2020 Fiscal Year Final Research Report

Development of a novel treatment for refractory ovarian clear cell carcinoma by targeting cell cycle monitoring mechanism

Research Project

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Project/Area Number	18K09235
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 56040:Obstetrics and gynecology-related
Research Institution	National Cancer Center Japan (2019-2020) Nara Medical University (2018)
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)
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)
Project Period (FY)	2018-04-01 – 2021-03-31
Keywords	細胞周期監視機構 / HNF-1beta / USP28 / Claspin / Chk1 / DNA damage response
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.
Free Research Field	腹腔鏡下手術
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。