Role of a novel bile acid receptor TGR5 in the development of oesophageal adenocarcinoma

Jie Hong, Jose Behar, Jack Wands, Murray Resnick, Li Juan Wang, Ronald A. DeLellis, David Lambeth, Rhonda F. Souza, Stuart J. Spechler, Weibiao Cao

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

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 Gaq and Gai3 proteins, but only Gaq 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 Gaq protein. These data may provide potential targets to prevent and/or treat Barrett's OA.

Original languageEnglish (US)
Pages (from-to)170-180
Number of pages11
JournalGut
Volume59
Issue number2
DOIs
StatePublished - Feb 2010

ASJC Scopus subject areas

  • Gastroenterology

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