| Project/Area Number |
18K15253
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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 50010:Tumor biology-related
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| Research Institution | Jikei University School of Medicine |
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Principal Investigator |
Yamada Kohji 東京慈恵会医科大学, 医学部, 講師 (90570979)
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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 |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | PKCδ / 肝がん / 細胞外分泌 / 細胞外局在 / 肝癌 / 腫瘍マーカー / がん / キナーゼ / ヘパラン硫酸プロテオグリカン / がん微小環境 |
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| Outline of Final Research Achievements |
Expression of human protein kinase C delta (PKCδ) protein has been linked to many types of cancers. Here we showed that full-length PKCδ was secreted to the extracellular space in living liver cancer cells under normal cell culture conditions and in xenograft mouse models. Patients with liver cancer showed higher levels of serum PKCδ than patients with chronic hepatitis or liver cirrhosis or healthy individuals. Furthermore, colocalization studies showed that extracellular PKCδ was anchored on the cell surface of liver cancer cells via association with glypican 3, a liver cancer-related heparan sulfate proteoglycan. Addition of exogenous PKCδ activated IGF-1 receptor (IGF1R) activation and subsequently enhanced activation of ERK1/2, which led to accelerated cell growth in liver cancer cells. Conversely, treatment with anti-PKCδ antibody reduced cell proliferation and spheroid formation of liver cancer cells and tumor growth in xenograft mouse models.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究によって、細胞内に局在するタンパク質が肝がんにおいて細胞外に分泌されることがわかった。現在、腫瘍組織においては壊死が起きることが知られているが自発的な分泌の発見は新規性がある。さらに、肝がん患者の血清で高値であるのは今後腫瘍マーカーになる可能性がある点で社会的意義が大きい。加えて、皮下移植モデルにおいてPKCδ抗体が抗腫瘍効果を持つ発見は、今後、抗体医薬品開発につながる可能性が非常に高く、治療法が未だ乏しい肝がんにおいてその医療ニーズに沿っている。
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