| Project/Area Number |
18K15807
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
Nio Kouki 金沢大学, 附属病院, 助教 (80807397)
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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 |
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 肝細胞癌 / がん幹細胞 / BMP9 / ID1 / BMP受容体阻害剤 / 癌幹細胞 / バイオマーカー / 血管新生 / CD105 |
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| Outline of Final Research Achievements |
In this study, we aimed to elucidate the role of BMP9 signaling in cancer stem cell (CSC) properties of hepatocellular carcinoma (HCC) and to assess the therapeutic effect of BMP receptor inhibitors in HCC. We have first identified that high BMP9 expression in serum from patients with HCC leads to poorer outcome. BMP9 promoted CSC properties in EpCAM-positive HCC subtype via enhancing ID1 expression in vitro. Additionally, ID1 knockdown significantly repressed BMP9-promoted HCC-CSC properties by suppressing Wnt/β-catenin signaling. Cells treated with BMP receptor inhibitors K02288 and LDN-212854 blocked HCC-CSC activation by inhibiting BMP9-ID1 signaling. Treatment with LDN-212854 suppressed HCC tumor growth by repressing ID1 and EpCAM in vivo. Our study demonstrates the pivotal role of BMP9-ID1 signaling in promoting HCC-CSC properties and the therapeutic potential of BMP receptor inhibitors in treating EpCAM-positive HCC.
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| Academic Significance and Societal Importance of the Research Achievements |
再発や転移、薬物療法抵抗性の源と考えられているがん幹細胞は、進行肝細胞癌において重要な治療標的と考えられている。今回我々は、BMP9シグナル（細胞情報伝達）による肝がん幹細胞活性化のメカニズムを解明し、BMP9シグナルを阻害するBMP受容体阻害剤が肝細胞癌における有望な治療法となる可能性を示した。今後、高悪性度（腫瘍が大きくなる速度が速い、腫瘍マーカーが高値）や難治性（薬物療法が効きにくい）の進行肝細胞癌に対する臨床応用が期待される。本研究結果は、国内および海外の学術集会での報告と英文誌掲載により広く社会・国民に発信した。
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