Investigation of TERT expression and development of a novel targeted therapy in ependymomas
| Project/Area Number |
16K10775
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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 |
Neurosurgery
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| Research Institution | National Cancer Center Japan |
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Principal Investigator |
ICHIMURA KOICHI 国立研究開発法人国立がん研究センター, 研究所, 分野長 (40231146)
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| Research Collaborator |
Takadera Mutsumi
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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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 上衣腫 / 融合遺伝子 / RELA / TERT / トランスジェニックマウス / マウス脳腫瘍モデル / レンチウイルス / ルシフェラーゼ / rs2853669 / 脳腫瘍 / Ependymoma |
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| Outline of Final Research Achievements |
We investigated a large number of surgical ependymoma samples for the presence of RELA-fusion and TERT expression. We found RELA-fusion in the majority of supratentorial ependymomas and elevated TERT expression in all of them. To investigate the mechanism of TERT overexpression, we generated a luciferase construct with TERT promoter mutations or rs2853669 SNP. We found that the transcriptional activity of TERT promoter affected by the mutations or SNP was variable according to the length of the promoter region. In order to make a mouse model of ependymoma, we generated conditional double transgenic mouse by mating Nestin-Cre and Cag-Cas9 mouse and lentivirally introduced a RELA-fusion together with a sgRNA for Cdkn2a into the mouse brain. This resulted in development of mouse brain tumors that histologically resembles human ependymomas.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、100例あまりの上衣腫検体においてTERTの発現、プロモーターの点突然変異及びメチル化、TERTコピー数異常、遺伝子再配列に対して詳細な解析を行い、TERT高発現の頻度とその機序を精査した。また、TERT promoter長やその領域の点変異やSNPの有無とTERTの転写活性変化の関連性を検討した。またRELA融合遺伝子の導入によるマウス上衣腫のモデルを作成した。本研究の成果は、マウスモデルを用いたTERT標的治療の効果の検証等による上衣腫に対する新規治療標的探索研究への応用が期待される。
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Report
(4 results)
Research Products
(11 results)
