title: Oncogenic RAS-induced senescence in human primary thyrocytes: molecular effectors and inflammatory secretome involved.
abstract: Oncogene-induced senescence (OIS) is a robust and sustained antiproliferative response to oncogenic stress and constitutes an efficient barrier to tumour progression. We have recently proposed that OIS may be involved in the pathogenesis of thyroid carcinoma by restraining tumour progression as well as the transition of well differentiated to more aggressive variants. Here, an OIS inducible model was established and used for dissecting the molecular mechanisms and players regulating senescence in human primary thyrocytes. We show that oncogenic RAS induces senescence in thyrocytes as judged by changes in cell morphology, activation of p16INK4a and p53/p21CIP1 tumour suppressor pathways, senescence-associated β-galactosidase (SA-β-Gal) activity, and induction of proinflammatory components including IL-8 and its receptor CXCR2. Using RNA interference (RNAi) we demonstrate that p16INK4a is necessary for the onset of senescence in primary thyrocytes as its depletion rescues RAS-induced senescence. Furthermore, we found that IL-8/CXCR2 network reinforces the growth arrest triggered by oncogenic RAS, as its abrogation is enough to resume proliferation. Importantly, we observed that CXCR2 expression coexists with OIS markers in thyroid tumour samples, suggesting that CXCR2 contributes to senescence, thus limiting thyroid tumour progression.
authors.affiliation: Molecular Mechanism Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Vizioli
authors.affiliation: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK.
authors.forename: Joana
authors.initials: J
authors.lastname: Santos
authors.affiliation: Laboratory of Molecular Pathology, Department of Pathology, IRCCS Foundation - Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: Molecular Mechanism Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Mazzoni
authors.affiliation: Molecular Mechanism Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Anania
authors.affiliation: Molecular Mechanism Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Miranda
authors.affiliation: Molecular Mechanism Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Pagliardini
authors.affiliation: Scientific Directorate, IRCCS Foundation - Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.affiliation: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK. Senior co-authors.
authors.forename: Jesus
authors.initials: J
authors.lastname: Gil
authors.affiliation: Molecular Mechanism Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Senior co-authors.
authors.forename: Angela
authors.initials: A
authors.lastname: Greco
mesh_terms: D049109:Cell Proliferation; D048430:Cell Shape; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D011905:Genes, ras; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D034622:RNA Interference; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013961:Thyroid Gland / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; C508606:CXCL8 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018836:Inflammation Mediators; D016209:Interleukin-8; D023063:Receptors, Interleukin-8B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase; D015689:Oncogene Protein p21(ras)