| Project/Area Number |
17K10973
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Kagoshima University |
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Principal Investigator |
Setoguchi Takao 鹿児島大学, 医歯学総合研究科, 客員研究員 (40423727)
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| Co-Investigator(Kenkyū-buntansha) |
小宮 節郎 鹿児島大学, 医歯学域医学系, 教授 (30178371)
永野 聡 鹿児島大学, 医歯学域医学系, 准教授 (50373139)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | UPS / 未分化多型肉腫 / HDAC阻害剤 / FOS-like antigen 1 / Neurotensin Receptor 1 / SR48692 / LBH589 / FOSL1 / ＵＰＳ / 未分化肉腫 / 未分類肉腫 / 分子標的 |
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| Outline of Final Research Achievements |
Undifferentiated pleomorphic sarcoma (UPS) is the second most common soft tissue sarcoma. We investigated the effects of Histone deacetylases (HDAC) inhibitor, LBH589,. LBH589 exhibits antitumor activities in UPS cell. Microarray identified the FOS-like antigen 1 (FOSL1) gene as a downregulated gene in response to LBH589. Knockdown of FOSL1 decreased UPS cell proliferation Next, we focused on neurotensin receptor 1 (NTSR1), which expression was changed by FOSL1 knockdown. Expression of NTSR1 messenger RNA was increased in UPS cells. Expression of NTSR1 protein is upregulated in UPS cell lines. Knockdown of NTSR1 prevented UPS cell proliferation. SR48692, an inhibitor of NTSR1, exhibited antitumor activities in UPS cells. The combination index showed that SR48692 and standard chemotherapeutic drugs prevented UPS cell proliferation synergistically. Mouse models showed that SR48692 enhanced the response to standard chemotherapeutic drugs. These drugs may be a new drug for UPS therapy.
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| Academic Significance and Societal Importance of the Research Achievements |
未分化/未分類肉腫（Undifferentiated pleomorphic sarcoma (UPS)は最も頻度の高い軟部肉腫であるが、有効な化学療法は未だ確立していない。HDAC inhibitorであるLBH589が従来の抗がん剤と相乗的にUPSの増殖を抑制することを見出した。さらに副作用減少のために下流分子メカニズムを解析し、FOSL1とNTSR1がその下流で機能してNTSR1阻害薬の SR48692が従来の抗がん剤と相乗的にUPSの増殖抑制することを示した。これら分子が治療標的となる可能性を示し、臨床的に有用であると判断する。
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