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BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells

Legge, Danny N., Shephard, Alex P., Collard, Tracey J., Greenhough, Alexander, Chambers, Adam C., Clarkson, Richard W., Paraskeva, Christos and Williams, Ann C. 2019. BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells. Disease Models and Mechanisms 12 (3) , 037697. 10.1242/dmm.037697

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Abstract

To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently, B-cell lymphoma 3 (BCL-3; a key regulator of NF-κB signalling) has been recognised as an important oncogenic player in solid tumours. Although reported to be overexpressed in a subset of colorectal cancers (CRCs), the role of BCL-3 expression in colorectal tumorigenesis remains poorly understood. Despite evidence in the literature that BCL-3 may interact with β-catenin, it is perhaps surprising, given the importance of deregulated Wnt/β-catenin/T-cell factor (TCF) signalling in colorectal carcinogenesis, that the functional significance of this interaction is not known. Here, we show for the first time that BCL-3 acts as a co-activator of β-catenin/TCF-mediated transcriptional activity in CRC cell lines and that this interaction is important for Wnt-regulated intestinal stem cell gene expression. We demonstrate that targeting BCL-3 expression (using RNA interference) reduced β-catenin/TCF-dependent transcription and the expression of intestinal stem cell genes LGR5 and ASCL2. In contrast, the expression of canonical Wnt targets Myc and cyclin D1 remained unchanged. Furthermore, we show that BCL-3 increases the functional stem cell phenotype, as shown by colorectal spheroid and tumoursphere formation in 3D culture conditions. We propose that BCL-3 acts as a driver of the stem cell phenotype in CRC cells, potentially promoting tumour cell plasticity and therapeutic resistance. As recent reports highlight the limitations of directly targeting cancer stem cells (CSCs), we believe that identifying and targeting drivers of stem cell plasticity have significant potential as new therapeutic targets.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0)
Publisher: Company of Biologists
ISSN: 1754-8403
Date of First Compliant Deposit: 19 January 2021
Date of Acceptance: 15 February 2019
Last Modified: 20 Jan 2021 11:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/137807

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