Abstract 300: Blockage of OPN induction via HGF/cMET signaling in multiple myeloma cells suppresses both MMP9 expression and RUNX2 expression of BMSCs associating with bone erosion of MM patients

Abstract

Abstract Dynamic interaction between multiple myeloma cells (MM) and bone marrow stromal cells plays critical roles in progression of MM. Hepatocyte growth factor (HGF), one of these factors, as a c-Met ligand, activates mitogenic activation protein kinase (MAPK). OPN binds with integrins and CD44 variants and activates cell signaling involved in invasiveness, angiogenesis and bone remodeling. Increasing lines of evidence provide that HGF and OPN, respectively, associate with the progression of MM. However, the role of HGF in MM largely remains unknown. In bone marrow serum of MM patients, HGF expression correlated with OPN expression (p=0,0095), suggesting that HGF derived from bone marrow stromal cells stimulates OPN expression in MM cells. Firstly, we found that expression levels of OPN in HFG-treated MM cells (fraction of CD138+ cells) obtained from MM patients was higher than either HFG-treated bone marrow stromal cells or HFG-treated MM cells (fraction of CD138- cells). Also, induction of DKK1 by HGF, suggesting the inhibition of osteogenesis, was found in U266 cells and RPMI8226, Both HGF-mediated MAPK and PI3K/AKT results in activating NF-kB and increasing OPN expression and DKK1. Those expressions were effectively down-regulated in U266 cells transfected with shRNA c-MET. RUNX2 mRNA and MMP-9 mRNA was increased in bone marrow stromal cells (BMSCs) treated with OPN. In addition, combined cMET inhibitor and PI3K inhibitor effectively inhibited the RUNX2 and the MMP9 mRNA expression in both OPN alone treatment and co-treatment with OPN and HGF in BMSCs. Taken together, since Induction of OPN and DKK1 by HGF in MM cells could be one of the major factors for the progression of MM through interaction of MM cells and BMSCs, blockage of HGF/cMET signaling leading to increasing levels of OPN and DKK1 may help to prevent from progressing bone erosion of MM patients. 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 300. doi:1538-7445.AM2012-300