| Project/Area Number |
26861069
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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 |
Digestive surgery
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2014-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 胆道癌 / 上皮間葉転換 / ヒストン脱アセチル化酵素阻害剤 / SMAD4 / TGF-β1 / 化学療法抵抗性 / ヒストン制御 |
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| Outline of Final Research Achievements |
Epithelial-mesenchymal transition (EMT) is involved in the characteristics of malignancy. In biliary tract cancer (BTC), EMT is induced by transforming growth factor-beta 1 (TGF-β1). We focused on histone deacetylase (HDAC) inhibitors as regulators of TGF-β1 signaling. We employed BTC cell lines and used vorinostat as the HDAC inhibitor. In the parent BTC cell lines, TGF-β1 induced EMT and chemoresistance; while, vorinostat inhibited the EMT and chemoresistance induced by TGF-β1. In gemcitabine-resistant cell lines that highly expressed TGF-β1, vorinostat inhibited EMT and attenuated chemoresistance. We showed that vorinostat inhibits nuclear translocation of SMAD4 which is a signaling factor of TGF-β1. Furthermore, combination therapy with vorinostat and gemcitabine improved survival time in the mice xenografted with gemcitabine resistant MzChA-1 cells. In conclusion, vorinostat regulated TGF-β1-induced EMT and chemoresistance through inhibition of SMAD4 nuclear translocation.
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