| Project/Area Number |
16K10868
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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 |
Izumi Toshihiko 鹿児島大学, 医歯学総合研究科, 客員研究員 (70768762)
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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)
瀬戸口 啓夫 鹿児島大学, 医歯学総合研究科, 特任准教授 (40423727)
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| Research Collaborator |
Saitoh Yoshinobu
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 整形外科 / 骨軟部腫瘍 / 未分化多型肉腫 / UPS / LBH589 / HDAC阻害剤 / FOSL1 / 未分化多形肉腫 / HDAC inhibitor / 軟部肉腫 |
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| Outline of Final Research Achievements |
Undifferentiated pleomorphic sarcoma (UPS) patients are treated with surgical resection and complementary radiotherapy. However, since standard chemotherapy has not been established, unresectable or metastatic cases result in a poor prognosis. In this study, we investigated the effects and mechanisms of an HDAC inhibitor, LBH589, in UPS cells. We confirmed that LBH589 exhibits antitumor activities in four human UPS cell lines. A xenograft model showed that LBH589 treatment suppressed tumor growth. FACS analysis showed that LBH589 induced apoptosis and G2/M cell cycle arrest. RNA microarray identified the FOS-like antigen 1 (FOSL1) gene as a downregulated gene in response to LBH589 in UPS cells. While knockdown of FOSL1 decreased UPS cell proliferation, overexpression induced cell proliferation. Our results show that LBH589 could be a promising chemotherapeutic agent in the treatment of UPS and downregulation of the FOSL1 gene could be the new olecular target of UPS treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
未分化/未分類肉腫: undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (UPS / MFH)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。日本でも難治性多発性骨髄腫の治療薬として認可されている、LBH589にUPS抑制効果があることを見出し、臨床応用可能と考える。また、LBH589の下流でFOS-like antigen 1 (FOSL1)がUPSの増殖を制御していることを見出した。FOSL1がUPSの分子標的治療として有望なことを示した。
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