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Published on: October 27, 2014
Wnt signaling can repress thrombospondin-1 expression in colonic tumorigenesis
Won-Seok Jo1, Yusuke Mizukami, Eva-Maria Duerr
1Gastrointestinal Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
Abstract:
The induction of new blood vessels is critical to the pathogenesis of colon cancer, and inhibition of vascular endothelial growth factor (VEGF) has proven to be an effective approach to the treatment of this malignancy. Another potential therapeutic strategy would utilize endogenous anti-angiogenic molecules such as thrombospondin-1 (TSP-1). However, the regulation of TSP-1 expression in colon cancer is poorly understood. Our results demonstrate that TSP-1 is strongly expressed in normal colonic epithelial cells. However, loss of TSP-1 was observed in early colonic adenomas and it became undetectable in invasive colon cancers. Activation of the Wnt signaling pathway in intestinal epithelial cells repressed TSP-1 gene expression, and inhibition of Wnt signaling in colon cancer cells reversed this repression. Although mutant K-ras also inhibited the TSP-1 promoter in intestinal epithelial cells, silencing of mutant K-ras in colon cancer cells with an activated Wnt pathway did not upregulate TSP-1 expression. Collectively, these findings suggest that activation of the Wnt pathway rather than K-ras plays a more important role in the downregulation of TSP-1 observed in colon cancer.
Insights
Thrombospondin-1 (TSP-1) is lost in colon cancer, with Wnt pathway activation repressing its expression. This suggests Wnt signaling, not K-ras, is key to TSP-1 downregulation in this malignancy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Angiogenesis, driven by vascular endothelial growth factor (VEGF), is crucial in colon cancer pathogenesis.
- Thrombospondin-1 (TSP-1), an endogenous anti-angiogenic molecule, has poorly understood regulation in colon cancer.
Purpose of the Study:
- To investigate the regulation of TSP-1 expression in the context of colon cancer development.
- To determine the roles of Wnt signaling and K-ras in TSP-1 downregulation.
Main Methods:
- Examined TSP-1 expression in normal colonic epithelial cells, adenomas, and invasive cancers.
- Investigated the effect of Wnt signaling pathway activation and inhibition on TSP-1 gene expression.
- Assessed the impact of mutant K-ras on TSP-1 promoter activity and TSP-1 expression.
Main Results:
- TSP-1 expression is high in normal colonic cells but decreases in adenomas and is undetectable in invasive cancers.
- Wnt pathway activation represses TSP-1 gene expression; Wnt inhibition reverses this repression in cancer cells.
- Mutant K-ras inhibits the TSP-1 promoter, but its silencing does not restore TSP-1 in Wnt-activated cancer cells.
Conclusions:
- Wnt pathway activation is a significant factor in TSP-1 downregulation during colon cancer progression.
- The Wnt pathway plays a more critical role than K-ras in the observed loss of TSP-1 in colon cancer.
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