肿瘤血管生成在肿瘤的形成和转移过程中发挥了非常重要的作用，抑制肿瘤血管的生成是现代治疗肿瘤的一个重要策略。血管内皮细胞生长因子（VEGF）是调节血管生成和新生的最重要调节因子。而最近发现的Raf激酶高尔基体锚定蛋白（RKTG）可通过与Raf的相互作用来抑制下游Raf/MEK/ERK信号的激活，然而RKTG是否通过对ERK信号通路的调节进而影响VEGF的功能和血管生成尚不清楚。
<<<借着上海世博会的良好契机，"第一届肿瘤基础和转化医学国际研讨会"于2010年10月12日在中国上海盛大开幕，这将为广大活跃在肿瘤基础和转化医学第一线的科研工作者提供一个互动交流的平台。
会议官方网站：www.cancerasia.org
Oncogene近日发表了中科院营养与代谢重点实验室陈雁研究组博士生张轶璇和姜晓萌等对RKTG调控VEGF信号通路的最新研究结果。作者利用体内和体外实验，从分子、细胞和动物整体水平，充分证明了在血管内皮细胞中，RKTG能够抑制VEGF诱导的内皮细胞增殖、迁移和血管生成过程。在缺氧条件下，RKTG通过干扰HIF-1α与p300之间的相互作用来阻断HIF转录激活活性，抑制由HIF-1α介导的VEGF自分泌。另外，在人肾透明细胞癌的临床样品中，发现RKTG在肿瘤组织中的表达水平与邻近的正常组织中相比有明显下降，并且这种表达的改变与VEGF的表达水平呈负相关。
肾透明细胞癌中血管含量十分丰富，上述RKTG与VEGF之间调节关系的研究，提供了肾透明细胞癌发生发展的一个新机制，并为肾透明细胞癌的治疗提供了一个全新的靶点。
上海市复旦大学附属肿瘤医院叶定伟教授和秦晓健医师、上海华东师范大学生命医学研究所刘明耀教授和易正芳博士、吉林大学第一医院肿瘤中心白欧医师、营养所方靖研究员等人对于该研究给予了合作和支持。
推荐原文出处：
Oncogene doi: 10.1038/onc.2010.270
RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma
Y Zhang1,5, X Jiang1,5, X Qin2, D Ye2, Z Yi3, M Liu3, O Bai4, W Liu1, X Xie1, Z Wang1, J Fang1 and Y Chen1
1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China
2 Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
3 Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
4 The First Hospital, Jilin University, Changchun, Jilin, China
5 These authors contributed equally to this work.
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 1α (HIF-1α) by inhibiting formation of HIF-1α/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.
