| Project/Area Number |
18KK0235
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| Research Category |
Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 50:Oncology and related fields
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| Research Institution | National Cancer Center Japan |
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Principal Investigator |
Shiotani Bunsyo 国立研究開発法人国立がん研究センター, 研究所, ユニット長 (10627665)
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| Co-Investigator(Kenkyū-buntansha) |
中田 慎一郎 大阪大学, 高等共創研究院, 教授 (70548528)
安原 崇哲 東京大学, 大学院医学系研究科(医学部), 助教 (90757056)
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| Project Period (FY) |
2019-02-07 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2021: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2019: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
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| Keywords | DNA複製ストレス / ゲノム不安定性 / RNA転写 / ヘテロクロマチン / ATR / PrimPol / KRAS / 肺がん / 発がん |
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| Outline of Final Research Achievements |
Genomic instability is a necessary property for the acquisition of gene mutations, deletions, amplifications, and translocations during tumor development process of normal cells and is one of the Hallmarks of cancer that is observed in almost all cancer cells. The present study demonstrated that oncogenic KRASG12V expression promotes transcription-dependent heterochromatinization of genomic DNA, which induces DNA replication stress, and that elevated expression of ATR, a DNA replication stress response factor, regulates DNA replication stress tolerance and leads to clonal expansion while acquiring genomic instability due to mutant KRASG12V. Furthermore, we found that high ATR expression is associated with poor prognosis of KRAS mutant lung cancers.
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| Academic Significance and Societal Importance of the Research Achievements |
変異型KRASG12V による転写依存的なヘテロクロマチン形成によってDNA複製ストレス要因となること、またATR-PrimPol依存的なDNA複製ストレス耐性によってヘテロクロマチン近傍で再プライミングが生じDNA複製を継続するが、同時に脆弱なssDNA露出を引き起こすことによってゲノム不安定性を誘発することを明らかにしたことにより、非遺伝性がんにおける高頻度ながんゲノム不安定性誘発メカニズムの一端が解明された学術的意義は大きい。またこの成果は変異型KRAS肺がん患者におけるATRシグナル経路を標的とする新規治療法の開発が期待され、社会的波及効果も大きい。
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