title: Multiple myeloma cells modify VEGF/IL-6 levels and osteogenic potential of bone marrow stromal cells via Notch/miR-223.
abstract: 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.
authors.affiliation: Department of Hematology, Oncology and Tumourimmunology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Rimma
authors.initials: R
authors.lastname: Berenstein
authors.affiliation: Department of Hematology, Oncology and Tumourimmunology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Nogai
authors.affiliation: Department of Hematology, Oncology and Tumourimmunology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Marlies
authors.initials: M
authors.lastname: Waechter
authors.affiliation: Department of Hematology, Oncology and Tumourimmunology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Blau
authors.affiliation: Department of Hematology, Oncology and Tumourimmunology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Kuehnel
authors.affiliation: Department of Hematology, Oncology and Tumourimmunology, Helios Clinic Berlin-Buch, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schmidt-Hieber
authors.affiliation: Department of Hematology, Oncology and Tumourimmunology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Kunitz
authors.affiliation: Department of Hematology, Oncology and Tumourimmunology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pezzutto
authors.affiliation: Department of Hematology, Oncology and Tumourimmunology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.affiliation: Department of Hematology, Oncology and Tumourimmunology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Igor Wolfgang
authors.initials: IW
authors.lastname: Blau
mesh_terms: D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D000072101:Jagged-2 Protein / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010012:Osteogenesis; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D000072101:Jagged-2 Protein; D035683:MicroRNAs; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C525067:MIR223, human
keywords: bone marrow stromal cells; jagged-2; miR-223; multiple myeloma; notch