DU145 human prostate carcinoma invasiveness is modulated by urokinase receptor (uPAR) downstream of epidermal growth factor receptor (EGFR) signaling
DU145 human prostate carcinoma invasiveness is modulated by urokinase receptor (uPAR) downstream of epidermal growth factor receptor (EGFR) signaling
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DOI：
10.1016/j.yexcr.2004.05.008
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发表时间：
2004-09-10
影响因子：
3.7
通讯作者：
Wells, A
中科院分区：
文献类型：
--
作者：
Mamoune, A;Kassis, J;Wells, A
肿瘤细胞的运动和侵袭与表皮生长因子受体（EGFR）和尿激酶型纤溶酶原激活物（uPAR）信号的上调有关。然而，我们不知道这些事件是相互依赖的还是不相关的，尽管有明显的诊断和治疗意义。基因芯片分析表明，EGFR信号通过磷脂酶c - γ (plcγ)诱导uPAR转录。我们利用了DU145人前列腺癌细胞系的两个亚系，这两个亚系经过基因工程改造，可以不同地激活EGFR/PLCgamma级联，并且在体外和体内具有不同的侵袭性。发现这些细胞中的uPAR蛋白水平依赖于PLC信号传导，PLC信号传导的药物抑制可降低uPAR表达。为了确定uPAR在egfr介导的侵袭中是否是必需元件，我们在两个DU145亚型中以正义或反义方向稳定地表达了uPAR cDNA。有趣的是，uPA的生产与uPAR在这些分支中并行调节，尽管程度较低。uPAR的反义可通过Matrigel抑制高侵袭性DU145 WT细胞的侵袭，降低裸鼠肿瘤的侵袭性。上调uPAR可通过Matrigel显著增加中度侵袭性DU145亲本（DU145 P）细胞的侵袭性，但在小鼠中未见这种增加的侵袭性。uPA活性似乎至少通过Matrigel促进了侵袭性，因为uPA或amiloride的抗体限制了迁移。这些结果支持了一个由自分泌EGFR信号促进的肿瘤侵袭模型，该模型涉及加强改变的基因表达，至少是uPAR，进一步诱导细胞运动。在这里，一些表达水平相互关联的关键分子（包括EGFR和uPAR）是必需的，但在缺乏其他促进肿瘤进展的关键分子的情况下，这些关键分子是不够的。(C) 2004 Elsevier Ire。版权所有。
Tumor cell motility and invasion have been linked to upregulated signaling from both the epidermal growth factor receptor (EGFR) and that for urokinase-type plasminogen activator (uPAR). However, we do not know whether these events are interdependent or unrelated, despite the obvious diagnostic and therapeutic implications. Gene microarray analyses have suggested that EGFR signaling via phospholipase C-gamma (PLCgamma) induces uPAR transcription. We utilized two sublines of the DU145 human prostate carcinoma cell line that are genetically engineered to differentially activate the EGFR/PLCgamma cascade and are variously invasive in vitro and in vivo. uPAR protein levels in these cells were found to be dependent on PLC signaling, pharmacologic inhibition of PLC signaling reduced uPAR expression. To determine whether uPAR was a required element in EGFR-mediated invasion, we stably expressed uPAR cDNA in either sense or antisense orientation in the two DU145 sublines. Interestingly, uPA production was modulated in parallel, although to a lesser degree, with uPAR in these sublines. Antisense to uPAR significantly restricted invasion of the highly invasive DU145 WT cells through Matrigel and reduced aggressiveness of tumors in nude mice. Up-regulation of uPAR significantly increased the invasiveness of the moderately invasive DU145 parental (DU145 P) cells through Matrigel, but this increased invasiveness was not seen in mice. uPA activity appears to contribute to invasiveness at least through Matrigel, as antibody to uPA or amiloride limited the transmigration. These results support a model of tumor invasion promoted by autocrine EGFR signaling involving reinforcing altered gene expression, of uPAR at least, that further induces cell motility. Herein, a number of key molecules whose expression levels are interrelated, including both EGFR and uPAR, are required but none are sufficient in the absence of other keys molecules in promoting tumor progression. (C) 2004 Elsevier Ire. All rights reserved.