title: Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells.
abstract: Valproic acid, a histone deacetylase inhibitor, increases the expression of cell surface MHC class I-related chain molecules (MICs) A and B (MICA and B) in osteosarcoma cells and decreases their secretion of soluble MICA and MICB, which are produced by the proteolytic cleavage of cell surface MICs. Osteosarcoma cells have been reported to produce high levels of matrix metalloproteinase (MMP)-2 and -9. In this study, we investigated the involvement of MMP-2 and -9 in the inhibitory action of valproic acid (VPA) on the proteolytic cleavage of cell surface MICs using the U-2 OS and SaOS-2 osteosarcoma cell lines. VPA caused a marked decrease in the expression of MMP-9 mRNA in the U-2 OS and SaOS-2 cells and in the expression of MMP-2 mRNA in the U-2 OS cells, but only a slight decrease in the expression of MMP-2 mRNA in the SaOS-2 cells. The transfection of small interfering RNA (siRNA) for MMP-9 decreased the secretion of soluble MICA and MICB by both U-2 OS and SaOS-2 cells, but that of siRNA for MMP-2 did not. The present study therefore demonstrates that the downregulation of MMP-9 mRNA by VPA plays a role in the inhibitory action of VPA on the secretion of soluble MICA and MICB in osteosarcoma cells.
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan. yamanegi@hyo-med.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanegi
authors.forename: Junko
authors.initials: J
authors.lastname: Yamane
authors.forename: Kenta
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohyama
authors.forename: Keiji
authors.initials: K
authors.lastname: Nakasho
authors.forename: Naoko
authors.initials: N
authors.lastname: Yamada
authors.forename: Masaki
authors.initials: M
authors.lastname: Hata
authors.forename: Satoru
authors.initials: S
authors.lastname: Fukunaga
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Futani
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Terada
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins / Q000096:biosynthesis; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D004151:Dipeptides; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; C098080:MICB antigen; D008565:Membrane Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014635:Valproic Acid; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9