| Project/Area Number |
13470358
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Otorhinolaryngology
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| Research Institution | Kanazawa University |
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Principal Investigator |
FURUKAWA Mitsuru KANAZAWA UNIVERSITY, Graduate School of Medical Science, Professor, 大学院・医学系研究科, 教授 (40092803)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIZAKI Tomokazu KANAZAWA UNIVERSITY, University Hospital, Assistant Professor, 医学部附属病院, 講師 (70262582)
竹下 元 金沢大学, 医学部附属病院, 助手 (40272976)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥11,800,000 (Direct Cost: ¥11,800,000)
Fiscal Year 2003: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2002: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2001: ¥6,800,000 (Direct Cost: ¥6,800,000)
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| Keywords | LMP1 / MMP9 / NF-κB / I-κB / Invasiveness / Metastasis / Gene targeted therapy / Aspirin / I-_κB / bFGF / VEGF / TGF-α / IL-8 |
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| Research Abstract |
Nasopharyngeal carcinoma(NPC), an epithelial tumor which is characterized by marked geographic and population differences in incidence, is found to be associated with Epstein-Barr virus(EBV) by serologic evidence, and the relationship was confirmed by the detection of EBVDNA and EB-encoded RNAs in NPC cells. While, NPC is highly metastatic carcinoma whose consistent associated with EBV has been established. Latent membrane protein 1(LMP1), an EBV membrane protein expressed in latent infection is considered to be the EBV oncoprotein. Matrix metalloproteinase 9(MMP9), one of the MMP families, degrades Type IV collagen, a major 4 component of extracellural matrix and is believed to be crucial for cancer invasion and metastasis. Although MMP9 is reported to be expressed in a variety of cancers, no reports concerning NPC have been published. We have shown that LMP1 induces MMP9 in vitro cell line, which suggests the possibility of mechanism in which LMP1 of EBV contributes to the metastasis
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and tumorgenesis of NPC by the induction of MMP9. Then the expression of LMP1 and MMP9 were immunohistochemically examined, and the relation of these proteins was statistically analyzed. We also analyzed the association of these proteins with clinical features. As results, both LMP1 and MMP9 proteins were predominantly immunolocalized in cancer nests. The expression of MMP9 showed a significant positive correlation with the expression of LMP1. Also, the expression of MMP9 correlated with lymphnode metastasis.
We also demonstrated that LMP1 enhances MMP9 expression by activation of nuclear factor(NF)κB and activator protein(AP)-1. We therefore tested whether up-regulation of MMP9 by LMP1 could be correlated with enhanced invasiveness of tumor cells in vitro. Whether aspirin and sodium salicylate could reduce invasiveness and whether LMP1 could enhance MMP9 expression in tumors grown in nude mice were also tested. CS3A cells stably expressing LMP1 had increased expression of MMP9 and showed greater invasion through reconstituted basement membrane compared with vector-transfected C33A cells. Treatment with aspirin and sodium salicylate inhibited invasiveness of the LMP1-expressing C33A cells and suppressed both the LMP1-induced MMP9 expewssion in zymographic analyses and LMP1-induced MMP9 promoter activity in CAT reporter assays. The inhibitory effect of aspirin on NF-κB activity was attributable to the inhibition of I-κB kinase activity. Finally, tumors derived from vector-transfected C3SA cells stably expressing LMP1 grown in nude mice showed enhanced MMP9 levels compared with tumors derived from vector-trancfected C33A cells. This enhancement was inhibited by treatment of the mice with aspirin. These results suggest that aspirin may be able to suppress invasion and metastasis of EBV-associated tumors that express LMP1 by suppression of MMP-9. Less
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