ROS Production and NF-κB Activation Triggered by RAC1 Facilitate WNT-Driven Intestinal Stem Cell Proliferation and Colorectal Cancer Initiation

The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic dev...

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Bibliographic Details
Published in:Cell stem cell 2013-06, Vol.12 (6), p.761-773
Main Authors: Myant, Kevin B., Cammareri, Patrizia, McGhee, Ewan J., Ridgway, Rachel A., Huels, David J., Cordero, Julia B., Schwitalla, Sarah, Kalna, Gabriela, Ogg, Erinn-Lee, Athineos, Dimitris, Timpson, Paul, Vidal, Marcos, Murray, Graeme I., Greten, Florian R., Anderson, Kurt I., Sansom, Owen J.
Format: Article
Language:English
Subjects:
Animals
Cell Proliferation
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
Intestine, Small - cytology
Intestine, Small - metabolism
Mice
Mice, Inbred C57BL
Neuropeptides - metabolism
NF-kappa B - metabolism
rac1 GTP-Binding Protein - metabolism
Reactive Oxygen Species - metabolism
Signal Transduction
Stem Cells - cytology
Stem Cells - metabolism
Wnt Proteins - metabolism
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Summary:The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we show that RAC1 is a critical mediator of tumorigenesis after APC loss. We find that RAC1 is required for expansion of the LGR5 intestinal stem cell (ISC) signature, progenitor hyperproliferation, and transformation. Mechanistically, RAC1-driven ROS and NF-κB signaling mediate these processes. Together, these data highlight that ROS production and NF-κB activation triggered by RAC1 are critical events in CRC initiation. [Display omitted] •RAC1 is required for tumorigenesis after APC loss•LGR5 ISC transformation requires RAC1•RAC1-driven ROS production and NF-κB activation are required for CRC initiation This study demonstrates that RAC1-mediated ROS production and NF-KB activation is required for LGR5 stem cell expansion and colorectal cancer initiation after loss of the APC gene.
ISSN:1934-5909
1875-9777
1875-9777
DOI:10.1016/j.stem.2013.04.006