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dc.contributor.authorGöktuna, S. I.en_US
dc.contributor.authorShostak, K.en_US
dc.contributor.authorChau, T.-L.en_US
dc.contributor.authorHeukamp, L.C.en_US
dc.contributor.authorHennuy, B.en_US
dc.contributor.authorDuong, H.-Q.en_US
dc.contributor.authorLadang, A.en_US
dc.contributor.authorClose, P.en_US
dc.contributor.authorKlevernic, I.en_US
dc.contributor.authorOlivier, F.en_US
dc.contributor.authorFlorin, A.en_US
dc.contributor.authorEhx, G.en_US
dc.contributor.authorBaron, F.en_US
dc.contributor.authorVandereyken, M.en_US
dc.contributor.authorRahmouni, S.en_US
dc.contributor.authorVereecke, L.en_US
dc.contributor.authorLoo, G. V.en_US
dc.contributor.authorBüttner, R.en_US
dc.contributor.authorGreten, F. R.en_US
dc.contributor.authorChariot, A.en_US
dc.date.accessioned2018-04-12T11:05:06Z
dc.date.available2018-04-12T11:05:06Z
dc.date.issued2016-05en_US
dc.identifier.issn0008-5472
dc.identifier.urihttp://hdl.handle.net/11693/37175
dc.description.abstractConstitutive 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.en_US
dc.language.isoEnglishen_US
dc.source.titleCancer Researchen_US
dc.relation.isversionofhttps://doi.org/10.1158/0008-5472.CAN-15-1473en_US
dc.subjectBeta cateninen_US
dc.subjectI kappa B kinase epsilonen_US
dc.subjectImmunoglobulin enhancer binding proteinen_US
dc.subjectInterleukin 17en_US
dc.subjectLipopolysaccharideen_US
dc.subjectMitogen activated protein kinase 1en_US
dc.subjectMitogen activated protein kinase 3en_US
dc.subjectMitogen activated protein kinase kinase 1en_US
dc.subjectMitogen activated protein kinase kinase 2en_US
dc.subjectProtein kinase Ben_US
dc.subjectStress activated protein kinase 1en_US
dc.subjectWnt proteinen_US
dc.subjectI kappa B kinaseen_US
dc.subjectInterleukin 17en_US
dc.subjectLipopolysaccharideen_US
dc.subjectWnt proteinen_US
dc.subjectAnimal cellen_US
dc.subjectAnimal experimenten_US
dc.subjectAnimal modelen_US
dc.subjectAnimal tissueen_US
dc.subjectApoptosisen_US
dc.subjectArticleen_US
dc.subjectCancer growthen_US
dc.subjectCancer incidenceen_US
dc.subjectCancer survivalen_US
dc.subjectControlled studyen_US
dc.subjectIntestine canceren_US
dc.subjectIntestine epithelium cellen_US
dc.subjectMouseen_US
dc.subjectNonhumanen_US
dc.subjectPositive feedbacken_US
dc.subjectPriority journalen_US
dc.subjectProtein expressionen_US
dc.subjectProtein functionen_US
dc.subjectProtein phosphorylationen_US
dc.subjectSignal transductionen_US
dc.subjectTumor associated leukocyteen_US
dc.subjectTumor microenvironmenten_US
dc.subjectTumor promotionen_US
dc.subjectAnimalen_US
dc.subjectDisease modelen_US
dc.subjectFlow cytometryen_US
dc.subjectHumanen_US
dc.subjectImmunoprecipitationen_US
dc.subjectIn situ hybridizationen_US
dc.subjectIntestine tumoren_US
dc.subjectMetabolismen_US
dc.subjectPathologyen_US
dc.subjectPhysiologyen_US
dc.subjectReal time polymerase chain reactionen_US
dc.subjectTransgenic mouseen_US
dc.subjectTumor cell lineen_US
dc.subjectAnimalsen_US
dc.subjectCell Line, Tumoren_US
dc.subjectDisease Models, Animalen_US
dc.subjectFlow Cytometryen_US
dc.subjectHumansen_US
dc.subjectI-kappa B Kinaseen_US
dc.subjectImmunoprecipitationen_US
dc.subjectIn Situ Hybridizationen_US
dc.subjectInterleukin-17en_US
dc.subjectIntestinal Neoplasmsen_US
dc.subjectLipopolysaccharidesen_US
dc.subjectMiceen_US
dc.subjectMice, Transgenicen_US
dc.subjectReal-Time Polymerase Chain Reactionen_US
dc.subjectSignal Transductionen_US
dc.subjectTumor Microenvironmenten_US
dc.subjectWnt Proteinsen_US
dc.titleThe prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestineen_US
dc.typeArticleen_US
dc.departmentDepartment of Molecular Biology and Genetics
dc.citation.spage2587en_US
dc.citation.epage2599en_US
dc.citation.volumeNumber76en_US
dc.citation.issueNumber9en_US
dc.identifier.doi10.1158/0008-5472.CAN-15-1473en_US
dc.publisherAmerican Association for Cancer Researchen_US


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