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      The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine

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      Author(s)
      Göktuna, S. I.
      Shostak, K.
      Chau, T.-L.
      Heukamp, L.C.
      Hennuy, B.
      Duong, H.-Q.
      Ladang, A.
      Close, P.
      Klevernic, I.
      Olivier, F.
      Florin, A.
      Ehx, G.
      Baron, F.
      Vandereyken, M.
      Rahmouni, S.
      Vereecke, L.
      Loo, G. V.
      Büttner, R.
      Greten, F. R.
      Chariot, A.
      Date
      2016-05
      Source Title
      Cancer Research
      Print ISSN
      0008-5472
      Publisher
      American Association for Cancer Research
      Volume
      76
      Issue
      9
      Pages
      2587 - 2599
      Language
      English
      Type
      Article
      Item Usage Stats
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      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 b-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 proinflammatory 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.
      Keywords
      Beta catenin
      I kappa B kinase epsilon
      Immunoglobulin enhancer binding protein
      Interleukin 17
      Lipopolysaccharide
      Mitogen activated protein kinase 1
      Mitogen activated protein kinase 3
      Mitogen activated protein kinase kinase 1
      Mitogen activated protein kinase kinase 2
      Protein kinase B
      Stress activated protein kinase 1
      Wnt protein
      I kappa B kinase
      Interleukin 17
      Lipopolysaccharide
      Wnt protein
      Animal cell
      Animal experiment
      Animal model
      Animal tissue
      Apoptosis
      Article
      Cancer growth
      Cancer incidence
      Cancer survival
      Controlled study
      Intestine cancer
      Intestine epithelium cell
      Mouse
      Nonhuman
      Positive feedback
      Priority journal
      Protein expression
      Protein function
      Protein phosphorylation
      Signal transduction
      Tumor associated leukocyte
      Tumor microenvironment
      Tumor promotion
      Animal
      Disease model
      Flow cytometry
      Human
      Immunoprecipitation
      In situ hybridization
      Intestine tumor
      Metabolism
      Pathology
      Physiology
      Real time polymerase chain reaction
      Transgenic mouse
      Tumor cell line
      Animals
      Cell Line, Tumor
      Disease Models, Animal
      Flow Cytometry
      Humans
      I-kappa B Kinase
      Immunoprecipitation
      In Situ Hybridization
      Interleukin-17
      Intestinal Neoplasms
      Lipopolysaccharides
      Mice
      Mice, Transgenic
      Real-Time Polymerase Chain Reaction
      Signal Transduction
      Tumor Microenvironment
      Wnt Proteins
      Permalink
      http://hdl.handle.net/11693/37175
      Published Version (Please cite this version)
      https://doi.org/10.1158/0008-5472.CAN-15-1473
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