2007 Fiscal Year Final Research Report Summary
Mechanism of inhibitory effect of protein C inhibitor on tumorigenesis and angiogenesis
| Project/Area Number |
18591749
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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 |
Urology
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| Research Institution | Mie University |
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Principal Investigator |
HAYASHI Tatsuya Mie University, Graduate School of Medicine, Associated professor (00242959)
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| Co-Investigator(Kenkyū-buntansha) |
OKUMOTO Takayuki Mie University, Graduate School of Medicine, Assistant professor (30378286)
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| Project Period (FY) |
2006 – 2007
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| Keywords | protein C inhibitor / angiogenesis / serine protease inhibitor / VEGF / heparin / MAPK |
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| Research Abstract |
Protein C inhibitor(PCI), which belongs to serine protease inhibitor(SERPIN) family, regulates the anticoagulant protein C pathway and also inhibits urinary plasminogen activator(uPA), a mediator of tumor cell invasion. PCI can bind to heparin, and inhibition of these proteases by PCI is accelerated in the presence of heparin. In the present study, we evaluated the effect of human PCI and its inactive derivatives on tumor growth, metastasis and angiogenesis. The invasiveness of MDA-231 cells was inhibited by recombinant intact PCI, but not by reactive site-modified PCI(R354APCI) or by the N-terminal fragment of protease-cleaved PCI(NTPCI). The in vitro invasiveness of MDA-231 cells expressing intact PCI(MDA-PCI) was also significantly decreased as compared to MDA-231 cells expressing R354APCI(MDA-R354APCI) or NTPCI(MDA-NTPCI). Further, in vivo growth and metastatic potential of MDA-PCI, MDA-R354APCI and MDA-NTPCI cells in severe combined immunodeficient(SCID) mice were significantly decreased as compared to MDA-Mock cells. Angiogenesis was also significantly decreased in Matrigel implant containing MDA-PCI, MDA-R354APCI or MDA-NTPCI cells as compared to that containing MDA-Mock cells. In vivo angiogenesis in rat cornea and in vitro tube formation were also inhibited by recombinant intact PCI, R354APCI and NTPCI. Furthermore, the anti-angiogenic, activity was strong as cleaved antithrombin and pigment epithelium-derived factor. Subsequently, we examined the effect of PCI on vascular endothelial growth factor(VEGF) -induced activation of mitogen-activated protein kinase(MAPK) in the presence or absence of heparin using Western- blot analysis, and suggests that MAPK activation is inhibited by PCI only in the presence of heparin.
Overall, this study showed that, PCI inhibits angiogenesis independently of its protease inhibitory activity by inhibiting MAPK activation, and heparin-binding site on PCI is important for exerting its anti-angiogenic activity
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[Journal Article] Protein C inhibitor regulates hepatocyte growth factor activator-mediated liver regeneration in mice2008
Author(s)
Hamada, T, Kamada, H, Hayashi, T, Nishioka, J, Gabazza, EC, Isaji, S, Uemoto, S, Suzuki, K
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] inhibitor directly and potently inhibits activated hepatocyte growth factor activator2007
Author(s)
Hayashi, T, Nishioka, J, Nakagawa, N, Kamada, H, Cabana, EC, Kobayashi, T, Hattori, A, Suzuki, K., Protein, C
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Journal Title
J Thromb Haemost 5
Pages: 1477-1485
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity2007
Author(s)
Asanuma, K, Yoshikawa, T, Hayashi, T, Akita, N, Nakagawa, N, Hamada, Y, Nishioka, J, Kamada, H, Gabazza, EC, Ido, M, Uchida, A, Suzuki, K
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Journal Title
Int J Cancer 121
Pages: 955-965
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Intracellular localization of protein C inhibitor(PCI)and urinary plasminogen activator in renal tubular epithelial cells from humans and human PCI gene transgenic mice2007
Author(s)
Song, Z, Ma, N, Hayashi, T, Gabazza, EC, Sugimura, Y, Suzuki, K
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Journal Title
Histchem Cell Biol 128
Pages: 293-300
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Inhibition of nuclear factor-kappa B in T cells suppresses lung fibrosis2007
Author(s)
Fujimoto, H, D'Alessandro-Gabazza, CN, Palanki, MS, Erdman, PE, Takagi, T, Gabazza, EC, Bruno, NE, Yano, Y, Hayashi, T, Tamaki, S, Sumida, Y, Adachi, Y, Suzuki, K, Taguchi, O
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Journal Title
Am J Respir Crit Care Med 176
Pages: 1251-1260
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Lipopolysaccharide-induced decreased protein S expression in liver cells is mediated by MEK/ERK signaling and NFkB activation : involvement of membrane-bound CD14 and toll-like receptor-42006
Author(s)
Hayashi, T, Kishiwada, M, Fujii, K, Yuasa, H, Nishioka, J, Ido, M, Gabazza, EC, Suzuki, K
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Journal Title
J Thromb Haemost 4
Pages: 1763-1773
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension2006
Author(s)
Nishii, Y, Cabazza, EC, Fujimoto, H, Nakahara, H, Takagi, T, Bruno, N, D'Alessandro-Gabazza, CN, Maruyama, J, Maruyama, K, Hayashi, T, Adachi, Y, Suzuki, K, Taguchi, O
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Journal Title
J Thromb Haemost 4
Pages: 2331-2339
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Differential regulation of protein S expression in hepatocytes and sinusoidal endothelial cells in rats with cirrhosis2006
Author(s)
Fujii, K, Kishiwada, M, Hayashi, T, Nishioka, J, Gabazza, EC, Okamoto, T, Uemoto, S, Suzuki, K
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Journal Title
J Thromb Haemost 4
Pages: 2607-2615
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Deficiency of tenascin C attenuates allergen-induced bronchial asthma in the mouse2006
Author(s)
Nakahara, H, Gabazza, EC, Fujimoto, H, Nishii, Y, D'Alessandro-Gabazza, CN, Bruno, NE, Takagi, T, Hayashi, T, Maruyama, J, Maruyama, K, Imanaka-Yoshida, K, Suzuki, K, Yoshida, T, Adachi, Y, Taguchi, O
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Journal Title
Eur J Immunol 36
Pages: 3334-3345
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Regulation of breast cancer cell growth, metastasis and angiogenesis by protein C inhibitor2007
Author(s)
Hayashi, T, Asanuma, K, Yoshikawa, T, Akita, N, Nakagawa, N, Hamada, Y, Nishioka, J, Kamada, H, Gabazza, EC, Ido, M, Uchida, A, Suzuki, K
Organizer
XXIth Congress of the International Society on Thrombosis and Haemostasis
Place of Presentation
Geneva, Switzerland
Year and Date
2007-07-11
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Regulation of protein S expression in hepatocytes and sinusoidal endothelial cells in rats with cirrhosis2007
Author(s)
Hayashi, T, Fujii, K, Kishiwada, M, Nishioka, J, Okamoto, T, Gabazza, EC, Uemoto, S, Suzuki, K
Organizer
XXIth Congress of the International Society on Thrombosis and Haemostasis
Place of Presentation
Geneva, Switzerland
Year and Date
2007-07-08
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Lipopolysaccharide(LPS)-induced decrease of protein S expression in hepatocytes and sinusoidal endothelial cells is mediated by activation of MEK/ERK and NFkB pathway2006
Author(s)
Hayashi, T, Kishiwada, M, Fujii, K, Yuasa, H, Nishioka, J, Gabazza, EC, Suzuki, K
Organizer
4th Conference of Asian-Pacific Society of Thrombosis and Hemostasis
Place of Presentation
Suzhou, China
Year and Date
2006-09-21
Description
「研究成果報告書概要(欧文)」より
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