Abstract B46: miRNA-193a-5p repression of p73 induces Cisplatine chemoresistance in bone-related sarcomas

Abstract

Abstract The purpose of this study is to better delineate the implication of the TAp73β/miRNA-193a-5p's axis in the Cisplatine chemoresistance, in the context of Osteosarcoma and Ewing Sarcoma, the two most common Bone Sarcomas. The last decade's improvement in the biomedical research field has widely contributed to improve the Bone Sarcomas outcome. Among the arsenal of chemotherapeutic-drugs currently used in those pathologies, the Cisplatine is a very common therapeutic option. Unfortunately, chemoresistance against this drug remains, often leading to the development of pulmonary metastases and the consequent relapse of the young patients suffering from these tumors. In the hope of eradicating these aggressive kinds of cancer, a better understanding of the molecular origins of such chemoresistance is needed. Through their gene's expression inhibitory role, the implication of the miRNAs in the Bone Sarcomas' chemoresistance is already clearly established. Furthermore, it has previously been demonstrated that through targeting the p53-family member TAp73β, the miR-193a-5p is implicated in the Cisplatine resistance in a carcinoma model. Thus, the aim of this work is to assess if TAp73β is also a mediator of the Cisplatine-induced apoptosis in Bone Sarcomas and consequently, if its modulation by the miR-193a-5p could be implicated in the chemoresistance mechanisms against this drug. In addition, this study also strives to bring the proof of concept of miR-193a-5p's as a new therapeutic-target to potentiate the Cisplatine anti-tumor's effects in Bone Sarcomas and override chemoresistance. Our qRT-PCR and viability assays results reveal that human Osteosarcoma and Ewing Sarcoma cell lines express the miR-193a-5p and TAp73β at various levels and display different Cisplatine sensitivities. In addition, an interesting correlation was found between the Cisplatine IC50 values and the miR-193a-5p expression levels. In line with these results, we have also demonstrated for the first time in this model that Cisplatine represses the miR-193a-5p expression and consequently induces TAp73β and its target-genes. Through TAp73β expression level modulation, we validated its implication in both the apoptosis and the clonogenic capabilities of the Bone Sarcoma cells. Our cellular viability assays also confirm the predicted role of TAp73β-mediated Cisplatine-sensitivity. In the same way, we show that modulating the miR-193a-5p expression level through transient transfections with synthesis miRNAs (pre-miR) or their inhibitory counterparts (anti-miRs) has a functional impact on the Cisplatine sensitivity and the apoptosis-induction (caspase 3/7 activity assay, PARPs cleavage). In conclusion, our body of data confirms that through targeting TAp73β, the miRNA-193a-5p modulates the viability, the clonogenic capabilities and the Cisplatine-induced apoptosis in Bone Sarcoma cells. Such results shed light on the implication of the miR-193a-5p in the Bone Sarcomas' Cisplatine-chemoresistance and open the road to new therapeutic opportunities provided by targeting the miR-193a-5p/TAp73β axis in the context of these pediatric cancers. In a fundamental approach, studying the Cisplatine-resistance might lead to better understand the role of miRNAs in therapeutic resistance. However, this miRNAs could also be used as “chemo-sensitizer” molecule in this context, improving the Bone Sarcoma outcome. Citation Format: Camille Jacques, François Lamoureux, Marc Baud'huin, Lidia Rodriguez Calleja, Dominique Heymann, Benjamin Ory. miRNA-193a-5p repression of p73 induces Cisplatine chemoresistance in bone-related sarcomas. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr B46.