| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Outline of Final Research Achievements |
In this study, we aimed to reveal mechanisms regulating fetal liver stem cells, hepatoblasts, and also to understand how disturbance of such mechanisms leads to the childhood liver cancer, hepatoblastoma. By using a newly developed in vitro culture method of hepatoblasts, we found that activation of the Hippo pathway effector, YAP, confers long-term self-renewal ability on hepatoblasts, while activation of beta-catenin promotes Wnt signaling-independent growth of hepatoblasts. Activation of both YAP and beta-catenin induced expression of IGF-1, thereby promoting growth factor-independent survival and proliferation of hepatoblasts. Moreover, transplantation of cultured and genetically modified hepatoblasts showed that simultaneous activation of YAP, beta-catenin, and c-Myc induces formation of hepatoblastoma-like tumors in immunodeficient mice. These results identify novel mechanisms regulating hepatoblast cell fate and suggest that disturbance of the mechanisms leads to hepatoblastoma.
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