腫瘤血管生成在腫瘤的形成和轉(zhuǎn)移過程中發(fā)揮了非常重要的作用，抑制腫瘤血管的生成是現(xiàn)代治療腫瘤的一個(gè)重要策略,。血管內(nèi)皮細(xì)胞生長因子（VEGF）是調(diào)節(jié)血管生成和新生的最重要調(diào)節(jié)因子,。而最近發(fā)現(xiàn)的Raf激酶高爾基體錨定蛋白（RKTG）可通過與Raf的相互作用來抑制下游Raf/MEK/ERK信號(hào)的激活，然而RKTG是否通過對(duì)ERK信號(hào)通路的調(diào)節(jié)進(jìn)而影響VEGF的功能和血管生成尚不清楚,。
>>>借著上海世博會(huì)的良好契機(jī),，"第一屆腫瘤基礎(chǔ)和轉(zhuǎn)化醫(yī)學(xué)國際研討會(huì)"將于2010年10月12日在中國上海盛大開幕，這將為廣大活躍在腫瘤基礎(chǔ)和轉(zhuǎn)化醫(yī)學(xué)第一線的科研工作者提供一個(gè)互動(dòng)交流的平臺(tái),。
會(huì)議官方網(wǎng)站：www.cancerasia.org
Oncogene近日發(fā)表了中科院營養(yǎng)與代謝重點(diǎn)實(shí)驗(yàn)室陳雁研究組博士生張軼璇和姜曉萌等對(duì)RKTG調(diào)控VEGF信號(hào)通路的最新研究結(jié)果,。作者利用體內(nèi)和體外實(shí)驗(yàn)，從分子,、細(xì)胞和動(dòng)物整體水平,，充分證明了在血管內(nèi)皮細(xì)胞中，RKTG能夠抑制VEGF誘導(dǎo)的內(nèi)皮細(xì)胞增殖,、遷移和血管生成過程,。在缺氧條件下，RKTG通過干擾HIF-1α與p300之間的相互作用來阻斷HIF轉(zhuǎn)錄激活活性，抑制由HIF-1α介導(dǎo)的VEGF自分泌,。另外,，在人腎透明細(xì)胞癌的臨床樣品中，發(fā)現(xiàn)RKTG在腫瘤組織中的表達(dá)水平與鄰近的正常組織中相比有明顯下降,，并且這種表達(dá)的改變與VEGF的表達(dá)水平呈負(fù)相關(guān),。
腎透明細(xì)胞癌中血管含量十分豐富，上述RKTG與VEGF之間調(diào)節(jié)關(guān)系的研究,，提供了腎透明細(xì)胞癌發(fā)生發(fā)展的一個(gè)新機(jī)制,，并為腎透明細(xì)胞癌的治療提供了一個(gè)全新的靶點(diǎn)。
上海市復(fù)旦大學(xué)附屬腫瘤醫(yī)院葉定偉教授和秦曉健醫(yī)師,、上海華東師范大學(xué)生命醫(yī)學(xué)研究所劉明耀教授和易正芳博士,、吉林大學(xué)第一醫(yī)院腫瘤中心白歐醫(yī)師、營養(yǎng)所方靖研究員等人對(duì)于該研究給予了合作和支持,。(生物谷Bioon.com)
生物谷推薦原文出處：
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.
