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Stomach
Original article
MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia
  1. Ting Li1,2,3,
  2. Hanqing Guo4,
  3. Hong Li5,
  4. Yanzhi Jiang1,
  5. Kun Zhuang4,
  6. Chao Lei1,
  7. Jian Wu1,
  8. Haining Zhou1,
  9. Ruixue Zhu1,
  10. Xiaodi Zhao1,
  11. Yuanyuan Lu1,
  12. Chongkai Shi1,6,
  13. Yongzhan Nie1,
  14. Kaichun Wu1,
  15. Zuyi Yuan2,3,
  16. Dai-Ming Fan1,
  17. Yongquan Shi1
  1. 1 State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi’an, China
  2. 2 Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, China
  3. 3 Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education, Xi’an, China
  4. 4 Department of Gastroenterology, Xi’an Central Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China
  5. 5 Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
  6. 6 The High School affiliated to Xi’an Jiaotong University, Xi’an Jiaotong University, Xi’an, China
  1. Correspondence to Professor Zuyi Yuan; zuyiyuan{at}xjtu.edu.cn, Professor Dai-Ming Fan, Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi’an 710032, China; daimingfan{at}fmmu.edu.cn, fandaim{at}fmmu.edu.cn and Dr Yongquan Shi; shiyquan{at}fmmu.edu.cn

Abstract

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.

  • bile reflux
  • gastric pre-cancer
  • molecular mechanisms
  • gastric inflammation
  • gastric metaplasia

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/.

https://doi.org/10.1136/gutjnl-2017-315318

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    Footnotes

    • TL, HG, HL and YJ contributed equally.

    • Contributors All authors included in this paper fulfill the criteria of authorship and have approved the submission of this manuscript. Specific contributions are as follows:. TL: design of study; technical and material support; analysis and interpretation of data; critical revision of manuscript; important intellectual content; drafting of manuscript. HG: design of study; technical and material support; analysis and interpretation of data; critical revision of manuscript; important intellectual content; drafting of manuscript. HL: design of study; technical and material support; analysis and interpretation of data; critical revision of manuscript; important intellectual content; drafting of manuscript. YJ: design of study; technical and material support; analysis and interpretation of data; important intellectual content; drafting of manuscript. KZ: technical and material support; important intellectual content, interpretation of data. CL: technical and material support; important intellectual content. JW: technical and material support; important intellectual content. HZ: technical and material support; important intellectual content. RZ: technical and material support; important intellectual content. XZ: technical and material support; important intellectual content. YL: technical and material support; important intellectual content. CS: technical and material support; important intellectual content. YN: analysis and interpretation of data; technical and material support; important intellectual content. KW: analysis and interpretation of data; critical revision of manuscript; important intellectual content. ZY: study concept; critical revision of manuscript; technical and material support; important intellectual content. D-MF: study concept; analysis and interpretation of data; critical revision of manuscript; important intellectual content. YS: study concept/design; analysis and interpretation of data; critical revision of manuscript; important intellectual content; drafting of manuscript.

    • Funding This work was supported by grants from National Key R&D Program of China (2018YFC1311505; 2018YFC1311504), National Natural Science Foundation of China (81430072 D-MF; 81270445 YS; 81370484 N Liu; 81470805 YS; 81400583 HG; 91639301 ZY), Shaanxi Foundation for Innovation Team of Science and Technology (S2018-ZC-TD-0069 YS), the Major Projects of Ministry of Science and Technology (2012ZX09303011-001, D-MF) and the Key Project of Research and Development Plan of Shaanxi Province (2017ZDCXL-SF-02-04-01, ZY).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval This study was approved by the Hospital’s Protection of Human Subjects Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.