ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation

Kevin B Myant; Patrizia Cammareri; Ewan J McGhee; Rachel A Ridgway; David J Huels; Julia B Cordero; Sarah Schwitalla; Gabriela Kalna; Erinn-Lee Ogg; Dimitris Athineos; Paul Timpson; Marcos Vidal; Graeme I Murray; Florian R Greten; Kurt I Anderson; Owen J Sansom

doi:10.1016/j.stem.2013.04.006

ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation

Kevin B Myant, Patrizia Cammareri, Ewan J McGhee, Rachel A Ridgway, David J Huels, Julia B Cordero, Sarah Schwitalla, Gabriela Kalna, Erinn-Lee Ogg, Dimitris Athineos, Paul Timpson, Marcos Vidal, Graeme I Murray, Florian R Greten, Kurt I Anderson, Owen J Sansom

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Pages (from-to)	761-73
Number of pages	13
Journal	Cell Stem Cell
Volume	12
Issue number	6
DOIs	https://doi.org/10.1016/j.stem.2013.04.006
Publication status	Published - 6 Jun 2013

Keywords / Materials (for Non-textual outputs)

Animals
Cell Proliferation
Colorectal Neoplasms
Intestine, Small
Mice
Mice, Inbred C57BL
NF-kappa B
Neuropeptides
Reactive Oxygen Species
Signal Transduction
Stem Cells
Wnt Proteins
rac1 GTP-Binding Protein

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10.1016/j.stem.2013.04.006

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Myant, K. B., Cammareri, P., McGhee, E. J., Ridgway, R. A., Huels, D. J., Cordero, J. B., Schwitalla, S., Kalna, G., Ogg, E.-L., Athineos, D., Timpson, P., Vidal, M., Murray, G. I., Greten, F. R., Anderson, K. I., & Sansom, O. J. (2013). ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell, 12(6), 761-73. https://doi.org/10.1016/j.stem.2013.04.006

@article{53fd341402d94851a8b371dfe24bf5f6,

title = "ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation",

abstract = "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.",

keywords = "Animals, Cell Proliferation, Colorectal Neoplasms, Intestine, Small, Mice, Mice, Inbred C57BL, NF-kappa B, Neuropeptides, Reactive Oxygen Species, Signal Transduction, Stem Cells, Wnt Proteins, rac1 GTP-Binding Protein",

author = "Myant, {Kevin B} and Patrizia Cammareri and McGhee, {Ewan J} and Ridgway, {Rachel A} and Huels, {David J} and Cordero, {Julia B} and Sarah Schwitalla and Gabriela Kalna and Erinn-Lee Ogg and Dimitris Athineos and Paul Timpson and Marcos Vidal and Murray, {Graeme I} and Greten, {Florian R} and Anderson, {Kurt I} and Sansom, {Owen J}",

year = "2013",

month = jun,

day = "6",

doi = "10.1016/j.stem.2013.04.006",

language = "English",

volume = "12",

pages = "761--73",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Elsevier",

number = "6",

}

Myant, KB, Cammareri, P, McGhee, EJ, Ridgway, RA, Huels, DJ, Cordero, JB, Schwitalla, S, Kalna, G, Ogg, E-L, Athineos, D, Timpson, P, Vidal, M, Murray, GI, Greten, FR, Anderson, KI & Sansom, OJ 2013, 'ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation', Cell Stem Cell, vol. 12, no. 6, pp. 761-73. https://doi.org/10.1016/j.stem.2013.04.006

TY - JOUR

T1 - ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation

AU - Myant, Kevin B

AU - Cammareri, Patrizia

AU - McGhee, Ewan J

AU - Ridgway, Rachel A

AU - Huels, David J

AU - Cordero, Julia B

AU - Schwitalla, Sarah

AU - Kalna, Gabriela

AU - Ogg, Erinn-Lee

AU - Athineos, Dimitris

AU - Timpson, Paul

AU - Vidal, Marcos

AU - Murray, Graeme I

AU - Greten, Florian R

AU - Anderson, Kurt I

AU - Sansom, Owen J

PY - 2013/6/6

Y1 - 2013/6/6

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Proliferation

KW - Colorectal Neoplasms

KW - Intestine, Small

KW - Mice

KW - Mice, Inbred C57BL

KW - NF-kappa B

KW - Neuropeptides

KW - Reactive Oxygen Species

KW - Signal Transduction

KW - Stem Cells

KW - Wnt Proteins

KW - rac1 GTP-Binding Protein

U2 - 10.1016/j.stem.2013.04.006

DO - 10.1016/j.stem.2013.04.006

M3 - Article

C2 - 23665120

SN - 1934-5909

VL - 12

SP - 761

EP - 773

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 6

ER -

ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation

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Keywords / Materials (for Non-textual outputs)

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