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Role of a novel bile acid receptor TGR5 in the development of oesophageal adenocarcinoma
  1. Jie Hong1,
  2. Jose Behar1,
  3. Jack Wands1,
  4. Murray Resnick2,
  5. Li Juan Wang2,
  6. Ronald A DeLellis2,
  7. David Lambeth3,
  8. Rhonda F Souza4,
  9. Stuart J Spechler4,
  10. Weibiao Cao1,2
  1. 1Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
  2. 2Department of Pathology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
  3. 3Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
  4. 4Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, USA
  1. Correspondence to Weibiao Cao, Department of Pathology & Medicine, The Warren Alpert Medical School of Brown University & Rhode Island Hospital, 55 Claverick St, Room 337, Providence, RI 02903, USA; wcao{at}hotmail.com

Abstract

Background and aims Mechanisms of the progression from Barrett's oesophagus to oesophageal adenocarcinoma (OA) are not fully understood. Bile acids may have an important role in this progression. This study aimed at examining the role of NADPH oxidase NOX5-S and a novel bile acid receptor TGR5 in taurodeoxycholic acid (TDCA)-induced increase in cell proliferation.

Methods Human Barrett's cell line BAR-T and OA cell line FLO were transfected by the Lipofectamine 2000 or Amaxa-Nucleofector-System. mRNAs were measured by real-time PCR. H2O2 was measured by a fluorescent assay. Cell proliferation was determined by measurement of thymidine incorporation.

Results NOX5-S was present in FLO cells. TDCA significantly increased NOX5-S expression, H2O2 production and thymidine incorporation in FLO and BAR-T cells. This increase in thymidine incorporation was significantly reduced by knockdown of NOX5-S. TGR5 mRNA and protein levels were significantly higher in OA tissues than in normal oesophageal mucosa or Barrett's mucosa. Knockdown of TGR5 markedly inhibited TDCA-induced increase in NOX5-S expression, H2O2 production and thymidine incorporation in FLO and BAR-T cells. Overexpression of TGR5 significantly enhanced the effects of TDCA in FLO cells. TGR5 receptors were coupled with Gαq and Gαi3 proteins, but only Gαq mediated TDCA-induced increase in NOX5-S expression, H2O2 production and thymidine incorporation in FLO cells.

Conclusions TDCA-induced increase in cell proliferation depends on upregulation of NOX5-S expression in BAR-T and FLO cells. TDCA-induced NOX5-S expression may be mediated by activation of the TGR5 receptor and Gαq protein. These data may provide potential targets to prevent and/or treat Barrett's OA.

  • Bile acid receptor
  • NADPH oxidase
  • G proteins
  • Barrett's oesophagus
  • esophageal adenocarcinoma
  • Barrett's carcinoma
  • bile acid
  • BO
  • Barrett's oesophagus
  • OA
  • oesophageal adenocarcinoma
  • TDCA
  • taurodeoxycholic acid
  • PPI
  • proton pump inhibitors
  • ROS
  • reactive oxygen species
  • NOX5-S
  • NAPDH oxidase short form
  • TGR5
  • G protein-coupled bile acid receptor 1
  • siRNA
  • small interfering RNA
  • H2O2
  • hydrogen peroxide
  • CREB
  • cyclic AMP response element binding protein
  • 5-RACE
  • rapid amplification of 5' complementary DNA ends

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Footnotes

  • These data were presented in part at the 109th annual meeting of the American Gastroenterological Association, in San Diego, California, USA, in May 2008.

  • Funding This work was supported by NIDDK R21 DK073327-02 and R01 DK080703-01A1. Others funders: NIH.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Rhode Island Hospital.

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

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