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We have previously reported that intravenous injection of miR\u2010143 significantly suppresses lung metastasis of human osteosarcoma cells (143B) in a mouse model. In this study, we examined the biological role and mechanism of miR\u2010143 in the metastasis of human osteosarcoma cells. We identified plasminogen activator inhibitor\u20101 (<jats:styled-content style=\"fixed-case\">PAI<\/jats:styled-content>\u20101) as a direct target gene of miR\u2010143. To determine the role of <jats:styled-content style=\"fixed-case\">PAI<\/jats:styled-content>\u20101 in human osteosarcoma cells, si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> was transfected into 143B cells for knockdown of <jats:styled-content style=\"fixed-case\">PAI<\/jats:styled-content>\u20101 expression. An in vitro study showed that downregulation of <jats:styled-content style=\"fixed-case\">PAI<\/jats:styled-content>\u20101 suppressed cell invasion activity, but not proliferation. Moreover, injection of <jats:styled-content style=\"fixed-case\">PAI<\/jats:styled-content>\u20101 si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> into a primary lesion in the osteosarcoma mouse model inhibited lung metastasis compared to control si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010injected mice, without influencing the proliferative activity of the tumor cells. Subsequent examination using 143B cells revealed that knockdown of <jats:styled-content style=\"fixed-case\">PAI<\/jats:styled-content>\u20101 expression resulted in downregulation of the expression and secretion of matrix metalloproteinase\u201013 (<jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\u201013), which is also a target gene of miR\u2010143 and a proteolytic enzyme that regulates tumor\u2010induced osteolysis. Immunohistochemical analysis using clinical samples showed that higher miR\u2010143 expressing cases showed poor expression of <jats:styled-content style=\"fixed-case\">PAI<\/jats:styled-content>\u20101 in the primary tumor cells. All such cases belonged to the lung metastasis\u2010negative group. Moreover, the frequency of lung metastasis\u2010positive cases was significantly higher in <jats:styled-content style=\"fixed-case\">PAI<\/jats:styled-content>\u20101 and <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\u201013 double\u2010positive cases than in <jats:styled-content style=\"fixed-case\">PAI<\/jats:styled-content>\u20101 or <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\u201013 single\u2010positive or double\u2010negative cases (<jats:italic>P\u00a0<\/jats:italic>&lt;<jats:italic>\u00a0<\/jats:italic>0.05). These results indicated that <jats:styled-content style=\"fixed-case\">PAI<\/jats:styled-content>\u20101, a target gene of miR\u2010143, regulates invasion and lung metastasis via enhancement of <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\u201013 expression and secretion in human osteosarcoma cells, suggesting that these molecules could be potential therapeutic target genes for preventing lung metastasis in osteosarcoma patients.<\/jats:p>","DOI":"10.1002\/cam4.651","type":"journal-article","created":{"date-parts":[[2016,1,28]],"date-time":"2016-01-28T07:33:11Z","timestamp":1453966391000},"page":"892-902","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["<scp>PAI<\/scp>\u20101, a target gene of miR\u2010143, regulates invasion and metastasis by upregulating <scp>MMP<\/scp>\u201013 expression of human osteosarcoma"],"prefix":"10.1002","volume":"5","author":[{"given":"Mio","family":"Hirahata","sequence":"first","affiliation":[{"name":"Division of Pathological Biochemistry Department of Biomedical Sciences Faculty of Medicine Tottori University  86 Nishi\u2010cho Yonago Tottori 683\u20108503 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuhiko","family":"Osaki","sequence":"additional","affiliation":[{"name":"Division of Pathological Biochemistry Department of Biomedical Sciences Faculty of Medicine Tottori University  86 Nishi\u2010cho Yonago Tottori 683\u20108503 Japan"},{"name":"Chromosome Engineering Research Center Tottori University  86 Nishi\u2010cho Yonago Tottori 683\u20108503 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Kanda","sequence":"additional","affiliation":[{"name":"Division of Pathological Biochemistry Department of Biomedical Sciences Faculty of Medicine Tottori University  86 Nishi\u2010cho Yonago Tottori 683\u20108503 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Division of Pathological Biochemistry Department of Biomedical Sciences Faculty of Medicine Tottori University  86 Nishi\u2010cho Yonago Tottori 683\u20108503 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Yoshioka","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Medicine National Cancer Center Research Institute National Cancer Center Hospital  5\u20101\u20101 Tsukiji Chuo\u2010ku Tokyo 104\u20100045 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyoshi","family":"Kosaka","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Medicine National Cancer Center Research Institute National Cancer Center Hospital  5\u20101\u20101 Tsukiji Chuo\u2010ku Tokyo 104\u20100045 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