Portal de Periódicos da CAPES

Bcl-2 is a critical mediator of intestinal transformation

2016; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/ncomms10916

2041-1723

Maartje van der Heijden, Cheryl Zimberlin, Anna M. Nicholson, Selçuk Çolak, Richard Kemp, Sybren L. Meijer, Jan Paul Medema, Florian R. Greten, Marnix Jansen, Douglas J. Winton, Louis Vermeulen,

Cell death mechanisms and regulation

Abstract Intestinal tumour formation is generally thought to occur following mutational events in the stem cell pool. However, active NF-κB signalling additionally facilitates malignant transformation of differentiated cells. We hypothesized that genes shared between NF-κB and intestinal stem cell (ISCs) signatures might identify common pathways that are required for malignant growth. Here, we find that the NF-κB target Bcl-2 , an anti-apoptotic gene, is specifically expressed in ISCs in both mice and humans. Bcl-2 is dispensable in homeostasis and, although involved in protecting ISCs from radiation-induced damage, it is non-essential in tissue regeneration. Bcl-2 is upregulated in adenomas, and its loss or inhibition impairs outgrowth of oncogenic clones, because Bcl-2 alleviates apoptotic priming in epithelial cells following Apc loss. Furthermore, Bcl-2 expression in differentiated epithelial cells renders these cells amenable to clonogenic outgrowth. Collectively, our results indicate that Bcl-2 is required for efficient intestinal transformation following Apc -loss and constitutes a potential chemoprevention target.