| Project/Area Number |
18591830
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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 |
Obstetrics and gynecology
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| Research Institution | Shinshu University |
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Principal Investigator |
ASHIDA Takashi Shinshu University, Obstetrics & Gynecology, Assistant professor (00334897)
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| Co-Investigator(Kenkyū-buntansha) |
SHIOZAWA Tanri Shinshu University, Obstetrics & Gynecology, Associate Professor (20235493)
KONISHI Ikuo Kyoto University Faculty of Medicine, Gynecology & Obstetrics, Professor (90192062)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | endometrial carcinoma / estrogen / MAP kinasae / IGF-1 / cychn / MAP Kinase |
|---|
| Research Abstract |
To examine estrogen-induced growth mechanisms of endometrial carcinoma, we investigated the estrogen-induced activation of the mitogen-activated protein kinase (MAPK) pathway and cell cycle regulators. Estradiol (E2) treatment at concentrations of 10^8M and 10^6M to estrogen receptor (ER)-positive endometrial carcinoma Ishikawa cells for 24 hours resulted in increased cell proliferation by 20% and 28%, respectively. The E2-induced proliferation was associated with activation of extracellular signal-regulated kinase (ERK)1/2 and up-regulation of cyclin Dl and E, which were suppressed by the addition of a MEK inhibitor (U0126) or an ER antagonist (ICI182,780). Then, our screening for estrogen-inducible growth factors identified that insulin-like growth factor (IGF)-1 was up-regulated remarkably by E2. Immunoprecipitation using conditioned medium of Ishikawa cells after E2 treatment confirmed the E2-induced secretion of IGF-1 protein. Treatment with recombinant IGF-1 stimulated cell proliferation in a dose-dependent fashion, in association with ERK1/2 phosphorylation and up-regulation of cyclin D1 and E. These IGF-1-induced responses were suppressed by treatment with ER antagonist, MEK inhibitor, or anti-IGF-1 receptor antibody. Immunohistochemical staining confirmed the expression of activated ERK1/2 in normal proliferative phase endometria and endometrial carcinomas, indicating the involvement of this pathway in actively proliferating endometrial tissues in vivo. These findings suggest that E2-induced proliferation of endometrial carcinoma cells is mediated by the ERK1/2 pathway via autocrine stimulation of IGF- 1.
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