Epithelial NAIPs protect against colonic tumorigenesis.
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.
Department of Biochemistry, Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor, Inselspital/Universitätsspital, 3010 Bern, Switzerland.
Ramanjaneyulu
R
Allam
Service of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital, 1015 Lausanne, Switzerland.
Michel H
MH
Maillard
Department of Biochemistry, Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
Aubry
A
Tardivel
Department of Biochemistry, Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
Vijaykumar
V
Chennupati
Service of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital, 1015 Lausanne, Switzerland.
Hristina
H
Bega
Department of Biochemistry, Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
Chi Wang
CW
Yu
Service of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital, 1015 Lausanne, Switzerland.
Dominique
D
Velin
Department of Biochemistry, Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
Pascal
P
Schneider
Department of Biochemistry, Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan kendle.maslowski@riken.jp.
Kendle M
KM
Maslowski
D000818:Animals; D003092:Colitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
D058847:Inflammasomes; C496801:Naip1 protein, mouse; C496802:Naip2 protein, mouse; C496806:Naip5 protein, mouse; C496807:Naip6 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse