| Project/Area Number |
17K15612
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Pathological medical chemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Research Collaborator |
Kubota Naoto 東京大学, 医学部附属病院, 准教授
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | インスリン受容体基質 / 肝癌 / インスリンシグナル / シグナル伝達 / 糖尿病 / 肥満 |
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| Outline of Final Research Achievements |
We investigated the roles of insulin receptor substrate (Irs) 1 and Irs2, both of which are the major molecules to be responsible for transducing insulin/IGF signaling in the liver, in the development of HCC by inducing chemical carcinogenesis using diethylnitrosamine (DEN) in mice. Liver-specific Irs1-knockout (LIrs1KO) mice exhibited suppression of DEN-induced HCC development, accompanied by reduced cancer cell proliferative activity and reduced activation of Akt. On the other hand, liver-specific Irs2-knockout (LIrs2KO) mice showed a similar pattern of HCC development to the DEN-treated control wild-type mice. We focused on Wnt/β-catenin signaling and demonstrated that Irs1 expression was induced by Wnt3a stimulation in the primary hepatocytes, associated with insulin-stimulated Akt activation. These data suggest that upregulated Irs1 by Wnt/β-catenin signaling plays a crucial role in the progression of HCC.
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| Academic Significance and Societal Importance of the Research Achievements |
LIrs1KO、LIrs2KOマウスは通常食下では脂肪肝を伴わず、正常耐糖能に近いことが先行研究や本研究で明らかになっている。高血糖や脂肪肝は肝癌の増悪因子であることが報告されているが、今回我々は、LIrs1KO、LIrs2KOマウスにDENで肝癌を誘発し、通常食下で観察することにより、高血糖や脂肪肝などの肝癌発症における交絡因子を除外した状態でインスリンシグナル関連分子の肝癌形成における役割を評価できた。LIrs1KOマウスで肝癌の進展が抑制されたことを踏まえると、今後Irs1が肝癌治療の分子ターゲットになる可能性もあると考えられた。
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