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MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia
BACKGROUND AND AIMS: Gastric 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 ep...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839796/ https://www.ncbi.nlm.nih.gov/pubmed/30635407 http://dx.doi.org/10.1136/gutjnl-2017-315318 |
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author | Li, Ting Guo, Hanqing Li, Hong Jiang, Yanzhi Zhuang, Kun Lei, Chao Wu, Jian Zhou, Haining Zhu, Ruixue Zhao, Xiaodi Lu, Yuanyuan Shi, Chongkai Nie, Yongzhan Wu, Kaichun Yuan, Zuyi Fan, Dai-Ming Shi, Yongquan |
author_facet | Li, Ting Guo, Hanqing Li, Hong Jiang, Yanzhi Zhuang, Kun Lei, Chao Wu, Jian Zhou, Haining Zhu, Ruixue Zhao, Xiaodi Lu, Yuanyuan Shi, Chongkai Nie, Yongzhan Wu, Kaichun Yuan, Zuyi Fan, Dai-Ming Shi, Yongquan |
author_sort | Li, Ting |
collection | PubMed |
description | BACKGROUND AND AIMS: Gastric 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. METHODS: We 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. RESULTS: We 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. CONCLUSION: These 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. |
format | Online Article Text |
id | pubmed-6839796 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-68397962019-11-12 MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia Li, Ting Guo, Hanqing Li, Hong Jiang, Yanzhi Zhuang, Kun Lei, Chao Wu, Jian Zhou, Haining Zhu, Ruixue Zhao, Xiaodi Lu, Yuanyuan Shi, Chongkai Nie, Yongzhan Wu, Kaichun Yuan, Zuyi Fan, Dai-Ming Shi, Yongquan Gut Stomach BACKGROUND AND AIMS: Gastric 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. METHODS: We 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. RESULTS: We 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. CONCLUSION: These 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. BMJ Publishing Group 2019-10 2019-01-11 /pmc/articles/PMC6839796/ /pubmed/30635407 http://dx.doi.org/10.1136/gutjnl-2017-315318 Text en © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Stomach Li, Ting Guo, Hanqing Li, Hong Jiang, Yanzhi Zhuang, Kun Lei, Chao Wu, Jian Zhou, Haining Zhu, Ruixue Zhao, Xiaodi Lu, Yuanyuan Shi, Chongkai Nie, Yongzhan Wu, Kaichun Yuan, Zuyi Fan, Dai-Ming Shi, Yongquan MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia |
title | MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia |
title_full | MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia |
title_fullStr | MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia |
title_full_unstemmed | MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia |
title_short | MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia |
title_sort | microrna-92a-1–5p increases cdx2 by targeting foxd1 in bile acids-induced gastric intestinal metaplasia |
topic | Stomach |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839796/ https://www.ncbi.nlm.nih.gov/pubmed/30635407 http://dx.doi.org/10.1136/gutjnl-2017-315318 |
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