肿瘤侵袭转移过程中基质金属蛋白酶作用机制系列研究

针对肿瘤侵袭转移过程中基质金属蛋白酶(MMPs)及其抑制物的作用和调节机制进行了较深入的系列研究。在包括肺癌、前列腺癌和黑色素瘤的几组具有不同转移潜能的人肿瘤细胞系中，癌细胞产生MMP-2和MMP-9的能力与其侵袭转移能力密切相关。进一步通过反义基因转染技术证实，抑制MMP-9基因表达可以明显降低高转移癌细胞的体外侵袭及裸鼠体内自发转移能力。将金属蛋白酶组织抑制因子TIMP-1，TIMP-2和TIMP-3基因分别导入高转移癌细胞，可以观察到转染细胞的侵袭转移能力受到明显抑制。说明通过选择性抑制MMPs基因表达或增强TIMPs基因表达均可在一定程度上达到抑制肿瘤侵袭转移的目的。与此同时，我们应用定时控制表达技术分别将正义或反义MMP-9基因导入MMP-9不表达或高表达的黑色素瘤细胞，通过四环素控制的分子开关成功实现了MMP-9基因的定时控制表达，为提高临床基因治疗的效果提供了初步实验依据。

Role of matrix metalloproteinases (MMPs) in tumor invasion and metastasis: serial studies on MMPs and TIMPs

We have conducted serial studies on the role of matrix metalloproteinases (MMPs), especially MMP 9, in tumor invasion and metastasis. In 9 human carcinoma cell lines derived from lung, prostate and melanoma, we found, by zymography and Western blot, that the expression levels of MMP 2 and MMP 9 correlated well with their invasive as well as metastatic abilities both in vitro and in nude mice. When anti sense MMP 9 cDNA was introduced into WM451, a highly metastatic human melanoma cell line with high expression level of MMP 9, a significant down regulation of MMP 9 protein expression was found. Meanwhile, the number of cells passing through Matrigel coated membrane ( in vitro invasion assay) and spontaneous metastases to lymph nodes and lungs were significantly reduced. Furthermore, when tissue inhibitors of metalloproteinases 1, 2 or 3 (TIMP 1, TIMP 2 or TIMP 3) cDNAs were individually transtected into metastatic cancer cells, remarkable inhibition of invasion and metastasis were also noticed in each group. These results demonstrate that either up regulation of TIMPs or down regulation of MMPs could significantly inhibit the expression of malignant phenotypes,suggesting the important role MMP 9 plays in tumor invasion and metastasis.