| Project/Area Number |
17H03578
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | Hiroshima University |
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Principal Investigator |
Naka Kazuhito 広島大学, 原爆放射線医科学研究所, 准教授 (70372688)
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| Co-Investigator(Kenkyū-buntansha) |
坂本 直也 広島大学, 医系科学研究科(医), 助教 (20571798)
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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 |
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2019: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
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| Keywords | がん幹細胞 / CML幹細胞 / 抗がん剤抵抗性 / Lgr4 / Wnt/beta-catenin / Foxo3a / CML / 代謝 / Wnt-beta-catenin / Wnt-beta-Catenin / Wnt/β-catenin / ゲノム編集 / 癌 / Wnt-β-catenin |
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| Outline of Final Research Achievements |
Recently, we found elevated expression of Lgr4/Gpr48, which encodes a leucine-rich repeat (LRR)-containing GPCR, in the most primitive long-term CML stem cells by RNA-Seq. Although the Lgr5/Gpr49 gene is reportedly responsible for the maintenance of intestinal and cancer stem cells, the biological function of Lgr4/Gpr48 is not yet fully understood. Here we investigated the role of Lgr4 in CML stem cells. To evaluate the self-renewal capacity of the CML-initiating cells in vivo, we performed bone marrow transplantation of CML LSK cells from Lgr4 gene trap (Gt) or wild type mice into irradiated recipients. To our surprise, Lgr4 Gt CML LSK cells displayed attenuated disease-initiating capacity in transplanted recipients. Importantly, the frequency and absolute number of CML LSK cells were significantly decreased in Lgr4 Gt CML mice compared with wild type CML mice. Thus, these results indicated that Lgr4 plays an important role for the long-term maintenance of CML stem cells in vivo.
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| Academic Significance and Societal Importance of the Research Achievements |
がん細胞中には，非常に少数ながら多くのがん細胞を生み出すがん幹細胞が存在する．このがん幹細胞は抗がん剤に対して抵抗性を示し，残存したがん幹細胞は再発の原因となる．そのため，がんの再発を克服するには，がん幹細胞の制御メカニズムの解明が重要である．本研究では，新たにLgr4/Gpr48がCML幹細胞の未分化性の維持に重要な役割を担うことを解明した．本研究成果は，Lgr4/Gpr48によるFoxo3aと活性化β-cateninの相互作用を制御する分子機構の解明，並びに副作用の少ない新しいCML幹細胞の治療法を開発するための分子基盤となる．
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