Functional analysis of membrane-anchored proteins in RCC bone metastasis and development of new targeted treatment

• Project/Area Number: 15K10598
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: University of Miyazaki
• Principal Investigator: Mukai Shoichiro 宮崎大学, 医学部, 准教授 (10315369)
• Co-Investigator(Kenkyū-buntansha): 賀本 敏行 宮崎大学, 医学部, 教授 (00281098) ; 片岡 寛章 宮崎大学, 医学部, 教授 (10214321) ; 杉江 悟 宮崎大学, 医学部, その他 (50626140) ; 山崎 浩司 宮崎大学, 医学部, 医員 (30777355)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 腎細胞癌 / 骨転移 / MET / HAI-2 / マトリプテース / HGF / 膜結合型セリンプロテアーゼ / 膜結合型セリンプロテアーゼ制御因子

Outline of Final Research Achievements

In this study, we employed a mouse model of RCC bone metastasis to clarify the significance of the HGF/MET signaling axis and the regulator of HGF activator inhibitor type-2 (HAI-2). Luciferase-transfected 786-O cells were injected into the left cardiac ventricle of mice to prepare the mouse model of bone metastasis. The formation of bone metastasis was confirmed by whole-body bioluminescent imaging, and specimens were extracted. Expression of HGF/MET-related molecules was analyzed. As a result, expression of HGF and matriptase was increased in bone metastasis compared with control, while that of HAI-2 was decreased. Furthermore, we confirmed increased phosphorylation of MET in bone metastasis. The expression of matriptase was upregulated, and both invasiveness and motility were increased significantly by knockdown of HAI-2. The significance of ligand-dependent MET activation in RCC bone metastasis is considered, and HAI-2 may be an important regulator in this system.

Research Products

• [Presentation] HAI-2 regulates the growth of RCC cells in bone metastasis through suppression of matripatese (2018)
  • Author(s): Shoichiro Mukai
  • Organizer: The 34th Korea∸Japan Urological Congress
  • Int'l Joint Research
• [Presentation] 腎細胞癌におけるHGF/MET pathwayを介したマトリプテース及びHAIの骨転移抑制 (2018)
  • Author(s): 山崎浩司、永井崇敬、上別府豊治、中原梢、寺田直樹、向井尚一郎、賀本敏行
  • Organizer: 第27回 泌尿器分子細胞研究会
• [Presentation] HAI-2 regulates the invasive growth of RCC cells in bone metastasis through suppression of matriptase-induced HGF activation (2017)
  • Author(s): Koji Yamasaki, Kozue Nakahara, Takahiro Nagai, Toyoharu Kamibeppu, Takayuki Goto, Noboru Shibasaki, Hiromasa Sakamoto, Naoki Terada, Hiromasa Tsukino, Shoichiro Mukai, Yoshinobu Toda, Toshiyuki Kamoto
  • Organizer: 112th AUA annual meeting
  • Int'l Joint Research
• [Presentation] HAI-2 regulates the invasive growth of RCC cells in bone metastasis through suppression of matriptase-induced HGF activation (2017)
  • Author(s): 山崎浩司、向井尚一郎、賀本敏行
  • Organizer: AUA2017 米国泌尿器科学会総会
  • Place of Presentation: 米国 ボストン
  • Int'l Joint Research