| Project/Area Number |
14032202
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Osaka University |
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Principal Investigator |
MEKADA Eisuke Osaka University, Research Institute for Microbial Diseases, Professor, 微生物病研究所, 教授 (20135742)
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| Co-Investigator(Kenkyū-buntansha) |
WAMOTO Ryoi Osaka University, Research Institute for Microbial Diseases, Assiociate Professor, 微生物病研究所, 助教授 (10213323)
宮戸 健二 大阪大学, 助手 (60324844)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥95,500,000 (Direct Cost: ¥95,500,000)
Fiscal Year 2004: ¥31,500,000 (Direct Cost: ¥31,500,000)
Fiscal Year 2003: ¥35,000,000 (Direct Cost: ¥35,000,000)
Fiscal Year 2002: ¥29,000,000 (Direct Cost: ¥29,000,000)
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| Keywords | HB-EGF / EGF family / growth factor / ovarian cancer / diphtheria toxin / CRM197 / 増殖因子 / 膜結合型 / 遺伝子ターゲッティング / 遺伝子欠損マウス / p38MAPK / 心不全 |
|---|
| Research Abstract |
HB-EGF is a member of the EGF family growth factors. This factor is synthesized as proHB-EGF, a membrane-anchored precursor protein, and is cleaved on the cell surface to yield the soluble growth factor. The conversion of proHB-EGF into the soluble form is critical for the activity of this growth factor, and therefore this process is tightly regulated. We found that, among the EGFR family of growth factors, HB-EGF gene expression in cancerous tissues of ovarian cancer and HB-EGF protein levels in patients' ascites fluid were significantly elevated. The human ovarian cancer cell lines SKOV3 and RMG-1 form tumors in nude mice. Tumor formation of these cells was enhanced by exogenous expression of proHB-EGF, and completely blocked by proHB-EGF gene RNA interference or by CRM197, a specific HB-EGF inhibitor. Transfection with mutant forms of HB-EGF indicated that the release of soluble HB-EGF is essential for tumor formation. These results indicate that HB-EGF is the primary member of the EGFR family of growth factors expressed in ovarian cancer and that LPA-induced ectodomain shedding of this growth factor is a critical step in tumor formation, making HB-EGF a novel therapeutic target for ovarian cancer.
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