| Project/Area Number |
13670878
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Dermatology
|
|---|
| Research Institution | Dermatology, Hamamatsu University School of Medicine |
|---|
Principal Investigator |
YAGI Hiroaki Hamamatsu University School of Medicine Dermatology assistant professor, 医学部附属病院, 講師 (20242779)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TOKURA Yoshiki University of Occupational and Environmental Health, Dermatology professor, 医学部, 教授 (00172156)
|
|---|
| Project Period (FY) |
2001 – 2002
|
| Project Status |
Completed (Fiscal Year 2002)
|
| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
|---|
| Keywords | Melanoma / Signal transduction / migration / IGF-1 / ras / ras蛋白 / シグナル伝達 / ホスホリパーゼA2活性 / トロンビン / ras変異 / cPLA2 / insulin-like growth factor-1 / 走化因子 |
|---|
| Research Abstract |
We have previously shown that migration of human melanocytes and melanoma cell lines is dependent on growth factor stimulation of cytoplasmic phospholipase A2 (cPLA2) mediated through activation of the ras signaling pathway. In this project we describe a highly distinctive biphasic movement response in melanocytes and melanoma in which maximal stimulation inhibits rather than enhancing migration.
Normal human melanocytes and low invasive-potential melanomas show strong chemotactic responses in Boyden chamber assays to growth factors such as IGF-1, ET-1 and bFGF. Thrombin also strongly induces migration in these cells associated with increased cPLA2 activity.
In contrast the highly metastatic melanoma cell line WM 1617 has high spontaneous migration associated with high cPLA2 activity, but addition of small amounts of ET-1 or thrombin decreases cell migration while causing further increases in cPLA2. Low invasive-potential melanoma cells transfected with activating ras mutations also showed high baseline migration which was inhibited by further growth factor stimulation. The increases in migration induced by growth factors in low invasive potential melanoma, and the inhibition of migration in invasive melanomas was blocked bv CDC, a selective 12-lipoxygenasc inhibitor. No effect on migration was found with indomethacin, a selective cyclooxygenase inhibitor.
We describe a biphasic movement response in melanocytes and melanomas, mediated by ras-dependent cPLA2 activation and lipoxygenase. The inhibitory portion of the reponse to added growth factors is most prominent in advanced melanomas. Better understanding of this biphasic response, and modulation with lipoxygenase inhibitors may influence progression of melanoma.
|
