Activation of the Interleukin-6/STAT3 Antiapoptotic Pathway in Esophageal Cells by Bile Acids and Low pH: Relevance to Barrett's Esophagus

• Published in: Clinical cancer research 2007-09, Vol.13 (18), p.5305-5313
• Main Authors: Dvorak, Katerina, Chavarria, Melissa, Payne, Claire M, Ramsey, Lois, Crowley-Weber, Cara, Dvorakova, Barbora, Dvorak, Bohuslav, Bernstein, Harris, Holubec, Hana, Sampliner, Richard E, Bernstein, Carol, Prasad, Anil, Green, Sylvan B, Garewal, Harinder
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - chemistry; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adult; Aged; Aged, 80 and over; Apoptosis; Barrett Esophagus - metabolism; Barrett Esophagus - pathology; Barrett's esophagus; bcl-X Protein - genetics; bcl-X Protein - metabolism; bile acids; Bile Acids and Salts - metabolism; Bile Acids and Salts - pharmacology; Esophageal Neoplasms - chemistry; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophagus - drug effects; Esophagus - metabolism; Esophagus - pathology; Female; Gastric Acid - metabolism; Humans; Hydrogen-Ion Concentration; IL-6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Male; Middle Aged; oxidative stress; RNA, Messenger - analysis; RNA, Messenger - metabolism; STAT3; STAT3 Transcription Factor - analysis; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tumor Cells, Cultured
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0483

Objectives: The molecular factors contributing to the development of Barrett's esophagus (BE) are unclear. Our previous studies showed that BE tissues secrete interleukin-6 (IL-6) and express proteins associated with IL-6 signaling, including IL-6 receptor, activated signal transducer and activators of transcription 3 (STAT3), and antiapoptotic proteins Bcl-x L and Mcl-1. Here, we test the hypothesis that bile acids and gastric acids, two components of refluxate associated with gastresophageal reflux disease, activate the IL-6/STAT3 pathway. Materials and Methods: Immunohistochemistry was used to assess levels of phosphorylated STAT3 in esophageal tissue samples from BE patients with different grades of dysplasia. Seg-1 esophageal adenocarcinoma cells were evaluated for STAT3 activation and IL-6 and Bcl-x L expression by molecular biology techniques, including Western blot, reverse transcription–PCR, and ELISA after exposure to control media (pH 7.4), media supplemented with a 0.1 mmol/L bile acid cocktail with media at pH 4 or media at pH 4 with bile acid cocktail. Results: Immunohistochemical analysis showed that activated, phosphorylated STAT3 is expressed in nuclei of dysplastic BE and cancer tissues. Treatment of Seg-1 cells with media containing bile acid cocktail and acidified to pH 4 resulted in increased activation of STAT3, IL-6 secretion, and increased expression of Bcl-x L . Inhibition of the STAT3 pathway using STAT3 small interfering RNA or Janus-activated kinase inhibitor resulted in increased apoptosis. Conclusions: The IL-6/STAT3 antiapoptotic pathway is induced by short exposure to bile acid cocktail and low pH. This alteration, if persistent in vivo , may underlie the development of dysplastic BE and tumor progression.