Anti-tumor approach based on the understanding of NFAT-EC activation system
| Project/Area Number |
17H03580
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | Kumamoto University |
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Principal Investigator |
Minami Takashi 熊本大学, 生命資源研究・支援センター, 教授 (00345141)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
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| Keywords | 血管内皮細胞 / 血管新生 / NFAT / ダウン症因子 / EndMT / 転写因子 ERG / 転写因子 FLI1 / がん微小環境 / ダウン症モデル / 担がんモデル / Notch シグナル / 血管分岐 / マイクロアレイ / 腫瘍血管新生 / ダウン症病態 / NFAT/DSCR-1 シグナル / 内皮エピゲノム病態 / 内皮ー間葉系形質転換 / Erg / FLI1 / 内皮エピゲノム制御 / 内皮多様性 / Notch / 腫瘍血管 / ChIP-seq / エピゲノム制御 / エクササイズ / NFAT/DSCR-1 |
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| Outline of Final Research Achievements |
Endothelial cell (EC) plasticity in pathological settings has been recognized as a driver of disease progression. Endothelial-to-mesenchymal transition (EndMT), in which ECs acquire mesenchymal properties, has been described for a wide range of pathologies, including cancer. However, the mechanism regulating EndMT in the tumor microenvironment and the contribution of EndMT in tumor progression are not fully understood. Here we found, combined knockdown of ERG and FLI1, induces EndMT coupled with dynamic epigenetic changes in ECs. Genome-wide analyses revealed that ERG/FLI1 are critical transcriptional activators for EC-specific genes, among which miR-126 partially contributes to blocking the EndMT induction. Moreover, we demonstrated that ERG and FLI1 expression is declined in ECs within tumor by soluble factors enriched in the tumor microenvironment. These data provide new insight into the mechanism of EndMT, functions of ERG and FLI1 in EC, and its behavior in pathological condition.
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| Academic Significance and Societal Importance of the Research Achievements |
内皮活性化に関わる NFAT/DSCR-1経路において、DSCR-1はダウン症の発症要因となる一方、DSCR-1 自体のトリソミー発現がダウン症の固形がん罹患率減少の主因となり、抗がんや抗転移における優れた有効性を持つ。また、がんの悪性化、転移において腫瘍血管内皮の EndMT 現象が関与することが考えられ、その分子メカニズムの一端が解明されたことにより、今後抗がんにおける腫瘍血管の動態解析の重要性が再認識され、新規な DSCR-1 安定化剤の創薬や臨床アプローチが進むことが期待される。
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Report
(4 results)
Research Products
(27 results)
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[Journal Article] Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice2019
Author(s)
Sato M, Miyata K, Tian Z, Kadomatsu T, Ujihara Y, Morinaga J, Horiguchi H, Endo M, Zhao J, Zhu S, Sugizaki T, Igata K, Muramatsu M, Minami T, Ito T, Bianchi ME, Mohri S, Araki K, Node K, Oike Y
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Journal Title
Circulation Journal
Volume: 83
Issue: 2
Pages: 368-378
DOI
NAID
ISSN
1346-9843, 1347-4820
Year and Date
2019-01-25
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation2018
Author(s)
3.Baba M, Endoh M, Ma W, Toyama H, Hirayama A, Nishikawa K, Takubo K, Hano H, Hasumi H, Umemoto T, Hashimoto M, Irie N, Esumi C, Kataoka M, Nakagata N, Soga T, Yao M, Kamba T, Minami T, Ishii M, and Suda T.
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Journal Title
Journal of Bone and Mineral Research
Volume: 33
Issue: 10
Pages: 1785-1798
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Dynamically and epigenetically coordinated GATA/ETS/SOX transcription is indispensable for endothelial cell differentiation2017
Author(s)
Kanki Y, Nakaki R, Shimamura T, Matsunaga T, Yamamizu K, Katayama S, Suehiro JI, Osawa T, Aburatani H, Kodama T, Wada Y, Yamashita JK, Minami T.
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Journal Title
Nucleic Acids Research
Volume: 印刷中
Issue: 8
Pages: 4344-4358
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Negative feedback loop of bone resorption by NFATc1-dependent induction of Cadm1.2017
Author(s)
Nakamura S, Koyama T, Izawa N, Nomura S, Fujita T, Omata Y, Minami T, Matsumoto M, Nakamura M, Fujita-Jimbo E, Momoi T, Miyamoto T, Aburatani H, Tanaka S.
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Journal Title
PLoS One
Volume: 12
Issue: 4
Pages: e0175632-e0175632
DOI
Related Report
Peer Reviewed / Open Access
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