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Regulation of MT1-MMP gene expression by HMGI-C

HMGI-C对MT1-MMP基因表达的调控

基本信息

批准号：
11694311
负责人：
OKADA Yasunori
金额：
$ 9.96万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11694311/
关键词：
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

项目摘要

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.

在本研究中，我们已证实MT1-MMPs介导的原MMP2活化与甲状腺浸润性癌和口腔鳞癌中癌细胞的淋巴转移密切相关。原位杂交和免疫组织化学检测结果显示，MT1-MMP在癌巢周围的癌细胞和间质细胞中均有表达，原位酶谱检测显示癌巢中有明胶溶解活性。在人脑胶质瘤中，有脑脊液播散的胶质母细胞瘤较未播散的胶质母细胞瘤的原基质金属蛋白酶-2的活性显著增强。这与MT1-MMPs表达增强、TIMP-2表达减少有关。MT1-MMPs与HMGI-C在人脑胶质瘤中表达的相关性正在研究中。除了癌组织外，我们还检测了MT1-MMPs在类风湿滑膜组织中的表达，并证明了MT1-MMPs在原MMP2激活中的意义。我们建立了MT1-MMP二步夹心酶联免疫测定法，结果显示口腔鳞癌组织中MT1-MMPs的表达水平高于非癌组织。在人肺癌中，有淋巴结转移的肺癌组织中MT1-MMP值明显高于无转移者。将巨噬细胞过度表达基质金属蛋白酶-1的转基因小鼠与ApoE基因敲除小鼠杂交，用西方高脂饲料喂养这些小鼠。与我们的预期相反，基质金属蛋白酶-1的过度表达导致动脉粥样硬化的改善。MT1-MMPs和HMGI-C在发育期和成年小鼠中未见共表达。此外，在两步化学致癌的小鼠皮肤肿瘤中未发现相关关系，提示HMGI-C可能不直接参与小鼠MT1-MMP基因的表达。