J Exp Med. 2015 Mar 9;212(3):369-83. doi: 10.1084/jem.20140474. Epub 2015 Mar 2.
Allam, R; Maillard, MH; Tardivel, A; Chennupati, V; Bega, H; Yu, CW; Velin, D; Schneider, P; Maslowski, KM
Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Switzerland Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor, Inselspital/Universitätsspital, 3010 Bern, Switzerland; Lausanne University Hospital, 1015 Lausanne, Switzerland; RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
NLR family apoptosis inhibitory proteins (NAIPs) belong to both the Nod-like receptor (NLR) and the inhibitor of apoptosis (IAP) families. NAIPs are known to form an inflammasome with NLRC4, but other in vivo functions remain unexplored. Using mice deficient for all NAIP paralogs (Naip1-6(Δ/Δ)), we show that NAIPs are key regulators of colorectal tumorigenesis. Naip1-6(Δ/Δ) mice developed increased colorectal tumors, in an epithelial-intrinsic manner, in a model of colitis-associated cancer. Increased tumorigenesis, however, was not driven by an exacerbated inflammatory response. Instead, Naip1-6(Δ/Δ) mice were protected from severe colitis and displayed increased antiapoptotic and proliferation-related gene expression. Naip1-6(Δ/Δ) mice also displayed increased tumorigenesis in an inflammation-independent model of colorectal cancer. Moreover, Naip1-6(Δ/Δ) mice, but not Nlrc4-null mice, displayed hyper-activation of STAT3 and failed to activate p53 18 h after carcinogen exposure. This suggests that NAIPs protect against tumor initiation in the colon by promoting the removal of carcinogen-elicited epithelium, likely in a NLRC4 inflammasome-independent manner. Collectively, we demonstrate a novel epithelial-intrinsic function of NAIPs in protecting the colonic epithelium against tumorigenesis.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 300 scientific publications are based on research using Ozgene mice.