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Search for synthetic lethal candidates for HNF1beta-USP28-CLASPIN-Chk1 inhibition

Research Project

Project/Area Number 20K09604
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56040:Obstetrics and gynecology-related
Research InstitutionNara Medical University

Principal Investigator

KIMURA Mai  奈良県立医科大学, 医学部, 助教 (30812333)

Co-Investigator(Kenkyū-buntansha) 吉元 千陽  奈良県立医科大学, 医学部, 研究員 (00526725)
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)
河原 直紀  奈良県立医科大学, 医学部, 助教 (70623495)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsHNF-1beta / 卵巣明細胞癌 / GSK-3beta / ミトコンドリア / 代謝 / NF-κB / 合成致死 / HNF1β
Outline of Research at the Start

我々は卵巣明細胞癌の特徴的な性質(HNF-1β異常高発現)に着目し、このタンパクが異常高発現しているときにだけ特異的に作用する「合成致死」候補遺伝子を細胞周期、DNA損傷応答および脱ユビキチン化に関わる遺伝子を中心に探索する。これによって新規治療法を確立し、安全性・有効性を確認するための前臨床試験を行う。近い将来、人類はがんを克服する時代を迎えることになると予想されるが、これには多角的な治療戦略を駆使することが必須であると考える。従って、本研究は治療方法の選択肢を広げることとなり、がん克服へ寄与することが出来ると考える。

Outline of Final Research Achievements

Ovarian clear cell carcinoma is characterized by overexpression of HNF-1beta (hepatocyte nuclear factor-1beta).To evaluate in detail the effects of HNF-1beta overexpression on cellular metabolism, we performed an inhibitor screening. As a result, we identified an inhibitor X that acts specifically on cell lines with high HNF-1beta expression. Addition of inhibitor X under the interference of HNF-1beta markedly reduced cell proliferation. We have previously reported that GSK-3beta is located downstream of HNF-1beta, and when GSK-3beta was interfered with TOV-21G and then treated with inhibitor X, a similar inhibition of cell proliferation was observed.

Academic Significance and Societal Importance of the Research Achievements

本研究により、阻害薬X投与が、現在難治性とされている卵巣明細胞癌に対する有効な治療の可能性があると示された。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (1 results)

All 2020

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results)

  • [Journal Article] GSK-3β mediates the effects of HNF-1β overexpression in ovarian clear cell carcinoma2020

    • Author(s)
      Kawahara Naoki、Mizutani Ayano、Matsubara Sho、Takeda Yoshinori、Kobayashi Hiroshi
    • Journal Title

      Experimental and Therapeutic Medicine

      Volume: 20 Issue: 5 Pages: 122-122

    • DOI

      10.3892/etm.2020.9250

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access

URL: 

Published: 2020-04-28   Modified: 2024-01-30  

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