RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma
RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma
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RKTG 通过抑制 MAPK 介导的自分泌 VEGF 信号传导来抑制血管生成，并在透明细胞肾细胞癌中下调
DOI：
10.1038/onc.2010.270
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发表时间：
2010-09-01
期刊：
影响因子：
8
通讯作者：
Chen, Y.
中科院分区：
文献类型：
--
作者：
Zhang, Y.;Jiang, X.;Chen, Y.
血管内皮生长因子(VEGFs)是血管生成和血管生成的重要调节因子。自分泌的血管内皮生长因子信号是维持血管系统动态平衡所必需的。血管生成失调与许多人类癌症的发生有关，尤其是肾透明细胞癌(CcRCC)，这是一种高度血管化的肿瘤。与此同时，抗血管生成已成为人类癌症治疗的支柱。在这项研究中，我们分析了Raf Kinase Trapping to Golgi，Raf/MEK/ERK，Raf Kinase Trapping to Golgi，Raf/MEK/通过一系列的体外和体内实验，我们发现RKTG对内皮细胞的增殖、迁移、发芽和血管生成有负面影响。RKTG通过抑制丝裂原活化蛋白激酶信号转导，通过抑制HIF-1α/p300复合体的形成和抑制血管内皮生长因子的转录，负向调节缺氧诱导因子1α的反式激活活性，从而减少缺氧诱导的血管内皮细胞生长因子的产生。RKTG在临床肾细胞癌组织中的表达水平显著下调，与血管内皮生长因子的表达水平呈负相关。这些结果突出了RKTG及其调控的Raf/ERK/MEK信号级联在血管生成和自分泌VEGF信号中的功能作用。此外，本研究提示RKTG可能通过调节血管生成参与肾细胞癌的发生发展。Oncogene(2010)29,5404-5415；doi：10.1038/onc.2010.270；2010年7月5日在线发布
Vascular endothelial growth factors (VEGFs) are crucial regulators of angiogenesis and vasculogenesis. The autocrine VEGF signaling is required for maintaining the homeostasis of vasculature. Dysregulation of angiogenesis is implicated in the development of many human cancers, especially in clear-cell renal cell carcinoma (ccRCC), a highly vascularized tumor. Meanwhile, antiangiogenesis has become a mainstay in the treatment of human cancers. In this study, we analyzed the functional roles of RKTG (Raf Kinase Trapping to Golgi), a negative regulator of mitogen-activated protein kinase (Raf/MEK/ERK) signaling, by sequestration of Raf kinase to the Golgi apparatus, in angiogenesis and ccRCC. Through a series of in vitro and in vivo experiments, we found that RKTG has a negative effect on cell proliferation, migration, sprouting and angiogenesis of endothelial cells. RKTG, by suppressing mitogen-activated protein kinase signaling, negatively regulates the transactivation activity of hypoxia-inducible factor 1 alpha (HIF-1 alpha) by inhibiting formation of HIF-1 alpha/p300 complex and suppressing VEGF transcription, thereby reducing hypoxia-induced VEGF production. The expression level of RKTG is significantly downregulated in clinical ccRCC tumor samples, with an inverse correlation with VEGF expression level. These results highlight the functional roles of RKTG and its regulated Raf/ERK/MEK signaling cascade in angiogenesis and autocrine VEGF signaling. In addition, this study indicates that RKTG is likely implicated in the development of ccRCC through its regulation on angiogenesis. Oncogene (2010) 29, 5404-5415; doi: 10.1038/onc.2010.270; published online 5 July 2010