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首页> 外文期刊>Molecular Cancer >The soluble Decoy Receptor 3 is regulated by a PI3K-dependent mechanism and promotes migration and invasion in renal cell carcinoma
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The soluble Decoy Receptor 3 is regulated by a PI3K-dependent mechanism and promotes migration and invasion in renal cell carcinoma

机译：可溶性诱饵受体3受PI3K依赖性机制调节，并促进肾细胞癌的迁移和侵袭

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Background Overexpression of Decoy Receptor 3 (DcR3), a soluble member of the tumor necrosis factor receptor superfamily, is a common event in several types of cancer. In renal cell carcinoma (RCC), DcR3 overexpression is associated with lymph node and distant metastasis as well as a poor prognosis. However, the functional role and regulation of DcR3 expression in RCC is so far unknown. Methods Modulation of DcR3 expression by siRNA and ectopic gene expression, respectively, was performed in ACHN and 769-P RCC cell lines. Functional effects of a modulated DcR3 expression were analyzed with regard to migration, invasion, adhesion, clonogenicity, and proliferation. Furthermore, quantitative RT-PCR and immunoblot analyses were performed to evaluate the expression of downstream mediators of DcR3. In further experiments, luciferase assays, quantitative RT-PCR and immunoblot analyses were applied to study the regulation of DcR3 expression in RCC. Additionally, an ex vivo tissue slice culture technique combined with immunohistochemistry was used to study the regulation of DcR3 expression in human RCC specimens. Results Here, we show that DcR3 promotes adhesion, migration and invasiveness of RCC cells. The DcR3-dependent increase in cellular invasiveness is accompanied with an up-regulation of integrin alpha 4, matrixmetalloproteinase 7 and urokinase plasminogen activator (uPA). Further, we identified a signaling pathway regulating DcR3 expression in RCC. Using in vitro experiments as well as an ex vivo RCC tissue slice culture model, we demonstrate that expression of DcR3 is regulated in a PI3K /AKT-dependent manner involving the transcription factor nuclear factor of activated T-cells ( NFAT ). Conclusions Taken together, our results identify DcR3 as a key driver of tumor cell dissemination and suggest DcR3 as a promising target for rational therapy of RCC.
机译：背景诱饵受体3（DcR3）（肿瘤坏死因子受体超家族的可溶性成员）的过表达是几种类型癌症中的常见事件。在肾细胞癌（RCC）中，DcR3过表达与淋巴结转移和远处转移以及预后不良有关。然而，迄今为止尚不清楚RCC中DcR3表达的功能作用和调控。方法在ACHN和769-P RCC细胞系中分别通过siRNA和异位基因表达调节DcR3表达。关于迁移，侵袭，粘附，克隆形成性和增殖，分析了调节的DcR3表达的功能作用。此外，进行了定量RT-PCR和免疫印迹分析，以评估DcR3下游介质的表达。在进一步的实验中，荧光素酶测定，定量RT-PCR和免疫印迹分析被用于研究Rc中DcR3表达的调节。另外，结合免疫组织化学的离体组织切片培养技术用于研究人RCC标本中DcR3表达的调节。结果在这里，我们显示DcR3促进了RCC细胞的粘附，迁移和侵袭性。 DcR3依赖性细胞侵袭性的增加伴随着整联蛋白α4，基质金属蛋白酶7和尿激酶纤溶酶原激活物（uPA）的上调。此外，我们鉴定了调节RCC中DcR3表达的信号通路。使用体外实验以及离体RCC组织切片培养模型，我们证明DcR3的表达以PI3K / AKT依赖性方式受到调节，涉及活化T细胞（NFAT）的转录因子核因子。结论综上所述，我们的结果确定DcR3是肿瘤细胞传播的关键驱动力，并建议DcR3作为合理治疗RCC的有希望的靶标。

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