| Project/Area Number |
16K11017
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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 |
Urology
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
西山 直隆 富山大学, 大学院医学薬学研究部(医学), 講師 (70619030)
進藤 哲哉 札幌医科大学, 医学部, 助教 (80749292)
新海 信雄 札幌医科大学, 医学部, 研究員 (40772398)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 転移性尿路上皮癌 / 化学療法抵抗性 / エピジェネティック治療 / 予後予測マーカー / 転移性膀胱癌 / エピジェネティクス治療 / シスプラチン耐性株 / ゲムシタビン耐性株 / ゲノム網羅的染色体構造解析 / 5-Aza-CdR / ヒストン脱アセチル化酵素阻害剤 / 薬剤耐性化 / 膀胱癌 / 尿路上皮癌 / DNAメチル基転移酵素阻害剤 / DNAメチル化 / ヒストン修飾 |
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| Outline of Final Research Achievements |
We found that the treatment with 5-Aza-CdR strikingly suppressed tumor formation by CDDP-resistant BCa cells in nude mice . Because 5-Aza-CdR alone was sufficient to completely block the xenograft formation, no synergistic effect of 5-Aza-CdR plus CDDP was observed.
miR-200b was associated with CDDP sensitivity in BCa cells, and its downregulation was associated with CpG island hypermethylation. Pharmacological demethylation using 5-aza-2'-deoxycytidine restored miR-200b expression, and the combination of 5-aza-2'-deoxycytidine + CDDP strongly inhibited T24RC cell proliferation. Microarray analysis revealed that miR-200b + CDDP induced genes involved in CDDP sensitivity or cytotoxicity, including IGFBP3, ICAM1 and TNFSF10, in the resistant cells. Expression and DNA methylation of miR-200b were inversely associated in primary BCa, and low expression/high methylation was associated with poor overall survival. T
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| Academic Significance and Societal Importance of the Research Achievements |
予後不良である転移性膀胱癌に対して5-Aza-CdRを組み合わせた2次治療が臨床応用されることで、新たな治療法の開発につながり、多くの膀胱癌患者の予後延長効果が期待される。5-Aza-CdRが有効な患者を選択するためのコンパニオン診断マーカー候補を同定、2次治療に対する新たな分子標的薬の開発が期待できる。
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