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Cancers 2015, 7(3), 1885-1899; doi:10.3390/cancers7030867

The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells

1
Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Faculty of Health and Applied Sciences, University of the West of England, Frenchay, Bristol BS16 1QY, UK
2
School of Cellular & Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Hui-Wen Lo
Received: 12 July 2015 / Revised: 26 August 2015 / Accepted: 11 September 2015 / Published: 17 September 2015
View Full-Text   |   Download PDF [503 KB, uploaded 17 September 2015]   |  

Abstract

Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, Cancers 2015, 7 1886 these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer. View Full-Text
Keywords: colorectal cancer; Wnt signalling; hedgehog signalling; E-cadherin; cyclopamine; β-catenin/Tcf; EMT; invasion colorectal cancer; Wnt signalling; hedgehog signalling; E-cadherin; cyclopamine; β-catenin/Tcf; EMT; invasion
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Qualtrough, D.; Rees, P.; Speight, B.; Williams, A.C.; Paraskeva, C. The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells. Cancers 2015, 7, 1885-1899.

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