Fischer K, Lutz V, Wilhelm O, Schmitt M, Graeff H, Heiss P, Nishiguchi T, Harbeck N, Kessler H, Luther T, Magdolen V, Reuning U
Frauenklinik der Technischen Universität München, Klinikum rechts der Isar, Munich, Germany.
FEBS Lett. 1998 Oct 30;438(1-2):101-5. doi: 10.1016/s0014-5793(98)01279-4.
Ovarian cancer metastasis is associated with an increase in the urokinase-type plasminogen activator (uPA) and its receptor uPAR. We present evidence that binding of uPA to uPAR provokes a mitogenic response in the human ovarian cancer cell line OV-MZ-6 in which endogenous uPA production had been significantly reduced by stable uPA 'antisense' transfection. High molecular weight (HMW) uPA, independent of its enzymatic activity, produced an up to 95% increase in cell number concomitant with 2-fold elevated [3H]thymidine incorporation as did the catalytically inactive but uPAR binding amino-terminal fragment of uPA, ATF. uPA-induced cell proliferation was significantly decreased by blocking uPA/uPAR interaction by the monoclonal antibody IIIF10 and by soluble uPAR. The efficiency of the uPAR binding synthetic peptide cyclo19,31 uPA19-31 to enhance OV-MZ-6 cell growth proved this molecular domain to be the minimal structural determinant for uPA mitogenic activity. Dependence of uPA-provoked cell proliferation on uPAR was further demonstrated in Raji cells which do not express uPAR and were thus not induced by uPA. However, upon transfection with full-length uPAR, Raji cells acquired a significant growth response to HMW uPA and ATF.
卵巢癌转移与尿激酶型纤溶酶原激活剂（uPA）及其受体uPAR的增加有关。我们提供的证据表明，uPA与uPAR的结合在人卵巢癌细胞系OV-MZ-6中引发了促有丝分裂反应，在该细胞系中，通过稳定的uPA“反义”转染，内源性uPA的产生已显著减少。高分子量（HMW）uPA，与其酶活性无关，使细胞数量增加了高达95%，同时[3H]胸苷掺入量增加了2倍，uPA的催化无活性但与uPAR结合的氨基末端片段ATF也有同样的效果。通过单克隆抗体IIIF10和可溶性uPAR阻断uPA/uPAR相互作用，可显著降低uPA诱导的细胞增殖。uPAR结合合成肽cyclo19,31 uPA19-31增强OV-MZ-6细胞生长的效率证明该分子结构域是uPA促有丝分裂活性的最小结构决定因素。uPA诱导的细胞增殖对uPAR的依赖性在不表达uPAR因而不受uPA诱导的Raji细胞中进一步得到证实。然而，用全长uPAR转染后，Raji细胞对HMW uPA和ATF产生了显著的生长反应。
