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.
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Myant
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cammareri
authors.forename: Ewan J
authors.initials: EJ
authors.lastname: McGhee
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.forename: David J
authors.initials: DJ
authors.lastname: Huels
authors.forename: Julia B
authors.initials: JB
authors.lastname: Cordero
authors.forename: Sarah
authors.initials: S
authors.lastname: Schwitalla
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kalna
authors.forename: Erinn-Lee
authors.initials: EL
authors.lastname: Ogg
authors.forename: Dimitris
authors.initials: D
authors.lastname: Athineos
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.forename: Marcos
authors.initials: M
authors.lastname: Vidal
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Murray
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
authors.forename: Kurt I
authors.initials: KI
authors.lastname: Anderson
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D007421:Intestine, Small / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; D051153:Wnt Proteins; D020830:rac1 GTP-Binding Protein