title: Activation of MUC1 mucin expression by bile acids in human esophageal adenocarcinomatous cells and tissues is mediated by the phosphatidylinositol 3-kinase.
abstract: BACKGROUND
  In esophageal adenocarcinoma, MUC1 mucin expression increases in early stages of the carcinogenetic sequence, during which bile reflux has been identified as a major carcinogen. However, no link between MUC1 overexpression and the presence of bile acids in the reflux has been established so far, and molecular mechanisms regulating MUC1 expression during esophageal carcinogenetic sequence are unknown. Our aim was to identify (1) the bile acids able to upregulate MUC1 expression in esophageal cancer cells and mucosal samples, (2) the regulatory regions in MUC1 promoter responsive to bile acids, and (3) the signaling pathway(s) involved in this regulation.
  
  
  METHODS
  MUC1 mRNA and mucin expression were studied by the means of real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry, both in the human esophageal OE33 adenocarcinoma cell line and in an ex vivo explant model. MUC1 promoter was cloned and transcription regulation was studied by transient cell transfection to identify the bile acid-responsive regions. Signaling pathways involved were identified using specific pharmacologic inhibitors and siRNA approach.
  
  
  RESULTS
  Taurocholic, taurodeoxycholic, taurochenodeoxycholic, glycocholic, sodium glycocholate, and deoxycholic bile acids upregulated MUC1 mRNA and protein expression. The highest induction was obtained with deoxycholic and taurocholic acids in both cellular and explant models. The bile acid-mediated upregulation of MUC1 transcription occurs at the promoter level, with responsive elements located in the -1472/-234 region of the promoter, and involves the phosphatidylinositol 3-kinase signaling pathway.
  
  
  CONCLUSIONS
  Bile acids induce MUC1 mucin overexpression in human esophageal adenocarcinoma cells and tissues by activating its transcription through a process involving phosphatidylinositol 3-kinase.
authors.affiliation: Inserm Unit 837, and Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille Cedex, France. c-mariette@chru-lille.fr
authors.forename: Christophe
authors.initials: C
authors.lastname: Mariette
authors.forename: Guillaume
authors.initials: G
authors.lastname: Piessen
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Leteurtre
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hémon
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Triboulet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D001647:Bile Acids and Salts / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003840:Deoxycholic Acid / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D055271:Mucin 5AC; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D009077:Mucins / Q000378:metabolism; D009092:Mucous Membrane / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013656:Taurocholic Acid / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation
chemical_list: D001647:Bile Acids and Salts; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D018396:Mucin-1; D009077:Mucins; D012333:RNA, Messenger; D003840:Deoxycholic Acid; D013656:Taurocholic Acid; D019869:Phosphatidylinositol 3-Kinases