Abstract 5036: Oncogenic role of Runx2 in the development of osteosarcoma.
Authors: Roos Alison , Yustein Jason T. , Donehower Larry 
Published: August 2014

Osteosarcoma (OS) is a potentially fatal bone malignancy principally affecting adolescents or young adults, and comprises about 3-4% of all pediatric tumors. Although the overall survival rate has approached 70% in patients with localized disease, outcomes are still inferior compared to most other pediatric malignancies and significant improvements have been difficult to obtain over the past 20 years. Current treatment for OS includes a combination of neoadjuvant chemotherapy and surgery, with patients being monitored for recurrence following treatment. The etiology of OS is not well defined; however, most OS tumors arise sporadically, and exhibit high genome instability and chromosomal abnormalities. One gene often found abnormally expressed in osteosarcoma is the transcription factor Runx2. Runx2 is the master regulatory protein of bone development, and activates the transcription of the genes necessary for osteoblast differentiation. Due to this obvious importance in normal bone development, we have hypothesized that Runx2 also has a pronounced role in osteosarcoma development and progression. Evidence to support this hypothesis include: (1) a report that Runx2 was the most significantly gained gene in copy number, resulting in a 9-fold over-expression in human osteosarcoma tumors; (2) patients with tumors expressing higher amounts of Runx2 have an overall poorer survival rate. Dysregulation of Runx2 results in constitutively high protein levels, however, the consequence of over-expression of Runx2 in osteosarcoma remains unclear. Our studies have focused on investigating the biological and functional role of Runx2 in OS. We have shown that the transcriptional activity of Runx2 is increased in osteosarcoma cells when compared to normal osteoblasts. Additionally, we have shown that the knockdown of Runx2 results in reduced OS cell and tumor growth in vitro and in vivo, respectively. Our functional data is corroborated by gene expression analysis, which shows Runx2 regulates multiple cellular pathways involved in cell cycle regulation, cell death, and proliferation. Moreover, our gene expression analysis reveals that Runx2 regulates pathways involved in drug metabolism, and we have shown that knockdown of Runx2 sensitizes cells to treatment with chemotherapeutics. We have provided a mechanism for the dox-induced apoptosis in our Runx2 knockdown, and have shown that c-Myc plays a role in the activation of caspase-3 after dox treatment, and inhibition of c-Myc results in a significant decrease in apoptosis in shRunx2 cells when compared to control cells. Thus, we have shown a novel role chemoprotective role for Runx2 in OS, and suggest that inhibitors of Runx2 are an encouraging therapeutic prospect for patients with OS.

Citation Format: Alison Roos, Jason T. Yustein, Larry Donehower. Oncogenic role of Runx2 in the development of osteosarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5036. doi:10.1158/1538-7445.AM2013-5036

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.