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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.

在目前的研究中，我们已经证明MT1-MMP介导的proMMP-2激活与人类浸润性甲状腺癌和口腔鳞状细胞癌中癌细胞的淋巴结转移相关。原位杂交和免疫组织化学显示MT1-MMP在癌细胞和邻近癌细胞巢的基质细胞中表达，并且原位酶谱显示癌细胞巢中的明胶分解活性。在人类胶质瘤中，与未发生脑脊液播散的胶质母细胞瘤相比，脑脊液播散的胶质母细胞瘤中 proMMP-2 的激活显着增强。这与 MT1-MMP 表达增强和 TIMP-2 产生减少有关。目前正在研究人类神经胶质瘤中 MT1-MMP 和 HMGI-C 表达之间的相关性。除了癌症组织外，我们还检测了类风湿滑膜组织中的 MT1-MMP 表达，并证明了 MT1-MMP 对 proMMP-2 激活的影响。我们开发了一种针对 MT1-MMP 的两步夹心酶免疫测定法，通过该测定法，口腔鳞状细胞癌中癌组织中的产生水平高于非癌组织中的产生水平。在人肺癌中，有淋巴结转移的癌中MT1-MMP水平较无转移的癌显着升高。将巨噬细胞中过度表达 MMP-1 的转基因小鼠与 ApoE 敲除小鼠杂交，并用西方高脂肪饮食喂养这些小鼠。与我们的预期相反，MMP-1的过度表达导致动脉粥样硬化的改善。在发育中或成年小鼠中未显示 MT1-MMP 和 HMGI-C 的共表达。此外，在小鼠两步化学致癌引起的皮肤肿瘤中未发现相关性，表明HMGI-C可能不直接参与小鼠MT1-MMP基因表达。