Development of novel therapeutic strategy based on malignant nature of colorectal cancer
| Project/Area Number |
16591313
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Osaka University |
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Principal Investigator |
YAMAMOTO Hirofumi Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (30322184)
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| Co-Investigator(Kenkyū-buntansha) |
SEKIMOTO Mistugu Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (10273658)
IKEDA Masataka Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (80335356)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | antisense cyclin D1 / TCF decoy / dominant negative TCF / colorectal cancer / liver metastasis / Wnt signal / cyclin D1 |
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| Research Abstract |
Beta-catenin and TCF complex is activated in a variety of gastrointestinal cancer. The down stream of this way contains cancer related gene including cyclin D1,MMP7,c-myc. To block this pathway may be useful strategy against cancer. We target TCF transcription and cyclin D1 oncogene.
1.Adnovirus dominant negative TCF
Adenovirus dominant negative TCF inhibited TCF transcription activity and the promoter activities of down stream genes including cyclin D1,MMP7,c-myc. It also inhibited in vivo subcutaneous tumor growth and liver metastasis. Therapeutic model for xenograft was also successful. These findings suggest that Adenovirus dominant negative TCF may be useful strategy for tumors that display high TCF transcription activity.
2.TCF decoy
To block TCF activity in safer way, we developed a novel TCF DNA decoy. In vitro assays indicated it inhibited TCF activity and the promoter activities of down stream genes including cyclin D1,MMP7,c-myc. successfully. It inhibited growth of tumor cell, but not non-tumor cells. However problem still remains with regard to its stability in vivo. FITC labeling revealed TCF decoy accumulate into nucleus within 24 hr and remained till 48-72 hr. These findings will be published in Mol Cancer Ther (in press).
3.Antisense cyclin D1
Adenovirus antisense cyclin D1 inhibited tumor growth and tumor associated vessels. One of the mechanism for anti-tumor vessel is a direct effects of antisense to cyclin D1 on vascular endothelial cells. As another mechanism, cyclin D1 inhibition caused inhibition of STAT-3 transcription factor, which leaded to inhibition of VEGF promoter activity. This occurs in a certain tumor cell type. These findings will be published in Clin Cancer Res (in press).
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Report
(3 results)
Research Products
(7 results)
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[Journal Article] Antisense to Cyclin D1 Inhibits VEGF-Stimulated Growth of Vascular Endothelial Cells. Implication of Tumor Vascularization
Author(s)
Yasui M, Yamamoto H, Ngan Chew Yee, Bazarragchaa D, Sugita Y, Fukunaga H, Gu J, Maeda M, Takemsa I, Ikeda M, Fujio Y, Sekimoto M. Matsuura N, I.Bernard Weinstein, Monden M.
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Journal Title
Clinical Cancer Research (in press)
Related Report
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[Journal Article] Construction of a novel DNA decoy that inhibits the oncogenic β-catenin/TCF pathway
Author(s)
Seki Y, Yamamoto H, Ngan Chew Yee, Yasui M, Tomita N, Kitani K, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, Chris Albanese, Kaneda Y, Richard G Pestell, Monden M.
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Journal Title
Molecular Cancer Therapeutics (in press)
Related Report
