&bgr;-catenin represses expression of the tumour suppressor 15-prostaglandin dehydrogenase in the normal intestinal epithelium and colorectal tumour cells. (English)

Background Cyclooxygenase-2 (COX-2) overexpression in colorectal cancer increases levels of its protumorigenic product prostaglandin E2 (PGE 2 ). 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/&bgr;-catenin signalling is also deregulated early in colorectal neoplasia, a study was undertaken to determine whether &bgr;-catenin represses 15-PGDH expression. Methods The effect of modulating Wnt/&bgr;-catenin signalling (using &bgr;-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 &bgr;-catenin deletion in vivo was addressed by 15-PGDH immunostaining of &bgr;-catenin -/lox -villin-creERT2 mouse tissue. 15-PGDH promoter occupancy was determined using chromatin immunoprecipitation and PGE 2 levels by ELISA. Results The study shows for the first time that &bgr;-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 &bgr;-catenin, also upregulated 15- PGDH; conversely, increasing &bgr;-catenin activity using Wnt3A or GSK3 inhibition downregulated 15-PGDH. Importantly, inducible &bgr;-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 &bgr;-catenin/TCF4 binding to the 15-PGDH promoter. &bgr;-catenin knockdown decreased PGE 2 levels, and this was significantly rescued by 15-PGDH siRNA. Conclusion These data suggest a novel role for bcatenin in promoting colorectal tumorigenesis through very early 15-PGDH suppression leading to increased PGE 2 levels, possibly even before COX-2 upregulation. [ABSTRACT FROM AUTHOR]

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