title: MicroRNA-375/SEC23A as biomarkers of the in vitro efficacy of vandetanib.
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.
authors.affiliation: Centre Hospitalier Universitaire de Nice, Laboratory of Clinical and Experimental Pathology, Nice, France.|Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081/CNRS UMR7284, Nice, France.|University of Nice Sophia-Antipolis, Nice, France.|Centre Hospitalier Universitaire de Nice, Hospital Integrated Biobank (BB 0033-00025), Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lassalle
authors.affiliation: Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081/CNRS UMR7284, Nice, France.|University of Nice Sophia-Antipolis, Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.
authors.forename: Joséphine
authors.initials: J
authors.lastname: Zangari
authors.affiliation: University of Nice Sophia-Antipolis, Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.|Institut de Pharmacologie Moléculaire et Cellulaire IPMC, CNRS UMR7275, Sophia-Antipolis, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Popa
authors.affiliation: Centre Hospitalier Universitaire de Nice, Laboratory of Clinical and Experimental Pathology, Nice, France.|Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081/CNRS UMR7284, Nice, France.|University of Nice Sophia-Antipolis, Nice, France.|Centre Hospitalier Universitaire de Nice, Hospital Integrated Biobank (BB 0033-00025), Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.
authors.forename: Marius
authors.initials: M
authors.lastname: Ilie
authors.affiliation: Centre Hospitalier Universitaire de Nice, Laboratory of Clinical and Experimental Pathology, Nice, France.|Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081/CNRS UMR7284, Nice, France.|University of Nice Sophia-Antipolis, Nice, France.|Centre Hospitalier Universitaire de Nice, Hospital Integrated Biobank (BB 0033-00025), Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Hofman
authors.affiliation: Centre Hospitalier Universitaire de Nice, Laboratory of Clinical and Experimental Pathology, Nice, France.|Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081/CNRS UMR7284, Nice, France.|University of Nice Sophia-Antipolis, Nice, France.|Centre Hospitalier Universitaire de Nice, Hospital Integrated Biobank (BB 0033-00025), Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Long
authors.affiliation: Hôpital Universitaire de Reims - Hôpital Robert Debré, Department of Pathology, Institut Jean Godinot, Reims, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Patey
authors.affiliation: Assistance Publique - Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Laboratory of Pathology, Paris, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.affiliation: Centre Hospitalier Universitaire de Bordeaux, Hôpital Universitaire de Pessac-Haut Lévêque, Laboratory of Pathology, Pessac, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Belléannée
authors.affiliation: Centre Hospitalier Universitaire de Bordeaux, Hôpital Universitaire de Pessac-Haut Lévêque, Laboratory of Pathology, Pessac, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Trouette
authors.affiliation: Centre Hospitalier Universitaire de Bordeaux, Department of Endocrinology, Pessac, France.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Catargi
authors.affiliation: Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.|Centre Antoine Lacassagne, Laboratory of Pathology, Nice, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Peyrottes
authors.affiliation: Centre Hospitalier Universitaire de Nice, Hôpital de l'Archet, Department of Endocrinology, Nice, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Sadoul
authors.affiliation: Centre Hospitalier Universitaire de Nice, Hospital Integrated Biobank (BB 0033-00025), Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bordone
authors.affiliation: Centre Hospitalier Universitaire de Nice, Hospital Integrated Biobank (BB 0033-00025), Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Bonnetaud
authors.affiliation: Centre Hospitalier Universitaire de Nice, Laboratory of Clinical and Experimental Pathology, Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Butori
authors.affiliation: Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081/CNRS UMR7284, Nice, France.|University of Nice Sophia-Antipolis, Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.|Centre Antoine Lacassagne, Head and Neck Institute, Surgery and Otorhinolaryngology Department, Nice, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bozec
authors.affiliation: Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.|Centre Antoine Lacassagne, Head and Neck Institute, Surgery and Otorhinolaryngology Department, Nice, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guevara
authors.affiliation: Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.|Centre Antoine Lacassagne, Head and Neck Institute, Surgery and Otorhinolaryngology Department, Nice, France.
authors.forename: José
authors.initials: J
authors.lastname: Santini
authors.affiliation: University of Nice Sophia-Antipolis, Nice, France.|Institut de Pharmacologie Moléculaire et Cellulaire IPMC, CNRS UMR7275, Sophia-Antipolis, France.
authors.forename: Imène Sarah
authors.initials: IS
authors.lastname: Hénaoui
authors.affiliation: Bayer CropScience SA, Research Center, Sophia Antipolis, Valbonne, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Lemaire
authors.affiliation: Bayer CropScience SA, Research Center, Sophia Antipolis, Valbonne, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Blanck
authors.affiliation: Institut Gustave Roussy, Translational Research Laboratory, Department of Pathology, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vielh
authors.affiliation: University of Nice Sophia-Antipolis, Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.|Institut de Pharmacologie Moléculaire et Cellulaire IPMC, CNRS UMR7275, Sophia-Antipolis, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Barbry
authors.affiliation: University of Nice Sophia-Antipolis, Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.|Institut de Pharmacologie Moléculaire et Cellulaire IPMC, CNRS UMR7275, Sophia-Antipolis, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.affiliation: Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081/CNRS UMR7284, Nice, France.|University of Nice Sophia-Antipolis, Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brest
authors.affiliation: Centre Hospitalier Universitaire de Nice, Laboratory of Clinical and Experimental Pathology, Nice, France.|Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081/CNRS UMR7284, Nice, France.|University of Nice Sophia-Antipolis, Nice, France.|Centre Hospitalier Universitaire de Nice, Hospital Integrated Biobank (BB 0033-00025), Nice, France.|Fédération Hospitalo-Universitaire "OncoAge", University of Nice Sophia Antipolis, Nice, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D010880:Piperidines; D011799:Quinazolines; C512739:SEC23A protein, human; D033921:Vesicular Transport Proteins; C452423:vandetanib
keywords: medullary thyroid carcinoma; microRNA; microRNA-375; treatment; vandetanib