Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression

Research Project

Project/Area Number	25462341
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Orthopaedic surgery
Research Institution	Kagoshima University
Principal Investigator	Yamamoto Takuya 鹿児島大学, 医学部・歯学部附属病院, 講師 (40381157)
Co-Investigator(Kenkyū-buntansha)	SETOGUCHI Takao 鹿児島大学, 医歯学総合研究科, 特任准教授 (40423727) KOMIYA Setsuro 鹿児島大学, 医歯学域医学系, 教授 (30178371) NAGANO Satoshi 鹿児島大学, 医歯学域医学系, 准教授 (50373139)
Project Period (FY)	2013-04-01 – 2016-03-31
Project Status	Completed (Fiscal Year 2015)
Budget Amount *help	¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000) Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000) Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords	骨肉腫 / Notch / HEY1 / 転移 / 肺転移 / NOTCH / MMP9 / 浸潤
Outline of Final Research Achievements	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. 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. Our findings suggested that HEY1 augmented the metastasis of osteosarcoma via upregulation of MMP9 expression. Inhibition of HEY1 may be a novel therapeutic strategy for preventing osteosarcoma metastasis.