PLASMINOGEN ACTIVATOR INHIBITOR--1 GENE EXPRESSION IN TUMOR METASTASIS

肿瘤细胞从恶性肿瘤原发部位转移 导致癌症患者死亡的原因。 的过程 转移是复杂的，涉及几个步骤，包括侵袭和 细胞外基质的降解、内渗、转运 血管、外渗和新肿瘤病灶的建立 远离原发肿瘤。 这些步骤可能涉及 几种蛋白水解酶的作用，这些酶在几个 在转移过程中暂时的水平。 UPA是一个关键的 参与代谢过程的酶，通过其激活 纤溶酶原转化为纤溶酶。 肿瘤细胞中uPA的活性可能与肿瘤细胞中uPA的活性有关。 通过uPA与抑制剂PAI-1的结合来调节。 初步 来自由细胞系组成的人骨肉瘤模型的数据 在无胸腺裸鼠中形成肿瘤和转移的不同能力 已经表明，膜结合UPA的水平而不是UPA的水平 分泌的uPA与肿瘤的侵袭和转移行为相关， 肿瘤细胞 用二倍体人胚胎细胞HEL299进行Southern杂交， 线，作为基因拷贝数的控制，我们已经发现， 在HOS、AD 110和KRIB细胞中，编码PAI-1和uPAR的基因是单拷贝的 通过北方印迹杂交，AD 110细胞表达约2 - 3个 稳定状态PAI-1 mRNA比HOS或KRIB细胞高1倍。 AD110 和KRIB表达相当水平的uPAR mRNA（大约5 - 10倍 高于HOS细胞）。 正在进行进一步的研究，以评估 这些细胞中编码PA 1 - 1的基因的转录调节。 PAI-1在调节uPA与uPAR结合中的作用及其与细胞凋亡的关系 PAI-1对AD 110侵袭转移的影响 被评价。

Metastasis of tumor cells from the primary site of a malignancy accounts for the majority of fatalities in cancer patients. The process of metastasis is complex and involves several steps including invasion and degradation of the extracellular matrix, intravasation, transit through the vasculature, extravasation, and establishment of new tumor foci distant from the primary tumor. These steps probably involve the actions of several proteolytic enzymes which are regulated at several levels temporally during the metastatic process. UPA is among pivotal enzymes involved in the metastic process through its ability to activate plasminogen to plasmin. The activity of uPA in tumor cells is probably regulated by the binding of uPA with the inhibitor PAI-1. Preliminary data from a human osteosarcoma model comprised of cell lines showing varying abilities to form tumors and metastasize in athymic nude mice has shown that the level of membrane bound UPA rather than the level of secreted uPA correlates with the invasive and metastatic behavior of the tumor cells. By Southern blot technique using HEL299, a diploid human embryonic cell line, as a control for gene copy number, we have found that the genes encoding PAI-1, and uPAR are single copy in HOS, AD110, and KRIB cells By Northern blot hybridization, AD110 cells express approximately 2-3 fold more steady state PAI-1 mRNA than either HOS or KRIB cells. AD110 and KRIB express equivalent levels of uPAR mRNA (approximately 5-10 fold greater than HOS cells). Further studies are underway to evaluate the transcriptional regulation of the gene encoding PA1-1 in these cells. The role of PAI-1 in regulating the binding of uPA to uPAR and the effect of PAI-1 on the invasive and metastatic properities of AD110 will be evaluated.