title: The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals.
abstract: NOD-like receptor (NLR) proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC) and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1(-/-) mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and interleukin 6 (IL-6). The tumor-suppressive function of NLRX1 originated primarily from the non-hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apc(min/+) genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apc(min/+) colon tumorigenesis, cellular proliferation, NF-κB, MAPK, STAT3 activation, and IL-6 levels. Application of anti-interleukin 6 receptor (IL6R) antibody therapy reduced tumor burden, increased survival, and reduced STAT3 activation in Nlrx1(-/-)Apc(min/+) mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a potential personalized therapy for colon cancers with reduced NLRX1.
authors.affiliation: The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
authors.forename: A Alicia
authors.initials: AA
authors.lastname: Koblansky
authors.affiliation: The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
authors.forename: Agnieszka D
authors.initials: AD
authors.lastname: Truax
authors.affiliation: The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA; Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Liu
authors.affiliation: The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Montgomery
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
authors.forename: Shengli
authors.initials: S
authors.lastname: Ding
authors.affiliation: The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Wilson
authors.affiliation: The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
authors.forename: W June
authors.initials: WJ
authors.lastname: Brickey
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Florida College of Medicine, Gainesville, FL 32611, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Mühlbauer
authors.affiliation: The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
authors.forename: Rita-Marie T
authors.initials: RM
authors.lastname: McFadden
authors.affiliation: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Peizhen
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zengshan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Florida College of Medicine, Gainesville, FL 32611, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
authors.forename: Pauline Kay
authors.initials: PK
authors.lastname: Lund
authors.affiliation: The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7295, USA. Electronic address: jenny_ting@med.unc.edu.
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001397:Azoxymethane / Q000633:toxicity; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D015850:Interleukin-6; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C555655:NLRX1 protein, mouse; D050796:STAT3 Transcription Factor; D016264:Dextran Sulfate; D020928:Mitogen-Activated Protein Kinases; C502936:tocilizumab; D001397:Azoxymethane