| Project/Area Number |
11694311
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Keio University |
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Principal Investigator |
OKADA Yasunori Keio University, School of Medicine, Professor, 医学部, 教授 (00115221)
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| Co-Investigator(Kenkyū-buntansha) |
IKEDA Eiji Keio University, School of Medicine, Lecturer, 医学部, 講師 (30232177)
UEDA Yoshimichi Kanazawa Medical University, Associate Professor, 助教授 (50271375)
YOSHIOKA Katsuji Cancer Research Institute, Kanazawa University, Professor, がん研究所, 教授 (60200937)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥15,560,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2001: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2000: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1999: ¥5,200,000 (Direct Cost: ¥5,200,000)
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| Keywords | Matrix metalloproteinase / Membrane type MMP / Gene expression / HMG / Invasion and metastasis / Transgenic and knockout mouse / Arteriosclerosis / 浸潤・転移 / 遺伝子欠損マウス |
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| Research Abstract |
In the present studies, we have demonstrated that proMMP-2 activation mediated by MT1-MMP is correlated with lymph node metastases of carcinoma cells in the human invasive thyroid carcinomas and oral squamous cell carcinomas. MT1-MMP was shown to be expressed in the carcinoma cells and stromal cells adjacent to the carcinoma cell nests by in situ hybridization and immunohistochemistry, and gelatinolytic activity was demonstrated in the carcinoma cell nests by in situ zymography. In human gliomas, activation of proMMP-2 was remarkably enhanced in the glioblastomas with cerebrospinal dissemination as compared with those without dissemination. This was related with enhanced expression of MT1-MMP and decreased production of TIMP-2. Correlation between the expression of MT1-MMP and HMGI-C in human gliomas is now under study. In addition to cancer tissues, we also examined MT1-MMP expression in rheumatoid synovial tissues and demonstrated the implications of MT1-MMP for the proMMP-2 activation. We developed a two-step sandwich enzyme immunoassay for MT1-MMP, by which production level in the carcinoma tissues was shown to be higher in the oral squamous cell carcinomas than in non-carcinoma tissues. In the human lung carcinomas, MT1-MMP level was significantly increased in the carcinomas with lymph node metastasis as compared with those without metastasis. Transgenic mice over-expressing MMP-1 in macrophages were crossed with ApoE-knockout mice, and those mice were fed with western high-fat diet. In contrary to our expectation, over-expression of MMP-1 resulted in improvement of atherosclerosis. Co-expression of MT1-MMP and HMGI-C was not shown in the developing or adult mice. In addition, no correlation was demonstrated in the skin tumors caused by two-step chemical carcinogenesis in mice, suggesting that HMGI-C may not be directly involved in the MT1-MMP gene expression in mice.
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