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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; Williams, Ann C.

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


Danny N. Legge

Alex P. Shephard

Tracey J. Collard

Adam C. Chambers

Richard W. Clarkson

Christos Paraskeva

Ann C. Williams


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 over-expressed in a subset of colorectal cancers (CRC), 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 signalling in colorectal carcinogenesis, that the functional significance of this interactions 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 colorectal cancer cells 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 C-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 (CSC), we believe that identifying and targeting drivers of stem cell plasticity have significant potential as new therapeutic targets.

Journal Article Type Article
Acceptance Date Feb 15, 2019
Online Publication Date Mar 4, 2019
Publication Date Mar 1, 2019
Deposit Date Feb 25, 2019
Publicly Available Date Feb 25, 2019
Journal DMM Disease Models and Mechanisms
Print ISSN 1754-8411
Electronic ISSN 1754-8411
Publisher Company of Biologists
Peer Reviewed Peer Reviewed
Volume 12
Issue 3
Article Number dmm037697
Keywords NF-kappaB, LGR5, ASCL2, Wnt, spheroid, BCL3
Public URL
Publisher URL
Contract Date Feb 25, 2019


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