Loss of miR-198 and -206 during primary tumor progression enables metastatic dissemination in human osteosarcoma
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Steven Georges1,2,*, Lidia Rodriguez Calleja1,2,*, Camille Jacques1,2,*, Melanie Lavaud1,2, Brice Moukengue1,2, Fernando Lecanda3, Thibaut Quillard1,2, Marta Tellez Gabriel1,6, Pierre-François Cartron4,5,6,7, Marc Baud’huin1,2, François Lamoureux1,2, Dominique Heymann4,6 and Benjamin Ory1,2,7
1INSERM, UMR-S 1238, Nantes 44035, France
2PhyOs, Sarcomes Osseux et Remodelage des Tissus Calcifiés, Université de Nantes, Nantes 44035, France
3Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medic al Research, University of Navarra, Pamplona, Navarra 31008, Spain
4Equipe Apoptose et Progression Tumorale, Centre de Recherche en Cancérologie et Immunologie Nantes Angers, CRCINA, INSERM, U1232, Université de Nantes, Université d'Angers, Nantes 44035, France
5LaBCT, Institut de Cancérologie de l'Ouest, Saint Herblain 44800, France
6European Associated Laboratory Sarcoma Research Unit, INSERM, University of Sheffield, Sheffield S10 2TN, UK
7Cancéropole Grand-Ouest, Réseau Epigénétique (RepiCGO), France
*These authors contributed equally to this work
Benjamin Ory, email: [email protected]
Keywords: osteosarcoma; microRNAs; metastasis; C-Met
Received: March 09, 2018 Accepted: October 23, 2018 Published: November 06, 2018
The metastatic dissemination is a complex multistep process by which tumor cells from a primary site enter into the systemic circulation to finally spread at distant sites. Even if this mechanism is rare at the tumor level, it remains the major cause of Osteosarcoma-patients’ relapse and mortality. MicroRNAs (miRNAs) have recently been described as novel epigenetics’ genes’ expression regulators actively implicated in cancer progression and dissemination. The understanding of their implication in the metastatic spreading could help clinicians to improve the outcome of osteosarcoma. We established the miRNA’s expression-profile between primary bone-tumors (PTs), circulating tumor cells (CTCs) and lung metastatic (META) samples from in vivo mice xenograft models. Our results show that the expression level of the miR-198 and -206 was decreased in META samples, in which the expression of the metastasis-related receptor C-Met was up-regulated. Those expression variations were validated in osteosarcoma patient biopsies from matching primary tumors and lung metastasis. We validated in vitro the endogenous miRNAs inhibitory effects on both migration and invasion, as well as we confirmed by luciferase assays that the C-Met receptor is one of their bona-fide targets. The anti-metastatic effect of these miRNAs was also validated in vivo, as their direct injections into the tumors reduce the number of lung-metastases and prolongs the overall survival of the treated animals. All together, our results suggest the absence of the miR-198 and -206 as powerful predictive biomarkers of the tumor cell dissemination and the rationale of their potential therapeutic use in the treatment of Osteosarcoma.
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