Abstract 1113: Role of the microRNA-23∼27∼24 clusters in osteosarcoma

Abstract

Abstract Osteosarcomas are rare but aggressive tumors that predominantly affect adolescents. These neoplasms of mesenchymal origin are biologically heterogeneous and produce immature osteoid or bone. The pathogenesis of osteosarcomas is poorly understood although defective osteogenic differentiation seems to play a key role. In order to elucidate the underlying molecular mechanisms, 16 osteosarcoma cell lines, 2 osteoblast cell lines and 45 osteosarcoma tumors were studied using a combination of high-throughput techniques such as microRNA (miRNA) and gene expression profiling, miRNA sequencing and array comparative genomic hybridization. Overexpression of the miRNA clusters miR-23a∼27a∼24-2 (19p13.13) and miR-23b∼27b∼24-1 (9q22.32) was identified in a subset of the osteosarcoma tumors and cell lines. Furthermore, quantitative RT-PCR revealed that the miR-23a and miR-23b clusters were downregulated during osteoblast differentiation of the osteosarcoma cell line HOS and overexpression of these miRNAs (by transient transfection of miRNA mimics) delayed osteoblast differentiation and matrix mineralization evaluated by alkaline phosphatase and Alizarin Red staining. Target gene identification experiments were then performed for each of the members of the miR-23a and miR-23b clusters. Gain of function (using miRNA mimics for exogenous expression) and loss of function (using antisense miRNAs to inhibit endogenous expression) experiments followed by downstream gene expression analysis identified several putative targets in osteosarcoma cell lines HOS and HuO3N1. The gene lists were highly enriched in targets (including differentiation genes) identified by TargetScan and other target prediction software. These results suggest that deregulation of the miR-23∼27∼24 clusters may play a role in defective osteogenic differentiation and osteosarcoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1113. doi:1538-7445.AM2012-1113