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

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BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells. / Legge, Danny; Shephard, Alex; Collard, Tracey; Greenhough, Alex; Chambers, Adam; Clarkson, Richard; Paraskeva, Christos; Williams, Ann.

In: Disease Models and Mechanisms, Vol. 12, No. 3, dmm037697, 04.03.2019.

Research output: Contribution to journalArticle

Harvard

Legge, D, Shephard, A, Collard, T, Greenhough, A, Chambers, A, Clarkson, R, Paraskeva, C & Williams, A 2019, 'BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells' Disease Models and Mechanisms, vol. 12, no. 3, dmm037697. https://doi.org/10.1242/dmm.037697

APA

Legge, D., Shephard, A., Collard, T., Greenhough, A., Chambers, A., Clarkson, R., ... Williams, A. (2019). BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells. Disease Models and Mechanisms, 12(3), [dmm037697]. https://doi.org/10.1242/dmm.037697

Vancouver

Legge D, Shephard A, Collard T, Greenhough A, Chambers A, Clarkson R et al. BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells. Disease Models and Mechanisms. 2019 Mar 4;12(3). dmm037697. https://doi.org/10.1242/dmm.037697

Author

Legge, Danny ; Shephard, Alex ; Collard, Tracey ; Greenhough, Alex ; Chambers, Adam ; Clarkson, Richard ; Paraskeva, Christos ; Williams, Ann. / BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells. In: Disease Models and Mechanisms. 2019 ; Vol. 12, No. 3.

Bibtex

@article{5a9ccd967984481dba5f7970c4cffec9,
title = "BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells",
abstract = "To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently 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 βcatenin/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",
keywords = "BCL3, Spheroid, Wnt, ASCL2, LGR5, NF-kB, NF-kappa B",
author = "Danny Legge and Alex Shephard and Tracey Collard and Alex Greenhough and Adam Chambers and Richard Clarkson and Christos Paraskeva and Ann Williams",
year = "2019",
month = "3",
day = "4",
doi = "10.1242/dmm.037697",
language = "English",
volume = "12",
journal = "Disease Models and Mechanisms",
issn = "1754-8403",
publisher = "Company of Biologists Ltd",
number = "3",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells

AU - Legge, Danny

AU - Shephard, Alex

AU - Collard, Tracey

AU - Greenhough, Alex

AU - Chambers, Adam

AU - Clarkson, Richard

AU - Paraskeva, Christos

AU - Williams, Ann

PY - 2019/3/4

Y1 - 2019/3/4

N2 - To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently 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 βcatenin/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

AB - To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently 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 βcatenin/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

KW - BCL3

KW - Spheroid

KW - Wnt

KW - ASCL2

KW - LGR5

KW - NF-kB

KW - NF-kappa B

UR - http://www.scopus.com/inward/record.url?scp=85062825864&partnerID=8YFLogxK

U2 - 10.1242/dmm.037697

DO - 10.1242/dmm.037697

M3 - Article

VL - 12

JO - Disease Models and Mechanisms

T2 - Disease Models and Mechanisms

JF - Disease Models and Mechanisms

SN - 1754-8403

IS - 3

M1 - dmm037697

ER -