2023 Fiscal Year Final Research Report
Combination therapy with epigenetic modulators hydralazine and sodium valproate as a novel therapeutic strategy for osteosarcoma.
| Project/Area Number |
20K09444
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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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| Review Section |
Basic Section 56020:Orthopedics-related
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| Research Institution | Hyogo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
山根木 康嗣 兵庫医科大学, 医学部, 講師 (00434944)
西浦 弘志 兵庫医科大学, 医学部, 講師 (90284760)
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Keywords | 骨肉腫 / 転移 / 血管新生 / 血行性転移抑制 / エピジェネティック試薬 |
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| Outline of Final Research Achievements |
Semaphorin(SEMA)3A is an endogenous angiogenesis inhibitor associated with endothelial cell proliferation, which suppresses tumor angiogenesis. In this study, the role of histone deacetylase (HDAC) inhibitors is evaluated to enhance the SEMA3A expression in osteosarcoma (OS) cells, thereby suppressing angiogenesis and inhibiting their proliferation and metastasis. OS cell lines and human microvascular endothelial (HMVE) cells were treated with sodium valproate (VPA) of HDAC inhibitor. VPA increased the expression of SEMA3A and its receptor NRP1 in both OS and HMVE cells. SEMA3A induced by VPA in OS cell culture medium inhibited vascular tube formation of HMVE cells, and overexpression of SEMA3A enhanced OS cell growth inhibition. This growth-inhibitory effect of SEMA3A induced G1/S cell cycle arrest in OS cells. In conclusion, HDAC inhibitors have anti-angiogenic and anti-tumor activities that can be, in part, mediated via the SEMA3A/NRP1/PLXNA1 autocrine and paracrine pathways.
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| Free Research Field |
整形外科
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| Academic Significance and Societal Importance of the Research Achievements |
骨肉腫の肺転移抑制に，ヒストン脱アセチル化阻害剤 (HDAC) の効果と作用機序を明らかにした．HDACのバルプロン酸 は，ヒト骨肉腫細胞 (OS) とヒト毛細血管内皮細胞 (HMVE) に作用してSemaphorin3A (SEMA3A) とそのレセプターであるNeuropilin1 (NRP1) とPlexinA1 (PLXNA1) の発現を亢進さて，HMVEの管腔形成阻害を認めた．SEMA3Aの亢進はG1/S細胞周期チェックポイントを制御して，OSの増殖抑制を認めた．以上，HDACはSEMA3A/NRP1/PLXNA1の経路を介して，骨肉腫の血管新生と細胞増殖を抑制できることを証明した．
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