Abstract 2028: RUNX3 knockdown inhibited oral cancer-induced bone destruction via reducing TGF-β-dependent responses

Abstract

Abstract Oral cancer ranks among the top 10 commonly diagnosed cancers. It easily invades underlying jaw bones and causes severe psychological and physical problems. When oral cancer cells infiltrate into jaw bones, survival rate of the patient is significantly decreased. Therefore, attention has been focused on molecular diagnostics and targeted therapy for oral cancer-induced bone destruction. However, there remains a lack of reliable biomarkers that can distinguish between bone-invasive and non-invasive oral cancers despite the recent advances in the field. The Runt domain transcription factor, RUNX3, has been found to be a tumor suppressor in many cancers through promoting transforming growth factor-β (TGF-β)-induced growth inhibition. However, the role of RUNX3 in oral cancer remains controversial. Here, we investigated whether RUNX3 has a critical role in oral cancer-induced bone destruction. In mice inoculated with RUNX3 knockdown oral cancer cells, tumor growth and bone destruction were significantly reduced. In oral cancer cells, RUNX3 knockdown significantly reduced cell viability in TGF-β-stimulated cells compared to unstimulated cells. Cell cycle analysis revealed that RUNX3 knockdown induced G1-specific cell-cycle arrest in the cancer cells without TGF-β treatment but G2-specific cell-cycle arrest in response to TGF-β treatment. RUNX3 knockdown inhibited cell migration and invasion in the absence or presence of TGF-β by changing both basal and TGF-β-induced level of epithelial-to-mesenchymal transition-related proteins. Furthermore, RUNX3 knockdown reduced parathyroid hormone-like protein expression, a major osteolytic factor, in oral cancer cells with or without TGF-β. We confirmed that RUNX3 knockdown in cancer cells decreased receptor activator of nuclear factor-kappaB ligand/osteoprotegerin ratio in osteoblastic hFOB1.19 cells treated with cancer cell-derived conditioned media. In summary, RUNX3 promotes oral cancer-induced bone destruction by enhancing interactions between cancer cells and bone cells as well as promoting malignant behavior of cancer cells. Therefore, RUNX3 may be a useful biomarker and potential therapeutic target for bone invasion of oral cancer. Citation Format: Junhee Park, Won-Yoon Chung, Kwang-Kyun Park. RUNX3 knockdown inhibited oral cancer-induced bone destruction via reducing TGF-β-dependent responses. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2028. doi:10.1158/1538-7445.AM2015-2028