Regulation of MT1-MMP gene expression by HMGI-C

在目前的研究中，我们证实了MT1-MMP介导的proMMP-2激活与人侵袭性甲状腺癌和口腔鳞状细胞癌中癌细胞的淋巴结转移有关。原位杂交和免疫组化结果显示，MT1-MMP在癌细胞和癌细胞巢附近的基质细胞中表达，原位酶谱分析显示，MT1-MMP在癌细胞巢中具有溶胶活性。在人类胶质瘤中，与未播散的胶质瘤相比，有脑脊液播散的胶质瘤中proMMP-2的激活显著增强。这与MT1-MMP的表达增强和TIMP-2的产生减少有关。MT1-MMP与HMGI-C在人类胶质瘤中的表达关系正在研究中。除了癌症组织外，我们还检测了MT1-MMP在类风湿滑膜组织中的表达，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的两步夹心酶免疫分析方法，通过该方法，口腔鳞状细胞癌的癌组织中MT1-MMP的产生水平高于非癌组织。在人肺癌中，有淋巴结转移的肺癌中MT1-MMP水平明显高于无淋巴结转移的肺癌。将巨噬细胞中过表达MMP-1的转基因小鼠与敲除apoe的小鼠杂交，并饲喂西式高脂饲料。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。MT1-MMP和HMGI-C在发育或成年小鼠中未见共表达。此外，在小鼠两步化学致癌皮肤肿瘤中未发现相关，提示HMGI-C可能不直接参与小鼠MT1-MMP基因的表达。

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.