Research Papers:
Identification of thyroid tumor cell vulnerabilities through a siRNA-based functional screening
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Abstract
Maria Chiara Anania1,*, Fabio Gasparri2,*, Elena Cetti1, Ivan Fraietta2, Katia Todoerti3, Claudia Miranda1, Mara Mazzoni1, Claudia Re2, Riccardo Colombo2, Giorgio Ukmar2, Stefano Camisasca2, Sonia Pagliardini1, Marco A. Pierotti4, Antonino Neri5,6, Arturo Galvani2, Angela Greco1
1Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
2Cell Biology Department, Nerviano Medical Sciences Srl, Nerviano (MI), Italy
3Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy
4Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
5Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
6Hematology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
*These authors have contributed equally to this work
Correspondence to:
Angela Greco, e-mail: [email protected]
Fabio Gasparri, e-mail: [email protected]
Keywords: thyroid cancer, non-oncogene addiction, MASTL, Cyclin D1, COPZ1
Received: June 06, 2015 Accepted: September 14, 2015 Published: September 25, 2015
ABSTRACT
The incidence of thyroid carcinoma is rapidly increasing. Although generally associated with good prognosis, a fraction of thyroid tumors are not cured by standard therapy and progress to aggressive forms for which no effective treatments are currently available. In order to identify novel therapeutic targets for thyroid carcinoma, we focused on the discovery of genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same degree for the viability of normal cells (non-oncogene addiction paradigm). We screened a siRNA oligonucleotide library targeting the human druggable genome in thyroid cancer BCPAP cell line in comparison with immortalized normal human thyrocytes (Nthy-ori 3–1). We identified a panel of hit genes whose silencing interferes with the growth of tumor cells, while sparing that of normal ones. Further analysis of three selected hit genes, namely Cyclin D1, MASTL and COPZ1, showed that they represent common vulnerabilities for thyroid tumor cells, as their inhibition reduced the viability of several thyroid tumor cell lines, regardless the histotype or oncogenic lesion. This work identified non-oncogenes essential for sustaining the phenotype of thyroid tumor cells, but not of normal cells, thus suggesting that they might represent promising targets for new therapeutic strategies.
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