PAI-1, a target gene of miR-143, regulates invasion and metastasis by upregulating MMP-13 expression of human osteosarcoma

Mio Hirahata, Mitsuhiko Osaki, Yusuke Kanda, Yui Sugimoto, Yusuke Yoshioka, Nobuyoshi Kosaka, Fumitaka Takeshita, Tomohiro Fujiwara, Akira Kawai, Hisao Ito, Takahiro Ochiya, Futoshi Okada

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42 Citations (Scopus)

Abstract

Despite recent improvements in the therapy for osteosarcoma, 30-40% of osteosarcoma patients die of this disease, mainly due to its lung metastasis. We have previously reported that intravenous injection of miR-143 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-143 in the metastasis of human osteosarcoma cells. We identified plasminogen activator inhibitor-1 (PAI-1) as a direct target gene of miR-143. To determine the role of PAI-1 in human osteosarcoma cells, siRNA was transfected into 143B cells for knockdown of PAI-1 expression. An in vitro study showed that downregulation of PAI-1 suppressed cell invasion activity, but not proliferation. Moreover, injection of PAI-1 siRNA into a primary lesion in the osteosarcoma mouse model inhibited lung metastasis compared to control siRNA-injected mice, without influencing the proliferative activity of the tumor cells. Subsequent examination using 143B cells revealed that knockdown of PAI-1 expression resulted in downregulation of the expression and secretion of matrix metalloproteinase-13 (MMP-13), which is also a target gene of miR-143 and a proteolytic enzyme that regulates tumor-induced osteolysis. Immunohistochemical analysis using clinical samples showed that higher miR-143 expressing cases showed poor expression of PAI-1 in the primary tumor cells. All such cases belonged to the lung metastasis-negative group. Moreover, the frequency of lung metastasis-positive cases was significantly higher in PAI-1 and MMP-13 double-positive cases than in PAI-1 or MMP-13 single-positive or double-negative cases (P < 0.05). These results indicated that PAI-1, a target gene of miR-143, regulates invasion and lung metastasis via enhancement of MMP-13 expression and secretion in human osteosarcoma cells, suggesting that these molecules could be potential therapeutic target genes for preventing lung metastasis in osteosarcoma patients.

Original languageEnglish
Pages (from-to)892-902
Number of pages11
JournalCancer medicine
Volume5
Issue number5
DOIs
Publication statusPublished - May 1 2016

Keywords

  • MMP-13
  • Metastasis
  • Osteosarcoma
  • PAI-1
  • miR-143

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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  • Cite this

    Hirahata, M., Osaki, M., Kanda, Y., Sugimoto, Y., Yoshioka, Y., Kosaka, N., Takeshita, F., Fujiwara, T., Kawai, A., Ito, H., Ochiya, T., & Okada, F. (2016). PAI-1, a target gene of miR-143, regulates invasion and metastasis by upregulating MMP-13 expression of human osteosarcoma. Cancer medicine, 5(5), 892-902. https://doi.org/10.1002/cam4.651