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

Zhou, Haining; Zhen, Ni; Li, Ting; Su, Linna; Zhang, Lianfeng; Liu, Na

doi:10.3892/ol.2018.8342

Cited by 22 publications

(31 citation statements)

References 30 publications

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“…Now, the mechanism of the transformation from normal gastric mucosal cells to intestinal cells is not clear. It is widely accepted that IM is the result of the interaction of a series of intestine related transcription factors and CDX2 plays an indispensable role in stimulating intestinal differentiation [22][23][24][25][26][27]. Recently, what attracts people's attention is the regulatory mechanism of CDX2 in intestinal differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…found that upregulation of CDX2 and MUC2 in BA-induced gastric IM cells resulted from activated FXR/NF-κB pathway [21]. Similarly, one of our previous studies found that FXR is responsible for the enhancement of CDX2 by a SHP-dependent way in gastric cells [22]. However, the study on the mechanisms of FXR promotes BA-induced gastric IM is still far from enough.…”

Section: Introductionmentioning

confidence: 87%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

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

Wang

Chen

Zeng

et al. 2020

Preprint

Self Cite

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“…However, it is ectopically expressed in IM lesions of the stomach and intestinal-type gastric carcinoma [1][2][3][4][5][6][7][8]. Several studies have reported that CDX2 acts as a tumor suppressor in gastric cancer [6][7][8][21][22][23][24][25][26][27][28][29][30][31].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have reported that CDX2 acts as a tumor suppressor in gastric cancer [6][7][8][21][22][23][24][25][26][27][28][29][30][31]. However, others consider CDX2 an oncogene in gastric cancer [1,2,[9][10][11][12][13][14][15][16][17][18][19][20]. These contradictory ndings imply that CDX2 plays a complex regulatory role in gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

CDX2 and Reg IV expression and correlation in gastric cancer

Chai

Hui-fen

et al. 2020

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Background: Ectopic expression of CDX2 is associated with the development and progression of gastric cancer. Previous studies showed that CDX2 may be an upstream regulator of Reg IV expression in gastric cancer, and our previous report showed that Reg IV upregulated SOX9 expression and enhanced cell migration and invasion in gastric cancer cells. However, the regulatory roles of CDX2 have not been clarified in gastric cancer, and the correlation between CDX2 and Reg IV requires further study. Methods: CDX2 and Reg IV were examined in gastric cancer specimens and paired adjacent tissues via real-time PCR and immunohistochemistry (IHC). The association between CDX2 and Reg IV was assessed using the χ 2 -test and Spearman’s rank correlation. To verify their relationship, knockdown and exogenous expression of CDX2 or Reg IV were performed in AGS and MKN-45 gastric cancer cells, and their expression was subsequently analyzed via a real-time PCR and western blotting. Wound-healing and Transwell assays were used to examine migration and invasion in AGS and MKN-45 cells following CDX2 silencing or overexpression. Results: A positive correlation was observed between CDX2 and Reg IV expression at the mRNA and protein levels in gastric cancer tissues. CDX2 silencing significantly downregulated Reg IV expression, and CDX2 overexpression significantly upregulated Reg IV expression in AGS and MKN-45 cells. Neither Reg IV silencing nor overexpression had any effect on CDX2 protein expression in AGS or MKN-45 cells, even though both affected the expression of CDX2 mRNA. Functionally, CDX2 silencing significantly inhibited cell migration and invasion, and CDX2 overexpression significantly promoted cell migration and invasion in AGS and MKN-45 cells. Conclusions: Our findings demonstrate that CDX2 expression was positively correlated with that of Reg IV in gastric cancer, and CDX2 promoted cell migration and invasion through upregulation of Reg IV expression in AGS and MKN-45 cells.

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“…The role of FXR is more controversial, or complex. FXR was demonstrated to be involved in the bile-acid dependent progression of intestinal metaplasia (37), possibly through a SHPdependent increase of CDX2 gene expression (38). In contrast, the deletion or downregulation of FXR favors hepatocarcinogenesis (27,39), suggesting that FXR plays a protective role.…”

Section: Discussionmentioning

confidence: 99%

System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells

Wigger

Casals-Casas

Baruchet

et al. 2019

Preprint

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Transcriptional regulations exert a critical control of metabolic homeostasis. In particular, the nuclear receptors (NRs) are involved in regulating numerous pathways of the intermediate metabolism. The purpose of the present study was to explore in liver cells the interconnectedness between three of them, LXR, FXR, and PPARα, all three known to act on lipid and glucose metabolism, and also on inflammation. The human cell line HepaRG was selected for its best proximity to human primary hepatocytes. Global gene expression of differentiated HepaRG cells was assessed after 4 hours and 24 hours of exposure to GW3965 (LXR agonist), GW7647 (PPARα agonist), and GW4064 and CDCA (FXR synthetic and natural agonist, respectively). Our work revealed that, contrary to our expectations, NR specificity is largely present at the level of target genes, with a smaller than expected overlap of the set of genes targeted by the different NRs. It also highlighted the much broader activity of the synthetic FXR ligand compared to CDCA. More importantly, our results revealed that activation of FXR has a pro-proliferative effect and decreases polyploidy of hepatocytes, while LXR inhibits the cell cycle progression, inducing hepatocyte differentiation and a higher polyploidism. Conclusion: these results highlight the importance of analyzing the different NR activities in a context allowing a direct confrontation of each receptor outcome, and reveals the opposite role of FXR and LXR in hepatocyte cells division and maturation. Gene Set Enrichment Analysis (GSEA)Gene set enrichment analysis (GSEA) was performed as described in (9) for each treatment at each time point. Most of the gene sets were taken from KEGG, while BIOCARTA sets from the Broad Institute's Molecular Signatures Database (MsigDB version 3.0: www.broadinstitute.org/gsea/msigdb) are explicitly mentioned. Genes that were part of a gene set but that were not found on the Affymetrix chip via their gene symbol were removed from the gene sets. Of these reduced gene sets, those that had fewer than 10 or more than 500 genes were discarded, leaving a total of 327 gene sets. The gene sets were scored against the ranked lists from the LIMMA analysis (four per time point). The absolute t-values from the moderated t-tests were used for both ranking and weighting the genes. P-values were computed using sample permutation with 500 iterations, separately for each of the two time points. At each iteration, the limma model with four contrasts described in the section above was run on the permuted data in order to compute gene set scores for all four treatmentcontrol comparisons. The estimated p-value for a gene set is the proportion of sample permutations that led to a higher score than the original data. To correct for multiple testing, the p-values of the gene sets were adjusted by the Benjamini-Hochberg method. This was done globally for the four gene set lists from time point 4 hours and for the four gene-set lists from time point 24h. We considered a gene set potentially enriched if it ha...

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

Cited by 22 publications

References 30 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

CDX2 and Reg IV expression and correlation in gastric cancer

System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells

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