Abstract
ABSTRACTTo 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.This article has an associated First Person interview with the first author of the paper.
Highlights
In 2014, there were around 15,900 deaths attributed to bowel cancer in the UK, placing it second when ranked against all cancer mortalities (Cancer Research UK, 2014)
B-cell lymphoma 3 (BCL-3) regulates colorectal spheroid and tumoursphere formation in 3D culture Given that BCL-3 promotes LGR5 and ASCL2 expression, we investigated the functional consequence of stemness marker regulation using an adapted version of the organoid model system pioneered by Sato et al (2009) to grow colorectal cancers (CRCs) cell lines as 3D spheroids
Given that BCL-3 is overexpressed in a subset of CRCs and is linked to poor prognosis (Puvvada et al, 2010), and that the Wnt pathway is deregulated in the vast majority of colorectal tumours (Segditsas and Tomlinson, 2006), the aim of this study was to investigate the role of the NF-κB co-regulator BCL-3 in β-catenin/T-cell factor (TCF)-mediated signalling in CRC cells
Summary
In 2014, there were around 15,900 deaths attributed to bowel cancer in the UK, placing it second when ranked against all cancer mortalities (Cancer Research UK, 2014). Environmental factors, including the inflammation and activation of NF-κB signalling, can promote the expansion of mutant cell populations, contributing both towards the earliest stages of tumorigenesis, and to the maintenance of the tumour, and subsequently to therapeutic resistance and poor prognosis (Schwitalla et al, 2013; Grivennikov et al, 2010; Vlantis et al, 2011; Shaked et al, 2012). Given its importance in gut development, maintenance and homeostasis (Clevers and Nusse, 2012), deregulation of Wnt signalling is an initiating factor in colorectal tumorigenesis; with adenomatous polyposis coli (APC) mutation being the most frequent event in colorectal cancers (CRCs) (Segditsas and Tomlinson, 2006). There are many proteins that interact with β-catenin to influence its role in the cell (Valenta et al, 2012), it was of interest that a solitary panel in a figure of a paper by Kim et al suggested that β-catenin may interact with the NF-κB co-regulator B-cell lymphoma 3 (BCL-3) (either directly or indirectly), the significance of the interaction was not described (Kim et al, 2005)
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