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β-catenin represses expression of the tumour suppressor 15-prostaglandin dehydrogenase in the normal intestinal epithelium and colorectal tumour cells

Smartt, Helena J. M., Greenhough, Alexander, Ordonez-Moran, Paloma, Talero, Elena, Cherry, Catherine A., Wallam, Catherine A., Parry, Lee, Al Kharusi, Manal Al, Roberts, Heather R., Mariadason, John M., Clarke, Alan Richard, Huelsken, Joerg, Williams, Ann C. and Paraskeva, Chris 2012. β-catenin represses expression of the tumour suppressor 15-prostaglandin dehydrogenase in the normal intestinal epithelium and colorectal tumour cells. Gut 61 (9) , pp. 1306-1314. 10.1136/gutjnl-2011-300817

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Abstract

Background: Cyclooxygenase-2 (COX-2) overexpression in colorectal cancer increases levels of its pro-tumorigenic product prostaglandin E2 (PGE2). The recently identified colorectal tumour suppressor 15-prostaglandin dehydrogenase (15-PGDH) catalyses prostaglandin turnover and is downregulated at a very early stage in colorectal tumorigenesis; however, the mechanism responsible remains unclear. As Wnt/β-catenin signalling is also deregulated early in colorectal neoplasia, a study was undertaken to determine whether β-catenin represses 15-PGDH expression. Methods: The effect of modulating Wnt/β-catenin signalling (using β-catenin siRNA, mutant TCF4, Wnt3A or GSK3 inhibition) on 15-PGDH mRNA, protein expression and promoter activity was determined in colorectal cell lines by immunoblotting, qRT-PCR and reporter assays. The effect of β-catenin deletion in vivo was addressed by 15-PGDH immunostaining of β-catenin−/lox-villin-creERT2 mouse tissue. 15-PGDH promoter occupancy was determined using chromatin immunoprecipitation and PGE2 levels by ELISA. Results: The study shows for the first time that β-catenin knockdown upregulates 15-PGDH in colorectal adenoma and carcinoma cells without affecting COX-2 protein levels. A dominant negative mutant form of TCF4 (dnTCF4), unable to bind β-catenin, also upregulated 15-PGDH; conversely, increasing β-catenin activity using Wnt3A or GSK3 inhibition downregulated 15-PGDH. Importantly, inducible β-catenin deletion in vivo also upregulated intestinal epithelial 15-PGDH. 15-PGDH regulation occurred at the protein, mRNA and promoter activity levels and chromatin immunoprecipitation indicated β-catenin/TCF4 binding to the 15-PGDH promoter. β-catenin knockdown decreased PGE2 levels, and this was significantly rescued by 15-PGDH siRNA. Conclusion: These data suggest a novel role for β-catenin in promoting colorectal tumorigenesis through very early 15-PGDH suppression leading to increased PGE2 levels, possibly even before COX-2 upregulation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > Q Science (General)
Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: BMJ Publishing Group
ISSN: 0017-5749
Last Modified: 04 Jun 2017 03:45
URI: http://orca.cf.ac.uk/id/eprint/26021

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