Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression.
BACKGROUND
Activation of the Notch pathway has been reported in various types of cancers. However, the role of the hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) in osteosarcoma is unknown. We examined the function of HEY1 in osteosarcoma.


METHODS
Expression of HEY1 was studied in human osteosarcoma. The effects of HEY1 in osteosarcoma were evaluated in vitro and in a xenograft model. Moreover, we examined the function of matrix metallopeptidase 9 (MMP9) as a downstream effector of HEY1.


RESULTS
HEY1 was upregulated in human osteosarcoma. Knockdown of HEY1 inhibited the invasion of osteosarcoma cell lines. In contrast, the forced expression of HEY1 increased the invasion of mesenchymal stem cell. In addition, lung metastases were significantly inhibited by the knockdown of HEY1. We found that MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells. Knockdown of HEY1 decreased the expression of MMP9. Addition of MMP9 rescued the invasion of osteosarcoma cells that had been rendered less invasive by knockdown of HEY1 expression.


CONCLUSIONS
Our findings suggested that HEY1 augmented the metastasis of osteosarcoma via upregulation of MMP9 expression. Therefore, inhibition of HEY1 may be a novel therapeutic strategy for preventing osteosarcoma metastasis.
Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Tsuru
The Near-Future Locomotor Organ Medicine Creation Course (Kusunoki Kai), Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Setoguchi
Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Matsunoshita
Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Nagao-Kitamoto
Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Nagano
Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Yokouchi
Department of Medical Joint Materials, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Maeda
Department of Medical Joint Materials, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Ishidou
Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Yamamoto
Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Komiya
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D020780:Matrix Metalloproteinase 9; C485631:HEY1 protein, human; C579270:MMP9 protein, human