| Project/Area Number |
25461602
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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 |
Pediatrics
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
KUWAHARA YASUMICHI 京都府立医科大学, 医学(系)研究科(研究院), 講師 (30590327)
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| Co-Investigator(Kenkyū-buntansha) |
HOSOI Hajime 京都府立医科大学, 大学院医学研究科, 教授 (20238744)
IEHARA Tomoko 京都府立医科大学, 大学院医学研究科, 准教授 (20285266)
TSUCHIYA Kunihiko 京都府立医科大学, 大学院医学研究科, 講師 (90381938)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | ラブドイド腫瘍 / SNF5 / クロマチンリモデリング / NOXA / 薬剤感受性 / アポトーシス / 悪性ラブドイド腫瘍 / 薬剤耐性 / Mcl-1 |
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| Outline of Final Research Achievements |
Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric cancer characterized by inactivation of SNF5, a core subunit of SWI/SNF complexes. Previously, we showed SNF5 contributes to transcriptional activation of NOXA, a pro-apoptotic protein that binds and inhibits the anti-apoptotic protein MCL-1. In this study, we found that NOXA expression was downregulated in both MRT cell lines and in clinical samples and that ectopically expressed NOXA bound MCL-1 and increased the sensitivity of MRT cell lines to doxorubicin (DOX) by promoting apoptosis. We also showed that knockdown of MCL-1 in MRT cell lines induced apoptosis and increased DOX sensitivity in MRT cells. Furthermore, we generate mice xenografts for both MCL-1 knockdown (KD) and control cell lines. We observed that mean tumor volume in the DOX-treated MCL-1 KD group was significantly smaller than that in the control group. Our results suggest that modulation of the NOXA/MCL-1 pathway underlies a chemoresistance in MRT.
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