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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/beta-catenin pathway, commonly deregulated during early colorectal neoplasia. Here we asked whether beta-catenin also regulates PGT expression. METHODS: The effect of beta-catenin deletion in vivo was addressed by PGT immunostaining of beta-catenin(-/lox)-villin-cre-ERT2 mouse tissue. The effect of siRNA-mediated beta-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 beta-catenin in murine intestinal epithelium in vivo upregulates PGT protein, especially in the crypt epithelium. Furthermore, beta-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 beta-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. British Journal of Cancer (2012) 107, 1514-1517. doi:10.1038/bjc.2012.430 www.bjcancer.com Published online 2 October 2012 (C) 2012 Cancer Research UK
Didier Trono, Evaristo Jose Planet Letschert, Nikolaos Lykoskoufis
Didier Trono, Laurence Gouzi Abrami, Evaristo Jose Planet Letschert, Julien Léonard Duc, Laia Simo Riudalbas, Sandra Eloise Kjeldsen, Alexandre Coudray, Sagane Dind