Bcl-2 is a critical mediator of intestinal transformation.
Maartje van der HeijdenCheryl D ZimberlinAnna M NicholsonSelcuk ColakRichard KempSybren L MeijerJan Paul MedemaFlorian R GretenMarnix JansenDouglas J WintonLouis VermeulenPublished in: Nature communications (2016)
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.
Keyphrases
- stem cells
- radiation induced
- induced apoptosis
- signaling pathway
- oxidative stress
- cell cycle arrest
- cell death
- pi k akt
- genome wide
- lps induced
- radiation therapy
- poor prognosis
- type diabetes
- gene expression
- transcription factor
- skeletal muscle
- copy number
- anti inflammatory
- mesenchymal stem cells
- mouse model
- adipose tissue
- bone marrow
- long non coding rna
- cell therapy