Oncotarget

Research Papers:

Oncogenic RAS-induced senescence in human primary thyrocytes: molecular effectors and inflammatory secretome involved

Maria Grazia Vizioli _, Joana Santos, Silvana Pilotti, Mara Mazzoni, Maria Chiara Anania, Claudia Miranda, Sonia Pagliardini, Marco A. Pierotti, Jesus Gil and Angela Greco

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Oncotarget. 2014; 5:8270-8283. https://doi.org/10.18632/oncotarget.2013

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Abstract

Maria Grazia Vizioli1,2, Joana Santos2, Silvana Pilotti3, Mara Mazzoni1, Maria Chiara Anania1, Claudia Miranda1, Sonia Pagliardini1, Marco A. Pierotti4, Jesus Gil2,*, Angela Greco1,*

1 Molecular Mechanism Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

2 Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK

3 Laboratory of Molecular Pathology, Department of Pathology, IRCCS Foundation - Istituto Nazionale dei Tumori, Milan, Italy

4 Scientific Directorate, IRCCS Foundation - Istituto Nazionale dei Tumori, Milan, Italy

* Senior co-authors

Correspondence:

Angela Greco, email:

Jesus Gil, email:

Keywords: thyroid carcinoma; senescence; oncogenes; tumour suppressor; SASP

Received: March 10, 2014 Accepted: May 26, 2014 Published: May 26, 2014

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.


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PII: 2013