Regulation of MT1-MMP gene expression by HMGI-C

在本研究中，我们已经证明，由MT 1-MMP介导的proMMP-2活化与人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。原位杂交和免疫组化显示MT 1-MMP在癌细胞和癌细胞巢附近的基质细胞中表达，原位酶谱显示癌细胞巢中有明胶溶解活性。在人脑胶质瘤中，proMMP-2的激活在有脑脊髓播散的胶质母细胞瘤中显著增强，与那些没有播散的胶质母细胞瘤相比。这与MT 1-MMP表达增强和TIMP-2产生减少有关。MT 1-MMP和HMGI-C在人脑胶质瘤中的表达相关性正在研究中。除癌组织外，我们还检测了MT 1-MMP在类风湿性滑膜组织中的表达，并证明了MT 1-MMP对proMMP-2活化的影响。我们建立了一种两步夹心酶联免疫法检测MT 1-MMP，结果表明，口腔鳞癌组织中MT 1-MMP的产生水平高于非癌组织。在人肺癌中，有淋巴结转移的癌组织中MT 1-MMP水平显著高于无淋巴结转移的癌组织。将在巨噬细胞中过表达MMP-1的转基因小鼠与ApoE基因敲除小鼠杂交，并以西方高脂饮食喂养这些小鼠。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。MT 1-MMP和HMGI-C的共表达在发育或成年小鼠中未显示。此外，在小鼠两步化学致癌引起的皮肤肿瘤中没有证明相关性，表明HMGI-C可能不直接参与小鼠MT 1-MMP基因表达。

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.