Osteopontin induces angiogenesis through activation of PI3K/AKT and ERK1/2 in endothelial cells
Osteopontin induces angiogenesis through activation of PI3K/AKT and ERK1/2 in endothelial cells
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骨桥蛋白通过激活内皮细胞中的 PI3K/AKT 和 ERK1/2 诱导血管生成
DOI：
10.1038/onc.2009.189
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发表时间：
2009-09-24
期刊：
影响因子：
8
通讯作者：
Guo, Y.
中科院分区：
文献类型：
--
作者：
Dai, J.;Peng, L.;Guo, Y.
血管生成是肿瘤生长和转移的关键步骤。骨桥蛋白（OPN）诱导内皮细胞血管生成的机制尚不清楚。本研究表明，OPN通过激活PI3K/Akt通路并随后上调Bcl-xL和活化核因子κ b来发挥细胞保护作用。OPN通过磷酸化Akt和细胞外信号调节激酶（ERK）来增强血管内皮生长因子（VEGF）的表达。反过来，opn诱导的VEGF作为正反馈信号激活PI3K/AKT和ERK1/2通路。通过抗vegf抗体、pi3激酶抑制剂或ERK抑制剂阻断反馈信号可部分抑制OPN诱导的人脐静脉内皮细胞（HUVEC）的运动、增殖和成管，而通过抗OPN或抗α v β 3抗体阻断反馈信号可完全消除OPN对HUVEC的生物学作用。此外，还在体内研究了血管的形成。抗opn抗体在体内的抗血管生成效果比抗vegf抗体更有效，后者仅阻断反馈信号。这些数据表明，OPN直接通过PI3K/AKT和erk介导的途径促进血管生成，VEGF作为正反馈信号。结果表明，OPN可能是开发新的抗血管生成治疗癌症的有价值的靶点。中华肿瘤杂志（2009）28 (3):344 - 344；doi: 10.1038 / onc.2009.189;2009年7月13日在线发布
Angiogenesis is a key step in tumor growth and metastasis. The mechanism by which osteopontin (OPN) induces the angiogenesis of endothelial cells remains unclear. Here, we show that OPN confers cytoprotection through the activation of the PI3K/Akt pathway with subsequent upregulation of Bcl-xL and activation of nuclear factor-kappa B. OPN enhances the expression of vascular endothelial growth factor (VEGF) through the phosphorylation of AKT and extracellular signal-regulated kinase (ERK). In turn, OPN-induced VEGF activates PI3K/AKT and the ERK1/2 pathway as a positive feedback signal. Blocking the feedback signal by anti-VEGF antibody, PI3-kinase inhibitor or ERK inhibitor can partially inhibit the OPN-induced human umbilical vein endothelial cell (HUVEC) motility, proliferation and tube formation, while blocking the signal by anti-OPN or anti-alpha v beta 3 antibody completely abrogates the biological effects of OPN on HUVECs. In addition, blood vessel formation is also investigated in vivo. The antiangiogenesis efficacy of anti-OPN antibody in vivo is more effective than that of anti-VEGF antibody, which only blocks the feedback signals. These data show that OPN enhances angiogenesis directly through PI3K/AKT and ERK-mediated pathways with VEGF acting as a positive feedback signal. The results suggest that OPN might be a valuable target for developing novel antiangiogenesis therapy for treatment of cancer. Oncogene (2009) 28, 3412-3422; doi: 10.1038/onc.2009.189; published online 13 July 2009