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PLoS One. 2011 Apr 6;6(4):e18562. doi: 10.1371/journal.pone.0018562.

Wnt/β-catenin signaling enhances cyclooxygenase-2 (COX2) transcriptional activity in gastric cancer cells.

Author information

1
Centro de Tecnología e Innovación para el Cáncer, Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile.

Abstract

BACKGROUND:

Increased expression of the cyclooxygenase-2 enzyme (COX2) is one of the main characteristics of gastric cancer (GC), which is a leading cause of death in the world, particularly in Asia and South America. Although the Wnt/β-catenin signaling pathway has been involved in the transcriptional activation of the COX2 gene, the precise mechanism modulating this response is still unknown.

METHODOLOGY/PRINCIPAL FINDINGS:

Here we studied the transcriptional regulation of the COX2 gene in GC cell lines and assessed whether this phenomenon is modulated by Wnt/β-catenin signaling. We first examined the expression of COX2 mRNA in GC cells and found that there is a differential expression pattern consistent with high levels of nuclear-localized β-catenin. Pharmacological treatment with either lithium or valproic acid and molecular induction with purified canonical Wnt3a significantly enhanced COX2 mRNA expression in a dose- and time-dependent manner. Serial deletion of a 1.6 Kbp COX2 promoter fragment and gain- or loss-of-function experiments allowed us to identify a minimal Wnt/β-catenin responsive region consisting of 0.8 Kbp of the COX2 promoter (pCOX2-0.8), which showed maximal response in gene-reporter assays. The activity of this pCOX2-0.8 promoter region was further confirmed by site-directed mutagenesis and DNA-protein binding assays.

CONCLUSIONS/SIGNIFICANCE:

We conclude that the pCOX2-0.8 minimal promoter contains a novel functional T-cell factor/lymphoid enhancer factor (TCF/LEF)-response element (TBE Site II; -689/-684) that responds directly to enhanced Wnt/β-catenin signaling and which may be important for the onset/progression of GC.

PMID:
21494638
PMCID:
PMC3071840
DOI:
10.1371/journal.pone.0018562
[Indexed for MEDLINE]
Free PMC Article

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