2020 Fiscal Year Final Research Report
Investigation of the molecular mechanisms and cellular origins of combined hepatocellular-cholangiocarcinoma using hepatocellular carcinoma-specific gene recombination system in mice
| Project/Area Number |
18K07994
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Uchino Koji 東京大学, 医学部附属病院, 届出研究員 (00748725)
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| Co-Investigator(Kenkyū-buntansha) |
中川 勇人 東京大学, 医学部附属病院, 助教 (00555609)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | 肝細胞癌 / 癌起源細胞 / 混合型肝癌 / 肝再生 |
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| Outline of Final Research Achievements |
We examined changes in the zonal distribution of the Wnt target gene Axin2 over time using Axin2-CreERT2;Rosa26-Lox-Stop-Lox-tdTomato mice (Axin2;tdTomato). We found that following tamoxifen administration at 3 weeks of age, approximately one-third of total hepatocytes that correspond to zone 3 were labeled in Axin2;tdTomato mice. Cell fate analysis revealed that zone 3 hepatocytes maintained their own lineage but rarely proliferated beyond their liver zonation during homeostasis; this indicated that our protocol enabled persistent genetic labeling of zone 3 hepatocytes. Using this system, we found that zone 3 hepatocytes generally had high neoplastic potential. However, the frequency of zone 3 hepatocyte-derived tumors varied depending on the regeneration pattern of the liver parenchyma in response to liver injury.
Furthermore, we established a new transgenic mouse line, AFP-CreERT mouse, that expresses CreERT under the regulation of AFP promoter.
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| Free Research Field |
消化器病学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、zone3肝細胞をgenetic labelingすることによって、肝細胞癌がどのzoneからできやすいのかを明らかするという、全く新しい視点から行われた研究である。本研究結果から、zone3は発癌ポテンシャルが高い細胞集団を多く含んでいる可能性が示唆された。zone3肝細胞は肝静脈内皮細胞からのWntシグナルを受けて同経路が活性化した状態にあるが、Wnt-βカテニン経路の活性化は肝発癌の特に初期段階に重要であると報告されており、同経路の阻害が肝癌予防に有用な可能性が示唆された。また今回新たに樹立されたAFP-CreERTマウスは肝病態の解明に非常に有用なツールになると期待される。
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