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COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signalling pathways in Barrett’s oesophagus and oesophageal adenocarcinoma
  1. Shumei Song1,
  2. Sushovan Guha1,
  3. Kaifeng Liu1,
  4. Navtej S Buttar2,
  5. Robert S Bresalier1
  1. 1
    Department of Gastrointestinal Medicine & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  2. 2
    Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, USA
  1. Robert S Bresalier, Department of Gastrointestinal Medicine and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030-4009, USA; rbresali{at}


Objectives: Bile reflux contributes to oesophageal injury and neoplasia. COX-2 is involved in both inflammation and carcinogenesis; however, the precise mechanisms by which bile acids promote COX-2 expression in the oesophagus are largely unknown. We analysed the molecular mechanisms that govern bile acid-mediated expression of COX-2 in Barrett’s oesophagus and oesophageal adenocarcinoma (OA).

Design: The effects of bile acids on COX-2 expression were analysed in immortalised Barrett’s oesophagus and OA cells using immunoblotting and transient transfections. Pharmacological inhibitors, phospho-specific antibodies, dominant-negative mutants and siRNA techniques were used to identify relevant signalling pathways. Flow cytometry and reactive oxygen species (ROS) scavengers were used to examine ROS involvement. Immunohistochemistry was performed on oesophageal mucosa obtained from an established rat model of bile reflux.

Results: Unconjugated bile acids potently stimulated COX-2 expression and induced AKT and ERK1/2 phosphorylation in concert with COX-2 induction. These findings were mimicked in the in vivo rat model. Dominant-negative (DN) AKT and LY294002 (PI3K inhibitor) or U0126 (MEK-1/2 inhibitor) blocked chenodeoxycholic acid (CD) and deoxycholic acid (DC) mediated COX-2 induction. CD and DC also induced CREB phosphorylation and AP-1 activity. CREB-specific siRNA and DN AP-1 blocked CD and DC-induced COX-2 induction. Finally, CD and DC increased intracellular ROS, while ROS scavengers blocked COX-2 induction and the signalling pathways involved.

Conclusions: Unconjugated bile acids induce CREB and AP-1-dependent COX-2 expression in Barrett’s oesophagus and OA through ROS-mediated activation of PI3K/AKT and ERK1/2. This study enhances our understanding of the molecular mechanisms by which bile acids promote the development of oesophageal adenocarcinoma.

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  • Competing interests: None.

  • Abbreviations:
    activator protein-1
    chenodeoxycholic acid
    cyclin AMP response element
    CRE binding protein
    cyclooxygenase 2
    deoxycholic acid
    extracellular signal-regulated kinase
    2,7-dichlorohydrofluorescein diacetate
    glycocholic acid
    glycochenodeoxycholic acid
    mitogen and extracellular signal-regulated kinase kinase
    phosphatidylinositol 3-kinase
    oesophageal adenocarcinoma
    protein kinase C
    reactive oxygen species
    taurochenodeoxycholic acid
    taurocholic acid
    taurodeoxycholic acid

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