| Project/Area Number |
14570183
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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 |
Experimental pathology
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| Research Institution | National Cancer Center (2003)
Hamamatsu University School of Medicine (2002) |
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Principal Investigator |
TANAKA Masamitsu National Cancer Center, Growth Factor Division, section head, 細胞増殖因子研究部, 室長 (20291396)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | Tiam1 / nm23 / Eph / ephrin / Rac1 / 低分子量G蛋白質 |
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| Research Abstract |
To know the effect of nm23H1 on the invasion and metastasis of Tiam1-expressing tumor cells, we have established a cell line "BW5147 nm23H1 Tet-ON cell". In this cell line, Tiam1 is stably overexpressed and nm23H1 is inducibly expressed by the addition of doxycycline. The expression of nm23H1 inhibited Tiam1-induced Rac1 activation, membrane ruffling and the formation of lamellipodia of BW5147 nm23H1 Tet-ON cell, By the analysis using Boyden chambers, we found that the migration and invasion of BW5147 cells were inhibited by the overexpression of nm23H1. On the other hand, nm23H1 mutant which lacks the ability of binding to Tiam1 had no effect to inhibit Tiam1-induced Rac1 activation and cell migration. The effect of nm23H1 on Tiam1 expressing tumors was also examined in vivo by feeding doxycycline-containing foods to the mice inoculated BW5147 nm23H1 Tet-ON cells. However we currently do not success to reduce the size of implanted tumor of BW5147 nm23H1 Tet-ON cells because of the modest expression level of nm23H1 in those tumors. On the other hand, we have identified EphA2 tyrosine kinase receptor and ephrin-B1 ligand as stimulators of Tiam1. Interaction of Tiam1 with EphA2 or ephrin-B1 activates Rac1 leading to the induction of neurite outgrowth of cortical neurons and neuroblastoma cells. Because the activation of Tiam1/Rac1 stimulates the cell motility of tumor cells, the results suggest the induction of nm23H1 expression may effectively inhibit the invasion of tumors, which express both Tiam1 and EphA2 or ephrin-B1.
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