title: TPL2 kinase is a suppressor of lung carcinogenesis.
abstract: Lung cancer is a heterogeneous disease at both clinical and molecular levels, posing conceptual and practical bottlenecks in defining key pathways affecting its initiation and progression. Molecules with a central role in lung carcinogenesis are likely to be targeted by multiple deregulated pathways and may have prognostic, predictive, and/or therapeutic value. Here, we report that Tumor Progression Locus 2 (TPL2), a kinase implicated in the regulation of innate and adaptive immune responses, fulfils a role as a suppressor of lung carcinogenesis and is subject to diverse genetic and epigenetic aberrations in lung cancer patients. We show that allelic imbalance at the TPL2 locus, up-regulation of microRNA-370, which targets TPL2 transcripts, and activated RAS (rat sarcoma) signaling may result in down-regulation of TPL2 expression. Low TPL2 levels correlate with reduced lung cancer patient survival and accelerated onset and multiplicity of urethane-induced lung tumors in mice. Mechanistically, TPL2 was found to antagonize oncogene-induced cell transformation and survival through a pathway involving p53 downstream of cJun N-terminal kinase (JNK) and be required for optimal p53 response to genotoxic stress. These results identify multiple oncogenic pathways leading to TPL2 deregulation and highlight its major tumor-suppressing function in the lung.
authors.affiliation: Molecular and Cellular Biology Laboratory, Division of Basic Sciences and Department of Pathology, University of Crete Medical School, 710 03 Heraklion, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Gkirtzimanaki
authors.forename: Kalliopi K
authors.initials: KK
authors.lastname: Gkouskou
authors.forename: Urszula
authors.initials: U
authors.lastname: Oleksiewicz
authors.forename: Georgios
authors.initials: G
authors.lastname: Nikolaidis
authors.forename: Dimitra
authors.initials: D
authors.lastname: Vyrla
authors.forename: Michalis
authors.initials: M
authors.lastname: Liontos
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Pelekanou
authors.forename: Dimitris C
authors.initials: DC
authors.lastname: Kanellis
authors.forename: Kostantinos
authors.initials: K
authors.lastname: Evangelou
authors.forename: Efstathios N
authors.initials: EN
authors.lastname: Stathopoulos
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gorgoulis
authors.forename: Triantafillos
authors.initials: T
authors.lastname: Liloglou
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
mesh_terms: D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000276:immunology / Q000503:physiopathology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C526503:MIRN370 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D018631:ras Proteins