| Project/Area Number |
17K16848
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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 |
Obstetrics and gynecology
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| Research Institution | Osaka University |
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Principal Investigator |
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| Research Collaborator |
Miyamoto Mayuko
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | 卵巣癌 / マイクロRNA / パクリタキセル / miR-522 / E2F2 / 細胞周期 / miRNA / 抗癌剤耐性化 / PACT |
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| Outline of Final Research Achievements |
Overcoming paclitaxel resistance is a critical issue in ovarian cancer treatment. Herein, we identified microRNAs (miRNA) which modulates paclitaxel resistance and pursued those potential as a therapeutic target. Paclitaxel resistant cell lines were established, and miRNA PCR arrays indicated that miR-522 was one of down-regulated miRNAs in paclitaxel-resistant cells. Restoration of miR-522 resensitized resistant cells to paclitaxel. We focused on E2F2, a cell cycle related protein, as a target gene of miR-522, and luciferase reporter assay revealed that E2F2 is a direct target of miR-522. Cell cycle analyses showed that miR-522 attenuated paclitaxel resistance by down-regulating E2F2, which causes G0/G1 arrest. Public database showed that patients with the low expression of miR-522 were significantly correlated with worse survival. In conclusion, our results show that miR-522 attenuates paclitaxel resistance and can be considered a therapeutic target for recurrent ovarian cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
卵巣癌が未だに半数以上の患者が亡くなる予後不良な疾患である。Key drug となるパクリタキセルと白金製剤の中心とした化学療法に対して初回治療では70%の奏効率を示すが残念ながら半数以上の症例で再発を来し、再発した卵巣癌において化学療法はもはや奏功しない。この現状を打破するために抗癌剤耐性化のメカニズムの解明が求められる。今回、パクリタキセル耐性株ではmiR-522 の発現低下が起こった結果、E2F2 の発現が上昇し、ゆえに癌細胞の細胞分裂が促進され、抗癌剤に対して抵抗性を示すようになるという耐性化獲得のメカニズムを解明した。卵巣癌の抗癌剤耐性化の打破につながる基礎的な研究データを供出した。
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