Farnesoid X receptor signal is involved in deoxycholic acid-induced intestinal metaplasia of normal human gastric epithelial cells

Li, Shu; Chen, Xin; Zhou, Lu; Wang, Bangmao

doi:10.3892/or.2015.4207

Cited by 14 publications

(16 citation statements)

References 45 publications

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“…We also provide evidence that FXR could stimulate the expression of downstream intestinal markers and the FXR speci c siRNA could abolish the enhancement of these markers induced by DCA. Consistently, there are some studies showed evidence that FXR was augmented in intestinal-type GC with IM as well as contributed to the increase of MUC2 and CDX2 in gastric cells [30,31]. Hence, we guess that there might be possible that FXR mediates the prometaplastic effect of DCA on gastric cells.…”

Section: Discussionsupporting

confidence: 78%

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

Wang

Chen

Zeng

et al. 2020

Preprint

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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.

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Section: Discussionsupporting

confidence: 78%

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

Wang

Chen

Zeng

et al. 2020

Preprint

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“…Previous studies using cell lines have showed that the activation of FXR may be involved in the induction of the expression of CDX2 and IM ( 6 , 7 ). However, the association between the expression of FXR and CDX2 in vivo and the exact molecule mechanisms remain to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…FXR also functions as a transcription factor and directly binds to DNA as a heterodimer with common partner retinoid X receptor to regulate the expression of downstream genes when activated by bile acid. It has been demonstrated that FXR is involved in the bile acid-induced progression of IM and the expression of various intestinal specific genes, including CDX2 ( 6 , 7 ). However, the molecular mechanism remains to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Activation of FXR promotes intestinal metaplasia of gastric cells via SHP‑dependent upregulation of the expression of CDX2

Zhou

Zhen

et al. 2018

Oncol Lett

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Gastric intestinal metaplasia (IM) induced by bile acid is a precancerous lesion of gastric adenocarcinoma and is associated with the expression of caudal-related homeobox 2 (CDX2). In the present study, the role of farnesoid X receptor (FXR) on the regulation of CDX2 in gastric cells was investigated and the underlying molecular mechanisms were examined. Human gastric cell lines were treated with chenodeoxycholic acid (CDCA) or FXR agonist GW4064. Cells were treated with CDCA in the presence or absence of the FXR antagonist or FXR siRNA transfection. Next, cells were treated with CDCA in the presence or absence of SHP siRNA transfection and FXR, CDX2 and SHP mRNA and protein levels were determined by reverse transcription-quantitative polymerase chain reaction and western blot analysis. A chromatin immunoprecipitation assay was performed to examine the relationship between FXR and SHP and the expressions of FXR and CDX2 in gastritis and IM tissues were detected using immunohistochemistry. The results revealed that CDCA was able to induce CDX2 expression, which could be blocked by inhibition or knockdown of FXR. Mechanistically, FXR directly induced the expression of small heterodimer partner (SHP). SHP knockdown significantly decreased CDCA-induced CDX2 expression. ChIP results indicated that FXR could directly bind SHP promoter and promote SHP expression. Finally, immunohistochemistry results demonstrated that the expression levels of CDX2 and FXR in human IM lesions were significantly higher, compared with those in gastritis lesions, and were positively correlated. Collectively, these results revealed that the activation of FXR and sequential direct transcriptional induction of SHP were involved in the expression of CDX2 induced by bile acid in gastric IM lesions.

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“…P65 and p50 are key factors in the NF-κB signaling pathway [54], but their function in GIM largely remained unclear [55, 56]. In the present study, we investigated the effect of p65/p50 on CDX2 expression in IM.…”

Section: Discussionmentioning

confidence: 99%

hTERT promotes gastric intestinal metaplasia by upregulating CDX2 via NF-κB signaling pathway

et al. 2017

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BackgroundhTERT has been reported involved in the proliferation and metastasis of gastric cancer, but the role of hTERT in gastric intestinal metaplasia, a premalignant lesion of the gastric mucosa was unknown. The aim of the present study was to investigate the role of hTERT in GIM and the effect of hTERT on CDX2 expression in gastric cells.ResultsExperiments showed that expression of hTERT was significantly higher in GIM than in normal gastric mucosa. Moreover, hTERT increased the KLF4 level via NF-κB during GIM. Furthermore, KLF4 is involved in the up-regulation of CDX2 induced by hTERT, and hTERT can interact with p50, thereby increasing the level of CDX2.Materials and MethodsImmunohistochemistry was used to detect the expression of hTERT in gastric intestinal metaplasia tissue. Then, effect of hTERT on the expression of CDX2 was detected by qRT-PCR, WB and dual luciferase experiment. The role of p65 and p50 in the regulation of CDX2 were further detected by WB, CO-IP and ChIP.ConclusionsWe may conclude that hTERT promotes GIM by up-regulating CDX2 via NF-κB signaling pathway.

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Farnesoid X receptor signal is involved in deoxycholic acid-induced intestinal metaplasia of normal human gastric epithelial cells

Cited by 14 publications

References 45 publications

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

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

Activation of FXR promotes intestinal metaplasia of gastric cells via SHP‑dependent upregulation of the expression of CDX2

hTERT promotes gastric intestinal metaplasia by upregulating CDX2 via NF-κB signaling pathway

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