title: Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1.
abstract: Exosomes are small endosome-derived vesicles containing a wide range of functional proteins, mRNA, and miRNA. Exosomal miRNA from cancer cells helps modulate the microenvironment. In multiple myeloma (MM), the massive proliferation of malignant plasma cells causes hypoxia. To date, the majority of in vitro hypoxia studies of cancer cells have used acute hypoxic exposure (3-24 hours). Thus, we attempted to clarify the role of MM-derived exosomes in hypoxic bone marrow by using MM cells grown continuously in vitro under chronic hypoxia (hypoxia-resistant MM [HR-MM] cells). The HR-MM cells produced more exosomes than the parental cells under normoxia or acute hypoxia conditions, and miR-135b was significantly upregulated in exosomes from HR-MM cells. Exosomal miR-135b directly suppressed its target factor-inhibiting hypoxia-inducible factor 1 (FIH-1) in endothelial cells. Finally, exosomal miR-135b from HR-MM cells enhanced endothelial tube formation under hypoxia via the HIF-FIH signaling pathway. This in vitro HR myeloma cell model will be useful for investigating MM cell-endothelial cell interactions under hypoxic conditions, which may mimic the in vivo bone marrow microenvironment. Although tumor angiogenesis is regulated by various factors, exosomal miR-135b may be a target for controlling MM angiogenesis.
authors.affiliation: Department of Molecular Science, Tokyo Medical University, Tokyo, Japan; Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Umezu
authors.affiliation: Department of Pharmaceutical Health Care and Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tadokoro
authors.affiliation: Department of Hematology and Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
authors.forename: Kenko
authors.initials: K
authors.lastname: Azuma
authors.affiliation: Department of Hematology and.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Yoshizawa
authors.affiliation: Department of Molecular Science, Tokyo Medical University, Tokyo, Japan; Department of Hematology and.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ohyashiki
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
authors.forename: Junko H
authors.initials: JH
authors.lastname: Ohyashiki
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001808:Blood Vessels / Q000254:growth & development / Q000378:metabolism; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D055354:Exosomes / Q000235:genetics* / Q000648:ultrastructure; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D046529:Microscopy, Electron, Transmission; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009101:Multiple Myeloma / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; D008156:Luciferases; C439790:HIF1AN protein, human