Hjortland Geir Olav, Lillehammer Trine, Somme Stig, Wang Junbai, Halvorsen Thomas, Juell Siri, Hirschberg Henry, Fodstad Øystein, Engebraaten Olav
Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, University of Oslo, 0310 Oslo, Norway.
Exp Cell Res. 2004 Mar 10;294(1):130-9. doi: 10.1016/j.yexcr.2003.10.013.
The level of plasminogen activator inhibitor-1 (PAI-1) in tumor tissue has been shown to be an independent negative prognostic factor in different cancers. There are several proposed reasons for this, among these, the influence of PAI-1 on tumor neovascularization and cell migration. We report that PAI-1 stimulates expression and release of vascular endothelial growth factor (VEGF) in the human glioma cell line D54Mg, and thereby stimulates the proliferation of human umbilical vein endothelial cells (HUVEC) in vitro. To search for possible molecular effects of PAI-1 on malignant cells, cDNA array hybridization analysis of D54Mg glioma cells transfected with an adenoviral PAI-1 expression vector was performed. This revealed that the VEGF response was accompanied with the simultaneous upregulation of GADD153, Rho GTPase activating protein 4 (p115), Collagen type VI alpha 1 and cell division cycle 42 (CDC42) transcripts. Exogenous treatment of D54Mg cells with a constitutively active recombinant PAI-1 protein confirmed an upregulation of VEGF expression in a time- and dose-dependent manner, and supernatants from such cultures stimulated the proliferation of human umbilical vein endothelial cells in vitro. In 44 human glioma biopsies, patients, the protein levels of PAI-1 correlated strongly with the levels of VEGF in the tumor tissues. Whereas VEGF expression correlated inversely with survival, there was no statistically significant prediction of survival by PAI-1 in this group of patients. These clinical data support and strengthen the hypothesis that PAI-1 is one of the factors regulating and inducing the VEGF expression in human gliomas. The induction of VEGF expression and thus endothelial cell proliferation may represent an as yet undiscovered mechanism whereby PAI-1 contributes to tumor neoangiogenesis.
肿瘤组织中纤溶酶原激活物抑制剂-1（PAI-1）的水平已被证明是不同癌症中一个独立的负面预后因素。对此有几种提出的原因，其中包括PAI-1对肿瘤新生血管形成和细胞迁移的影响。我们报告PAI-1刺激人胶质瘤细胞系D54Mg中血管内皮生长因子（VEGF）的表达和释放，从而在体外刺激人脐静脉内皮细胞（HUVEC）的增殖。为了寻找PAI-1对恶性细胞可能的分子效应，对用腺病毒PAI-1表达载体转染的D54Mg胶质瘤细胞进行了cDNA阵列杂交分析。这表明VEGF反应伴随着GADD153、Rho GTPase激活蛋白4（p115）、VI型胶原α1和细胞分裂周期42（CDC42）转录本的同时上调。用组成型活性重组PAI-1蛋白对D54Mg细胞进行外源处理，证实VEGF表达呈时间和剂量依赖性上调，并且来自此类培养物的上清液在体外刺激人脐静脉内皮细胞的增殖。在44例人类胶质瘤活检患者中，PAI-1的蛋白水平与肿瘤组织中VEGF的水平密切相关。虽然VEGF表达与生存率呈负相关，但在这组患者中，PAI-1对生存率没有统计学上的显著预测作用。这些临床数据支持并强化了PAI-1是调节和诱导人类胶质瘤中VEGF表达的因素之一这一假设。VEGF表达的诱导以及因此内皮细胞的增殖可能代表了一种尚未发现的机制，通过该机制PAI-1促进肿瘤新生血管形成。
