title: miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors.
abstract: Osteosarcoma and Ewing Sarcoma are the two most common types of Bone Sarcomas, principally localized at the long bones of the extremities and mainly affecting adolescents and young adults. Cisplatin is one of the current options in the therapeutic arsenal of drugs available to cure these aggressive cancers. Unfortunately, chemoresistance against this agent is still a major cause of patient relapse. Thus, a better understanding of the molecular pathways by which these drugs induce cancer cell death, together with a better delineation of the origins of chemoresistance are required to improve the success rate of current treatments. Furthermore, as p53 is frequently mutated in Bone Sarcomas, other pathways in these cancers must mediate drug-induced cell death. Here, we demonstrate for the first time that TAp73β, a p53-family protein, is implicated in Cisplatin-induced apoptosis of Bone Sarcomas'. Furthermore, while acquired resistance developed by cancer cells against such drugs can have multiple origins, it is now well accepted that epigenetic mechanisms involving microRNAs (miRNAs) are one of them. We show that miRNA-193a-5p modulates the viability, the clonogenic capacity and the Cisplatin-induced apoptosis of the Bone Sarcoma cells through inhibition of TAp73β. Collectively, these results shed light on the involvement of miR-193a-5p in Cisplatin chemoresistance of Bone Sarcomas', and they open the road to new therapeutic opportunities provided by targeting the miR-193a-5p/TAp73β axis in the context of these malignancies.
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Jacques
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Lidia Rodriguez
authors.initials: LR
authors.lastname: Calleja
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Nantes, France.|Nantes University Hospital, Nantes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Baud'huin
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Quillard
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Nantes, France.|Nantes University Hospital, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: François
authors.initials: F
authors.lastname: Lamoureux
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ory
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D000072160:Tumor Protein p73 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin
keywords: chemoresistance; microRNAs; p73