Development of a novel treatment for refractory ovarian clear cell carcinoma by targeting cell cycle monitoring mechanism
| Project/Area Number |
18K09235
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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 56040:Obstetrics and gynecology-related
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| Research Institution | National Cancer Center Japan (2019-2020)
Nara Medical University (2018) |
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Principal Investigator |
Tanase Yasuhito 国立研究開発法人国立がん研究センター, 中央病院, 医員 (20423915)
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| Co-Investigator(Kenkyū-buntansha) |
山田 有紀 奈良県立医科大学, 医学部, 助教 (20588537)
小林 浩 奈良県立医科大学, 医学部, 研究員 (40178330)
川口 龍二 奈良県立医科大学, 医学部, 准教授 (50382289)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 細胞周期監視機構 / HNF-1beta / USP28 / Claspin / Chk1 / DNA damage response / 卵巣明細胞癌 / CLASPIN / 卵巣癌 / チェックポイント / 明細胞癌治療 |
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| Outline of Final Research Achievements |
Transcription factor hepatocyte nuclear factor 1-beta (HNF-1β) enhances checkpoint kinase 1 (Chk1) activation and promotes G2/M cell cycle progression in ovarian clear cell carcinoma (CCC) following exposure to diverse genotoxic agents including bleomycin. Loss-of-function studies using RNAi-mediated gene silencing indicated that HNF-1β facilitated the Claspin expression after treatment with a genotoxic agent bleomycin, resulting in accumulation of phosphorylated Chk1 (p-Chk1) and promotion of survival in CCC cell lines. This study showed for the first time that USP28, a de-ubiquitinase crucial for Claspin expression, is one target gene of HNF-1β. Knockdown of endogenous USP28 suppressed the Claspin expression and p-Chk1 activation and cell viability.
Our findings identify a novel pathway of the HNF-1β―USP28―Claspin―Chk1 axis in checkpoint signal amplification in response to DNA damage. Targeting this pathway may represent a putative, novel, anticancer strategy in ovarian CCC.
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| Academic Significance and Societal Importance of the Research Achievements |
卵巣明細胞癌は細胞周期監視機構の異常によって抗癌剤に対する治療抵抗性を獲得していることが示唆されている。本研究により、細胞周期監視機構に異常を誘発する原因の1つとされるHNF-1β-USP28-Claspin-Chk1経路を阻害することで、卵巣明細胞癌の抗癌剤への感受性が増幅することが示された。
細胞周期監視機構を標的とした治療法が確立されることにより、従来、予後不良とされていた卵巣明細胞癌に対する化学療法の治療成績の向上が見込まれる。
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Report
(4 results)
Research Products
(5 results)
