title: The Prosurvival IKK-Related Kinase IKKε Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine.
abstract: Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkε in Wnt-driven tumor development. We found that Ikkε was activated in intestinal tumors forming upon loss of the tumor suppressor Apc Genetic ablation of Ikkε in β-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkε to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkε was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding pro-inflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkε-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkε phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkε to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9); 2587-99. ©2016 AACR.
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium. Department of Molecular Biology and Genetics, Bilkent University, Bilkent, Ankara, Turkey.
authors.forename: Serkan Ismail
authors.initials: SI
authors.lastname: Göktuna
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
authors.forename: Kateryna
authors.initials: K
authors.lastname: Shostak
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
authors.forename: Tieu-Lan
authors.initials: TL
authors.lastname: Chau
authors.affiliation: Institute for Pathology-University Hospital Cologne, Germany.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. GIGA Transcriptomic Facility, University of Liege, CHU, Sart-Tilman, Liège, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Hennuy
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
authors.forename: Hong-Quan
authors.initials: HQ
authors.lastname: Duong
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ladang
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Cancer Signaling, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Close
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
authors.forename: Iva
authors.initials: I
authors.lastname: Klevernic
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Animal Facility, Liège, University of Liege, Belgium.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Olivier
authors.affiliation: Institute for Pathology-University Hospital Cologne, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Florin
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Unit of Hematology and Department of Medicine, Division of Hematology, GIGA-I, University of Liege, Liège, Belgium.
authors.forename: Grégory
authors.initials: G
authors.lastname: Ehx
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Unit of Hematology and Department of Medicine, Division of Hematology, GIGA-I, University of Liege, Liège, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baron
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Unit of Immunology and Infectious Diseases, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
authors.forename: Maud
authors.initials: M
authors.lastname: Vandereyken
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Unit of Immunology and Infectious Diseases, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium.
authors.forename: Souad
authors.initials: S
authors.lastname: Rahmouni
authors.affiliation: Inflammation Research Centre (IRC), VIB, Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Lars
authors.initials: L
authors.lastname: Vereecke
authors.affiliation: Inflammation Research Centre (IRC), VIB, Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.affiliation: Institute for Pathology-University Hospital Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, Liège, Belgium. Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, Liège, Belgium. Walloon Excellence in Life Sciences and Biotechnology (WELBIO), University of Liege, Liège, Belgium. alain.chariot@ulg.ac.be.
authors.forename: Alain
authors.initials: A
authors.lastname: Chariot
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D020381:Interleukin-17 / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D008070:Lipopolysaccharides; D051153:Wnt Proteins; D051550:I-kappa B Kinase