Oncotarget

Research Papers:

MicroRNA-375/SEC23A as biomarkers of the in vitro efficacy of vandetanib

Sandra Lassalle, Joséphine Zangari, Alexandra Popa, Marius Ilie, Véronique Hofman, Elodie Long, Martine Patey, Frédérique Tissier, Geneviève Belléannée, Hélène Trouette, Bogdan Catargi, Isabelle Peyrottes, Jean-Louis Sadoul, Olivier Bordone, Christelle Bonnetaud, Catherine Butori, Alexandre Bozec, Nicolas Guevara, José Santini, Imène Sarah Hénaoui, Géraldine Lemaire, Olivier Blanck, Philippe Vielh, Pascal Barbry, Bernard Mari, Patrick Brest and Paul Hofman _

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Oncotarget. 2016; 7:30461-30478. https://doi.org/10.18632/oncotarget.8458

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Abstract

Sandra Lassalle1,2,3,4,5,*, Joséphine Zangari2,3,5,*, Alexandra Popa3,5,6, Marius Ilie1,2,3,4,5, Véronique Hofman1,2,3,4,5, Elodie Long1,2,3,4,5, Martine Patey7, Frédérique Tissier8, Geneviève Belléannée9, Hélène Trouette9, Bogdan Catargi10, Isabelle Peyrottes5,11, Jean-Louis Sadoul12, Olivier Bordone4,5, Christelle Bonnetaud4,5, Catherine Butori1,5, Alexandre Bozec2,3,5,13, Nicolas Guevara5,13, José Santini5,13, Imène Sarah Hénaoui3,6, Géraldine Lemaire14, Olivier Blanck14, Philippe Vielh15, Pascal Barbry3,5,6, Bernard Mari3,5,6,*, Patrick Brest2,3,5,*, Paul Hofman1,2,3,4,5,*

 1Centre Hospitalier Universitaire de Nice, Laboratory of Clinical and Experimental Pathology, Nice, France

 2Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081/CNRS UMR7284, Nice, France

 3University of Nice Sophia-Antipolis, Nice, France

 4Centre Hospitalier Universitaire de Nice, Hospital Integrated Biobank (BB 0033-00025), Nice, France

 5Fédération Hospitalo-Universitaire “OncoAge”, University of Nice Sophia Antipolis, Nice, France

 6Institut de Pharmacologie Moléculaire et Cellulaire IPMC, CNRS UMR7275, Sophia-Antipolis, France

 7Hôpital Universitaire de Reims - Hôpital Robert Debré, Department of Pathology, Institut Jean Godinot, Reims, France

 8Assistance Publique - Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Laboratory of Pathology, Paris, France

 9Centre Hospitalier Universitaire de Bordeaux, Hôpital Universitaire de Pessac-Haut Lévêque, Laboratory of Pathology, Pessac, France

10Centre Hospitalier Universitaire de Bordeaux, Department of Endocrinology, Pessac, France

11Centre Antoine Lacassagne, Laboratory of Pathology, Nice, France

12Centre Hospitalier Universitaire de Nice, Hôpital de l’Archet, Department of Endocrinology, Nice, France

13Centre Antoine Lacassagne, Head and Neck Institute, Surgery and Otorhinolaryngology Department, Nice, France

14Bayer CropScience SA, Research Center, Sophia Antipolis, Valbonne, France

15Institut Gustave Roussy, Translational Research Laboratory, Department of Pathology, Villejuif, France

*These authors have contributed equally to this work

Correspondence to:

Paul Hofman, email: [email protected]

Keywords: microRNA, medullary thyroid carcinoma, microRNA-375, treatment, vandetanib

Received: November 25, 2015     Accepted: March 10, 2016     Published: March 29, 2016

ABSTRACT

In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib.

Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.


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