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Original article
microRNA-145 in Barrett's oesophagus: regulating BMP4 signalling via GATA6
  1. Jantine W P M van Baal1,
  2. Romy E Verbeek1,
  3. Pauline Bus1,
  4. Matteo Fassan2,
  5. Rhonda F Souza3,
  6. Massimo Rugge2,
  7. Fiebo J W ten Kate4,
  8. Frank P Vleggaar1,
  9. Peter D Siersema1
  1. 1Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2Department of Medical Diagnostic Sciences and Special Therapies, Surgical Pathology and Cytopathology Unit, University of Padova, Padova, Italy
  3. 3Department of Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
  4. 4Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
  1. Correspondence to Jantine W P M van Baal, Department of Gastroenterology and Hepatology, F02.816, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands; j.w.p.m.vanbaal-2{at}umcutrecht.nl

Abstract

Objective Barrett's oesophagus (BE) is a metaplastic condition of the distal oesophagus which predisposes to oesophageal adenocarcinoma (EAC). It has been suggested that microRNAs (miRNAs) are involved in the process of development of BE and EAC; however, few functional miRNA data are available. The aim of the study was to perform a tissue-specific miRNA profile and, based on this, to examine the function of miRNA-145 in the oesophagus.

Design miRNA expression profiling using microarray analysis in EAC, BE and normal squamous epithelium of the oesophagus (SQ) was performed and validated using real-time PCR in samples from 15 patients and in situ hybridisation in samples from 10 patients. The proliferative effect of miRNA-145 precursor transfection in the SQ (HET-1A) and BE cell line (BAR-T) was measured. Downstream targets of miRNA-145 were determined by analysing mRNA and protein expression from miRNA-145 transfected cells.

Results Three unique miRNA expression profiles were found in tissue from EAC, BE and SQ, which showed that miRNA-145 was upregulated in BE compared with EAC and SQ. Overexpression of miRNA-145 in HET-1A and BAR-T cells reduced cell proliferation and inhibited GATA6, BMP4 and SOX9 mRNA expression. Furthermore, altered BMP4 signalling was observed in vitro on miRNA-145 overexpression. These effects were blocked when cells were co-transfected with a miRNA-145 specific inhibitor. Additionally, BMP4 incubation of HET-1A cells altered miRNA-145 and GATA6 expression over time.

Conclusion These results imply that miRNA-145 indirectly targets BMP4 via GATA6 and is potentially involved in the development of BE.

  • Barrett's oesophagus
  • microRNA profiling
  • microRNA-145
  • bone morphogenetic protein 4
  • cell signalling
  • Barrett's metaplasia
  • Barrett's carcinoma
  • Barrett's oesophagus
  • gene expression
  • Barrett's carcinoma
  • Barrett's oesophagus
  • carcinogenesis
  • molecular pathology
  • molecular oncology
  • molecular carcinogenesis
  • gastric adenocarcinoma
  • gastric metaplasia
  • gastrointestinal pathology
  • pre-malignancy—GI tract
  • helicobacter pylori—damage
  • hepatitis
  • endoscopy
  • colorectal carcinoma
  • quality of life
  • oesophageal cancer
  • palliation of oesophageal cancer
  • oesophageal disease
  • brachytherapy
  • stents

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Footnotes

  • Funding PDS received unrestricted research grant support from AstraZeneca BV and Janssen BV.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethical approval was obtained from the Medical Ethical Committees of the UMC Utrecht, The Netherlands and University of Padova, Italy.

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

  • Data sharing statement All authors have read the manuscript, agree to its submission and are willing to share the data written in this manuscript.

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