Unseld M, Chilla A, Pausz C, Mawas R, Breuss J, Zielinski C, Schabbauer G, Prager G W
Gernot Schabbauer, Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria, Tel.: +43 1 40160 31427, Fax: +43 1 40160 93101, E-mail:
Gerald W. Prager, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria, Tel.: +43 1 40400 4450, Fax: +43 1 40400 4451, e-mail:
Thromb Haemost. 2015 Aug;114(2):379-89. doi: 10.1160/TH15-01-0016. Epub 2015 Apr 30.
The tumour suppressor phosphatase and tensin homologue (PTEN), mutated or lost in many human cancers, is a major regulator of angiogenesis. However, the cellular mechanism of PTEN regulation in endothelial cells so far remains elusive. Here, we characterise the urokinase receptor (uPAR, CD87) and its tumour-derived soluble form, suPAR, as a key molecule of regulating PTEN in endothelial cells. We observed uPAR-deficient endothelial cells to express enhanced PTEN mRNA- and protein levels. Consistently, uPAR expression in endogenous negative uPAR cells, down-regulated PTEN and activated the PI3K/Akt pathway. Additionally, we found that integrin adhesion receptors act as trans-membrane signaling partners for uPAR to repress PTEN transcription in a NF-κB-dependent manner. Functional in vitro assays with endothelial cells, derived from uPAR-deficient and PTEN heterozygous crossbred mice, demonstrated the impact of uPAR-dependent PTEN regulation on cell motility and survival. In an in vivo murine angiogenesis model uPAR-deficient PTEN heterozygous animals increased the impaired angiogenic phenotype of uPAR knockout mice and were able to reverse the high invasive potential of PTEN heterozygots. Our data provide first evidence that endogenous as well as exogenous soluble uPAR down-regulated PTEN in endothelial cells to support angiogenesis. The uPAR-induced PTEN regulation might represent a novel target for drug interference, and may lead to the development of new therapeutic strategies in anti-angiogenic treatment.
肿瘤抑制因子磷酸酶和张力蛋白同源物（PTEN）在许多人类癌症中发生突变或缺失，是血管生成的主要调节因子。然而，迄今为止，PTEN在内皮细胞中的细胞调控机制仍不清楚。在此，我们将尿激酶受体（uPAR，CD87）及其肿瘤衍生的可溶性形式suPAR鉴定为内皮细胞中调节PTEN的关键分子。我们观察到uPAR缺陷的内皮细胞表达增强的PTEN mRNA和蛋白水平。同样，在内源性uPAR阴性细胞中表达uPAR会下调PTEN并激活PI3K/Akt途径。此外，我们发现整合素黏附受体作为uPAR的跨膜信号伴侣，以NF-κB依赖的方式抑制PTEN转录。对源自uPAR缺陷和PTEN杂合杂交小鼠的内皮细胞进行的体外功能测定，证明了uPAR依赖的PTEN调节对细胞运动和存活的影响。在体内小鼠血管生成模型中，uPAR缺陷的PTEN杂合动物增强了uPAR基因敲除小鼠受损的血管生成表型，并能够逆转PTEN杂合子的高侵袭潜能。我们的数据首次证明，内源性和外源性可溶性uPAR均可下调内皮细胞中的PTEN以支持血管生成。uPAR诱导的PTEN调节可能代表药物干预的新靶点，并可能导致抗血管生成治疗新策略的发展。
