| Project/Area Number |
17K18436
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Biological pharmacy
Tumor therapeutics
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| Research Institution | Osaka City University |
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Principal Investigator |
yamagishi ryota 大阪市立大学, 大学院医学研究科, 助教 (30793145)
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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 |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 悪性中皮腫 / 合成致死 / mRNA代謝 |
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| Outline of Final Research Achievements |
Mesothelioma is a poor prognosis cancer caused by asbestos exposure. Although the number of people diagnosed with mesothelioma is increasing, the effective treatment is still to be established. In this study, we are trying to identify synthetic lethal gene to LATS2 and NF2, which are typical causative gene of mesothelioma, and will analyze the molecular mechanism for the synthetic lethal phenotype and verify the possibility as new therapeutic target. Therefore, I performed screening using shRNA library in mesothelioma cells with LAST2 or NF2 mutation. As a result, phenotype of synthetic lethal was observed by knockdown of an endonuclease SMG6 in mesothelioma cell with LATS2 mutation. Although SMG6 is well known as an essential factor in nonsense mediated mRNA decay (NMD), synthetic lethal between LATS2 and SMG6 was independent of NMD. In addition, LATS2 was shown synthetic lethal with SMG6 by TAZ-dependent Hippo signaling pathway.
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| Academic Significance and Societal Importance of the Research Achievements |
悪性中皮腫は、アスベスト暴露後20～40年の長期にわたる潜伏期間を経て発症し、現在、日本において新規患者数は年々増加しておりピークとされる2030年頃には年間3,000人に達すると予想されている。悪性中皮腫においては、化学療法、手術療法、放射線療法の併用療法が行われているが、確定診断後の患者の予後は極めて不良であり新たな治療法の開発が求められている。本研究では、悪性中皮腫の原因遺伝子ががん抑制遺伝子に限られるという特徴を踏まえ、原因遺伝子の合成致死遺伝子を分子標的とすることでこれまで有効な治療法がなかった悪性中皮腫に対する新規治療法の開発を目的としている。
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