title: MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression.
abstract: Pulmonary metastases are the main cause of death in patients with osteosarcoma, however, the molecular mechanisms of metastasis are not well understood. To detect lung metastasis-related microRNA (miRNA) in human osteosarcoma, we compared parental (HOS) and its subclone (143B) human osteosarcoma cell lines showing lung metastasis in a mouse model. miR-143 was the most downregulated miRNA (P < 0.01), and transfection of miR-143 into 143B significantly decreased its invasiveness, but not cell proliferation. Noninvasive optical imaging technologies revealed that intravenous injection of miR-143, but not negative control miRNA, significantly suppressed lung metastasis of 143B (P < 0.01). To search for miR-143 target mRNA in 143B, microarray analyses were performed using an independent RNA pool extracted by two different comprehensive miR-143-target mRNA collecting systems. Western blot analyses revealed that MMP-13 was mostly protein downregulated by miR-143. Immunohistochemistry using clinical samples clearly revealed MMP-13-positive cells in lung metastasis-positive cases, but not in at least three cases showing higher miR-143 expression in the no metastasis group. Taken together, these data indicated that the downregulation of miR-143 correlates with the lung metastasis of human osteosarcoma cells by promoting cellular invasion, probably via MMP-13 upregulation, suggesting that miRNA could be used to develop new molecular targets for osteosarcoma metastasis.
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan. osamitsu@med.tottori-u.ac.jp
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Osaki
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Takeshita
authors.forename: Yui
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kosaka
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Eisuke
authors.initials: E
authors.lastname: Kobayashi
authors.forename: Tesshi
authors.initials: T
authors.lastname: Yamada
authors.forename: Akira
authors.initials: A
authors.lastname: Kawai
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Inoue
authors.forename: Hisao
authors.initials: H
authors.lastname: Ito
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D012516:Osteosarcoma / Q000150:complications*; D016133:Polymerase Chain Reaction
chemical_list: D035683:MicroRNAs; C059821:atelocollagen; D003094:Collagen; D053509:Matrix Metalloproteinase 13