miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors
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Camille Jacques1,2, Lidia Rodriguez Calleja1,2, Marc Baud’huin1,2,3, Thibaut Quillard1,2, Dominique Heymann1,2,3, François Lamoureux1,2 and Benjamin Ory1,2
1 INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France
2 Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Nantes, France
3 Nantes University Hospital, Nantes, France
Benjamin Ory, email:
Keywords: chemoresistance, microRNAs, p73
Received: June 30, 2016 Accepted: July 14, 2016 Published: July 29, 2016
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.
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