title: β-catenin negatively regulates expression of the prostaglandin transporter PGT in the normal intestinal epithelium and colorectal tumour cells: a role in the chemopreventive efficacy of aspirin?
abstract: BACKGROUND
  Levels of the pro-tumorigenic prostaglandin PGE(2) are increased in colorectal cancer, previously attributed to increased synthesis through COX-2 upregulation and, more recently, to decreased catabolism. The functionally linked genes 15-prostaglandin dehydrogenase (15-PGDH) and the prostaglandin transporter PGT co-operate in prostaglandin degradation and are downregulated in colorectal cancer. We previously reported repression of 15-PGDH expression by the Wnt/β-catenin pathway, commonly deregulated during early colorectal neoplasia. Here we asked whether β-catenin also regulates PGT expression.
  
  
  METHODS
  The effect of β-catenin deletion in vivo was addressed by PGT immunostaining of β-catenin(-/lox)-villin-cre-ERT2 mouse tissue. The effect of siRNA-mediated β-catenin knockdown and dnTCF4 induction in vitro was addressed by semi-quantitative and quantitative real-time RT-PCR and immunoblotting.
  
  
  RESULTS
  This study shows for the first time that deletion of β-catenin in murine intestinal epithelium in vivo upregulates PGT protein, especially in the crypt epithelium. Furthermore, β-catenin knockdown in vitro increases PGT expression in both colorectal adenoma- and carcinoma-derived cell lines, as does dnTCF4 induction in LS174T cells.
  
  
  CONCLUSIONS
  These data suggest that β-catenin employs a two-pronged approach to inhibiting prostaglandin turnover during colorectal neoplasia by repressing PGT expression in addition to 15-PGDH. Furthermore, our data highlight a potential mechanism that may contribute to the non-selective NSAID aspirin's chemopreventive efficacy.
authors.affiliation: Cancer Research UK Colorectal Tumour Biology Research Group, School of Cellular and Molecular Medicine, University Walk, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: H J M
authors.initials: HJ
authors.lastname: Smartt
authors.forename: A
authors.initials: A
authors.lastname: Greenhough
authors.forename: P
authors.initials: P
authors.lastname: Ordóñez-Morán
authors.forename: M
authors.initials: M
authors.lastname: Al-Kharusi
authors.forename: T J
authors.initials: TJ
authors.lastname: Collard
authors.forename: J M
authors.initials: JM
authors.lastname: Mariadason
authors.forename: J
authors.initials: J
authors.lastname: Huelsken
authors.forename: A C
authors.initials: AC
authors.lastname: Williams
authors.forename: C
authors.initials: C
authors.lastname: Paraskeva
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000517:prevention & control*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D027361:Organic Anion Transporters / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D027361:Organic Anion Transporters; D051176:beta Catenin; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D001241:Aspirin