Asai M, Kato M, Asai N, Iwashita T, Murakami H, Kawai K, Nakashima I, Takahashi M
Department of Pathology, Nagoya University School of Medicine.
Jpn J Cancer Res. 1999 Jan;90(1):86-92. doi: 10.1111/j.1349-7006.1999.tb00670.x.
We recently established a metallothionein-I(MT)/RET transgenic mouse line in which skin melanosis, benign melanocytic tumor and malignant melanoma develop stepwise. Malignant melanoma cells but not benign melanocytic tumor cells had metastatic ability in transgenic mice. In the present study, we investigated the expression of several matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs), including MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MT1-MMP, TIMP-1 and TIMP-2, in these tumors. Western and northern blot analyses revealed that malignant transformation of melanocytic tumors developed in MT/RET transgenic mice accompanied with upregulation of MMP-9 and downregulation of TIMP-2. Expression of other MMP and TIMP genes examined was very low or undetectable in both benign and malignant tumors. Since activation of MMP-9 in malignant tumors was detected by gelatin zymography, these results suggest that imbalance of expression of the MMP-9 and TIMP-2 genes might be associated with metastatic ability of melanoma cells developed in MT/RET transgenic mice.
我们最近建立了一种金属硫蛋白-I（MT）/RET转基因小鼠品系，其中皮肤黑色素沉着、良性黑素细胞肿瘤和恶性黑色素瘤会逐步发展。在转基因小鼠中，恶性黑色素瘤细胞具有转移能力，而良性黑素细胞肿瘤细胞则没有。在本研究中，我们调查了这些肿瘤中几种基质金属蛋白酶（MMPs）和基质金属蛋白酶组织抑制剂（TIMPs）的表达情况，包括MMP-1、MMP-2、MMP-3、MMP-7、MMP-9、MT1-MMP、TIMP-1和TIMP-2。蛋白质免疫印迹和Northern印迹分析显示，MT/RET转基因小鼠中发生的黑素细胞肿瘤的恶性转化伴随着MMP-9的上调和TIMP-2的下调。在良性和恶性肿瘤中，所检测的其他MMP和TIMP基因的表达都非常低或无法检测到。由于通过明胶酶谱法检测到恶性肿瘤中MMP-9的激活，这些结果表明MMP-9和TIMP-2基因表达的失衡可能与MT/RET转基因小鼠中产生的黑色素瘤细胞的转移能力有关。
