| Project/Area Number |
17K15654
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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 |
Human pathology
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| Research Institution | Kitasato University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | 卵巣明細胞癌 / 上皮間葉転換 / がん幹細胞 / Lefty / LEFTY / EMT / CSC / プロテオミクス / TGF-β / ショットガンプロテオミクス / Smad2 / バイオマーカー |
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| Outline of Final Research Achievements |
We focused on the functional roles of the left-right determinantion factor(LEFTY) in ovarian clear cell carcinoma(OCCCa). OCCCa cell lines that were cultured in STK2 or treated with TGF-β1, underwent morphological changes toward an epithelial-mesenchymal transition(EMT) appearance and showed cancer stem cell(CSC) properties. Inhibition of LEFTY expression induced decreases in the number of spindle-shaped cells and CSC features. Finally, treatment of cells with TGF-β1 led to increased LEFTY expression and activation of Akt, which subsequently induced inactivation of GSK-3β, while inhibition of GSK-3β resulted in increased expression of both LEFTY and Snail. In clinical samples, LEFTY expression showed a tendency for positive associations with expression of vimentin, as well as Sox2 and ALDH1. In conclusion, TGF-β-mediated LEFTY/Akt/GSK-3β/Snail axis may contribute to the establishment and maintenance of phenotypic characteristics of OCCCas through modulation of EMT/CSC properties.
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| Academic Significance and Societal Importance of the Research Achievements |
本邦ではOCCAの発生頻度が高く（卵巣癌の約20％）、その臨床的特徴として、①子宮内膜症性嚢胞からの発癌、②抗癌剤に抵抗性で再発癌は極めて予後不良、などがある。しかし、現時点で、OCCAの発癌機構を含む生物学的特性は不明な点が多い。本研究は、申請者のグループが卵巣癌検体のショットガンプロテオミクス法による網羅的解析により独自に同定したLefty遺伝子に焦点を絞り、そのシグナルネットワークによるOCCAの細胞動態やEMTの調整を介した腫瘍転移・進展制御に関する分子機構を解明することによってOCCAの新たな臨床的・生物学的特性の一側面を明らかにすることに学術的特色がある。
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