| Project/Area Number |
16K10589
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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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| Research Field |
Digestive surgery
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| Research Institution | Chiba University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
高野 重紹 千葉大学, 大学院医学研究院, 助教 (20436380)
高屋敷 吏 千葉大学, 大学院医学研究院, 講師 (30456024)
久保木 知 千葉大学, 医学部附属病院, 講師 (50571410)
清水 宏明 帝京大学, 医学部, 教授 (80272318)
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| Research Collaborator |
SUGIURA kaneyasu
MISHIMA takashi
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 肝内胆管癌 / 癌源細胞 / 上皮間葉転換 / stemness / yes-associated protein / EMT / 表面マーカー / YAP / TAZ / 血管新生 / 脱分化 / コンランギオパチー / 分化・脱分化 |
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| Outline of Final Research Achievements |
YAP was expressed in 71% of cases with intrahepatic cholangiocarcinoma. YAP expression was significantly associated with the expression of EMT-related markers and a hepatic progenitor cell marker. Survival of patients with positive YAP expression was significantly worse than that of patients with negative YAP expression. In in vitro cell line studies, EMT-related markers and stemness properties were significantly downregulated when YAP expression was knocked out by siRNA. Similar findings were observed after treatment with verteporfin, an inhibitor of YAP function. Furthermore, inhibition of tumor growth in mouse models was found by administration of verteporfin. These results suggest that the YAP/Hippo pathway plays a role in the induction or maintenance of cancer-initiating cells, and that inhibition of this pathway may be a new thrapeutic option.
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| Academic Significance and Societal Importance of the Research Achievements |
肝内胆管癌は，現状で外科切除以外有効な治療法がなく，外科切除しえたとしても高率に再発し，その予後は不良である。本研究ではそのような疾患に対し，その予後を悪くしている一因と考えられる癌源細胞に注目し，その誘導あるいは維持のためにはYAP/Hippo経路が重要であることを明らかにするとともに，その機能発現抑制剤であるverteporfinがin vitro, in vivoで本疾患に対して有効であることを示し，新たな治療法になりうる可能性を示唆した。
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