Epithelial NAIPs protect against colonic tumorigenesis.

Abstract

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.

• Authors: Ramanjaneyulu Allam, Michel H Maillard, Aubry Tardivel, Vijaykumar Chennupati, Hristina Bega, Chi Wang Yu, Dominique Velin, Pascal Schneider, Kendle M Maslowski
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 212 Issue 3 Pg. 369-83 (Mar 09 2015) ISSN: 1540-9538 [Electronic] United States
• PMID: 25732303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Allam et al.

Chemical References

• Inflammasomes
• Naip1 protein, mouse
• Naip2 protein, mouse
• Naip5 protein, mouse
• Naip6 protein, mouse
• Neuronal Apoptosis-Inhibitory Protein
• STAT3 Transcription Factor
• Stat3 protein, mouse

Topics

• Animals
• Colitis (genetics, metabolism, pathology)
• Colonic Neoplasms (genetics, metabolism, pathology)
• Disease Models, Animal
• Epithelial Cells (metabolism, pathology)
• Inflammasomes (genetics, metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Neuronal Apoptosis-Inhibitory Protein (genetics, metabolism)
• STAT3 Transcription Factor (genetics, metabolism)