title: NLRX1 Acts as an Epithelial-Intrinsic Tumor Suppressor through the Modulation of TNF-Mediated Proliferation.
abstract: The mitochondrial Nod-like receptor protein NLRX1 protects against colorectal tumorigenesis through mechanisms that remain unclear. Using mice with an intestinal epithelial cells (IEC)-specific deletion of Nlrx1, we find that NLRX1 provides an IEC-intrinsic protection against colitis-associated carcinogenesis in the colon. These Nlrx1 mutant mice have increased expression of Tnf, Egf, and Tgfb1, three factors essential for wound healing, as well as increased epithelial proliferation during the epithelial regeneration phase following injury triggered by dextran sodium sulfate. In primary intestinal organoids lacking Nlrx1, stimulation with TNF resulted in exacerbated proliferation and expression of the intestinal stem cell markers Olfm4 and Myb. This hyper-proliferation response was associated with increased activation of Akt and NF-κB pathways in response to TNF stimulation. Together, these results identify NLRX1 as a suppressor of colonic tumorigenesis that acts by controlling epithelial proliferation in the intestine during the regeneration phase following mucosal injury.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8 Toronto, Canada; Department of Immunology, University of Toronto, M5S 1A8 Toronto, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tattoli
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8 Toronto, Canada.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Killackey
authors.affiliation: Department of Immunology, University of Toronto, M5S 1A8 Toronto, Canada.
authors.forename: Elisabeth G
authors.initials: EG
authors.lastname: Foerster
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8 Toronto, Canada.
authors.forename: Raphael
authors.initials: R
authors.lastname: Molinaro
authors.affiliation: Department of Immunology, University of Toronto, M5S 1A8 Toronto, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Maisonneuve
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8 Toronto, Canada; Department of Immunology, University of Toronto, M5S 1A8 Toronto, Canada.
authors.forename: Muhammed A
authors.initials: MA
authors.lastname: Rahman
authors.affiliation: Department of Pathology, Toronto General Hospital, University of Toronto, M5S 1A8 Toronto, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: Winer
authors.affiliation: Department of Pathology, Toronto General Hospital, University of Toronto, M5S 1A8 Toronto, Canada.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Winer
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8 Toronto, Canada; Saint Michael's Hospital, University of Toronto, M5S 1A8 Toronto, Canada.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Streutker
authors.affiliation: Department of Immunology, University of Toronto, M5S 1A8 Toronto, Canada.
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8 Toronto, Canada. Electronic address: stephen.girardin@utoronto.ca.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis; D049109:Cell Proliferation; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D024101:Mitochondrial Proteins / Q000378:metabolism*; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D019394:Ki-67 Antigen; D024101:Mitochondrial Proteins; C555655:NLRX1 protein, mouse; D020598:Proto-Oncogene Proteins c-myb; D014409:Tumor Necrosis Factor-alpha; C584470:olfactomedin 4, mouse; D016264:Dextran Sulfate