92a-1–5p levels were correlated with low FOXD1 levels and high CDX2 levels in IM tissues.ConclusionThese findings suggest a miR-92a-1–5p/FOXD1/NF-κB/CDX2 regulatory axis plays key roles in the generation of IM phenotype from gastric cells. Suppression of miR-92a-1–5p and restoration of FOXD1 may be a preventive approach for gastric IM in patients with bile regurgitation.

Bile acids increase intestinal markers via FXR/SNAI2/miR-1 axis in the stomach

“…Recently, what attracts people's attention is the regulatory mechanism of CDX2 in intestinal differentiation. In a previous study, our group con rmed that increased miR-92 is involved in the upregulation of CDX2 and the downstream IM markers in gastric cells treated by BA [18]. Besides, our in vivo and in vitro experiments provided evidence that downregulation of miR-1 facilitated the formation of a positive feedback loop involving HDAC6/HNF4α and then stimulated CDX2 expression in BA-induced IM cells.…”

“…At present, many studies have provided evidence that miRNAs participate in the development, differentiation and formation of the digestive tract, so it also exert great in uence in the occurrence of IM, such as miR-30, miR-194 and miR-490 [16,17]. Moreover, it should be noted that our team has successfully constructed a cell model of BA-induced gastric IM, and found that miR-92 promotes the expression of IM markers Caudal-related homeobox 2 (CDX2), Krüppellike factor 4 (KLF4) and VILLIN 1 (VIL1) by targeting FOXD1 [18]. We also discovered that miR-1 was signi cantly reduced in tissues of patients with IM and cell models of BA-induced IM, as well as the reduction of which promoted the signi cant increase of CDX2, MUC2, KLF4 via targeting both HDAC6 and HNF4α (manuscript submitted for publication).…”

“…The BA-induced IM cell model was described previously [18]. GES-1 and AGS (purchased from ATCC) were cultured in PRIM-1640 medium (Gibco, USA) with 10% fetal bovine serum (Gibco, USA), 100 mg/ml streptomycin and 100 U/ml penicillin.…”

Identification of PGC-related ncRNAs and their relationship with the clinicopathologic features of gastric cancer

“…Relationship between miRNAs and GC has been reported in the previous studies [25]. For example, miR-92a-1-5p could increase CDX2 by targeting FOXD1 and mediate gastric intestinal metaplasia [26]. MiR-143-3p may inhibit GC growth and be more sensitive to cisplatin by targeting BRD2 [27].…”

TGR5-HNF4α axis contributes to bile acid-induced gastric intestinal metaplasia markers expression

“…Clinical researches indicated that bile acids (BAs) concentrations in gastric juice were positively correlated with the degree of IM regardless of Hp infection 7 , both in antrum 8 and cardia 9 . Our previous study first uncovered that BAs exposure could significantly induce gastric epithelial cells columnar genes expression through microRNA-mRNA networks involving a miR-92a-5p/ FOXD1/nuclear factor-κB (NF-κB) axis 10 . These results verified the key role of BAs reflux in gastric IM initiation and progression.…”