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

Smartt, H. J.M.; Smartt, HJM; Greenhough, A.; Ord��ez-Mor�n, P.; Al-Kharusi, M.; Collard, T. J.; Mariadason, J. M.; Huelsken, J.; Williams, A. C.; Paraskeva, C.

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 aspirins chemopreventive efficacy. © 2012 Cancer Research UK All rights reserved.

• Journal Article Type: Article
• Acceptance Date: Aug 30, 2012
• Online Publication Date: Oct 2, 2012
• Publication Date: Oct 23, 2012
• Deposit Date: Feb 19, 2019
• Publicly Available Date: Feb 19, 2019
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Springer Nature [academic journals on nature.com]
• Peer Reviewed: Peer Reviewed
• Volume: 107
• Issue: 9
• Pages: 1514-1517
• DOI: https://doi.org/10.1038/bjc.2012.430
• Public URL: https://uwe-repository.worktribe.com/output/942750
• Publisher URL: https://doi.org/10.1038/bjc.2012.430
• Contract Date: Feb 19, 2019