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

Abstract

Background Intestinal metaplasia (IM) is a precancerous lesion that increases risk of subsequent gastric cancer (GC). However, factors governing the transformation from normal gastric epithelial cells to IM remain unclear. Previously, miR-1 turned out to play an essential role in the initiation of bile acids (BA)-induced IM. Here, we investigate the mechanism underlying miR-1 inhibition by BA in gastric cells. Methods We conducted IPA analysis to determine the potential molecular interacting BA with miR-1. The changes of FXR and SNAI2 after BA treatment were detected by western blot and qRT-PCR. IHC was performed to assess the expression level of FXR and SNAI2 in normal and IM tissue microarrays. The transcriptional regulation of SNAI2 or miR-1 was verified by bioinfamatics, luciferase reporter assay and chromatin immunoprecipitation PCR. Results BA treatment caused aberrant expression of FXR and IM markers in gastric cells. Augmented FXR led to the transcriptional activation of SNAI2 which further stimulates the expression of downstream IM markers. Bioinformatics analysis indicated that SNAI2 had miR-1 promoter binding region and we identified that SNAI2 negatively regulated miR-1 transcription. Both FXR and SNAI2 were increased in patients with IM. Conclusions This study demonstrated that FXR might be responsible for a series molecular changes in gastric cells after BA, and FXR/SNAI2/miR-1 axis exert a crucial role in BA-induced IM progression. Blocking the activation of the FXR-oriented axis may provide a promising approach for IM or even GC treatment.