Abstract 3158: MicroRNA signatures associate with pathogenesis and progression of osteosarcoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Osteosarcoma is the most common sarcoma in the skeleton, but remains elusive with regard to molecular etiology. MicroRNAs (miRNAs) have demonstrated far-reaching effects on the cellular biology of development as well as oncogenesis. Here we identify an miRNA signature reflecting the pathogenesis of conventional (osteoblastic/fibroblastic) osteosarcoma from surgically procured samples from human patients. The signature includes high expression of miR-181a, miR-181b, and miR-181c as well as reduced expression of miR-29b, miR-16, and miR-142-5p. Osteosarcomas of varied histology subtype co-localized on unsupervised hierarchical clustering, suggesting that the signature profile relates to oncogenesis itself, rather than simply a differentiation phenotype. We also demonstrated that miR-181b and miR-29b exhibit restricted expression to distinct cell populations in the tumor tissue. Further, higher expression of miR-27a and miR-181c* in pre-treatment biopsy samples characterized patients who developed clinical metastatic disease. In addition, higher expression of miR-451 and miR-15b in pre-treatment samples correlated with subsequent positive response to chemotherapy. In vitro functional validation of miR-16 and miR-27a confirmed opposing roles in human osteoblast and osteosarcoma cell lines. Furthermore, predicted target genes for miR-16 and miR-27a were confirmed as down-regulated by real-time PCR. Affymetrix array profiling of cDNAs from osteosarcoma specimens and controls were interrogated according to predicted targets of miR-16, miR142-5p, miR-29b, miR-181a/b, and miR-27a. This analysis revealed positive and negative correlations highlighting pathways of known importance to osteosarcoma, as well as novel genes. Thus, our findings establish miRNA signatures associated with pathogenesis, metastasis, and responsiveness to treatment in 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 3158. doi:1538-7445.AM2012-3158