Epithelial NAIPs protect against colonic tumorigenesis

Research output: Contribution to journalArticle

Authors

  • Ramanjaneyulu Allam
  • Michel H Maillard
  • Aubry Tardivel
  • Vijaykumar Chennupati
  • Hristina Bega
  • Chi Wang Yu
  • Dominique Velin
  • Pascal Schneider

Colleges, School and Institutes

External organisations

  • 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.
  • Service of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital, 1015 Lausanne, Switzerland.
  • Department of Biochemistry, Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.

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.

Details

Original languageEnglish
Pages (from-to)369-83
Number of pages15
JournalThe Journal of Experimental Medicine
Volume212
Issue number3
Publication statusPublished - 9 Mar 2015

Keywords

  • Animals, Colitis, Colonic Neoplasms, Disease Models, Animal, Epithelial Cells, Inflammasomes, Mice, Inbred C57BL, Mice, Knockout, Neuronal Apoptosis-Inhibitory Protein, STAT3 Transcription Factor, Journal Article, Research Support, Non-U.S. Gov't