Multiple myeloma cells modify VEGF/IL-6 levels and osteogenic potential of bone marrow stromal cells via Notch/miR-223

Bone marrow mesenchymal stromal cells (BMMSCs) represent a crucial component of multiple myeloma (MM) microenvironment supporting its progression and proliferation. Recently, microRNAs have become an important point of interest for research on micro‐environmental interactions in MM with some evidence of tumor supportive roles in MM. In this study, we examined the role of miR‐223 for MM support in BMMSCs of 56 patients with MM (MM‐BMMSCs). miR‐223 expression in MM‐BMMSCs was reduced by the presence of MM cells in vitro in a cell‐contact dependent manner compared to mono‐cultured MM‐BMMSCs. Co‐cultivation of MM cells and MM‐BMMSCs induced activation of notch amongst others via jagged‐2/notch‐2 leading to increased expression of Hes1, Hey2, or Hes5 in both cell types. Cultivation of MM‐BMMSCs with increasing levels of recombinant jagged‐2 reduced miR‐223 and increased Hes1 levels in a concentration‐dependent manner. Transient reduction of miR‐223 levels increased VEGF and IL‐6 expression and secretion by MM‐BMMSCs. In addition, reduction of miR‐223 degraded the osteogenic differentiation potential of MM‐BMMSCs. Inhibition of notch signaling induced apoptosis in both MM cells and MM‐BMMSCs. Furthermore, it increased miR‐223 levels and reduced expression of VEGF and IL‐6 by both cell types. These data provide first evidence that miR‐223 participates in different MM supporting pathways in MM‐BMMSCs inlcuding regulation of cytokine secretion and expression as well as osteogenic differentiation of MM‐BMMSCs. More insights on the role of miR‐223 in MM‐BMMSCs and in cellular interactions between MM cells and MM‐BMMSCs could provide starting points for a more efficient anti‐myeloma treatment by targeting of notch signaling. © 2015 Wiley Periodicals, Inc.