Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis
Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis
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DOI：
10.1038/sj.onc.1205260
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发表时间：
2002-03-21
期刊：
影响因子：
8
通讯作者：
Yu, H
中科院分区：
文献类型：
--
作者：
Niu, GL;Wright, KL;Yu, H
非受体和受体酪氨酸激酶，如Src和EGF受体(EGFR)，是血管内皮生长因子(VEGF)的主要诱导者，而血管内皮生长因子是最有效的血管生成介质之一。虽然酪氨酸激酶通过多条途径传递信号，但信号转导和转录激活3(STAT3)是其中许多途径的汇合点，并在广泛的癌细胞中以高频率被结构性激活。在这里，我们表明，在不同的人类癌细胞系中，血管内皮生长因子的表达与STAT3的活性相关。激活的STAT3突变体(Stat3C)上调血管内皮生长因子的表达，刺激肿瘤血管生成。当血管内皮生长因子启动子中的STAT3结合位点发生突变时，Stat3C诱导的血管内皮生长因子上调被取消。此外，用显性阴性的STAT3蛋白或STAT3反义寡核苷酸阻断肿瘤细胞中的STAT3信号转导可下调血管内皮生长因子的表达。与STAT3在多种致癌酪氨酸激酶诱导的血管内皮生长因子上调中的重要作用一致，当STAT3信号被阻断时，v-Src介导的血管内皮生长因子表达被抑制。此外，染色质免疫沉淀分析表明，STAT3蛋白在体内与血管内皮生长因子启动子结合，并且血管内皮生长因子启动子中STAT3结合位点的突变取消了v-Src诱导的血管内皮生长因子启动子活性。这些研究为血管内皮生长因子基因直接受STAT3蛋白调控提供了证据，并表明STAT3在人类肿瘤中是一个共同的分子靶点，可以阻断多条信号通路诱导的血管生成。
Non-receptor and receptor tyrosine kinases, such as Src and EGF receptor (EGFR), are major inducers of vascular endothelial growth factor (VEGF), one of the most potent mediators of angiogenesis. While tyrosine kinases signal through multiple pathways, signal transducer and activation of transcription 3 (Stat3) is a point of convergence for many of these and is constitutively activated with high frequency in a wide range of cancer cells. Here, we show that VEGF expression correlates with Stat3 activity in diverse human cancer cell lines. An activated Stat3 mutant (Stat3C) up-regulates VEGF expression and stimulates tumor angiogenesis. Stat3C-induced VEGF up-regulation is abrogated when a Stat3-binding site in the VEGF promoter is mutated. Furthermore, interrupting Stat3 signaling with dominant-negative Stat3 protein or Stat3 antisense otigonucleotide in tumor cells down-regulates VEGF expression. Consistent with an important role of Stat3 in VEGF up-regulation induced by various oncogenic tyrosine kinases, v-Src-mediated VEGF expression is inhibited when Stat3 signaling is blocked. Moreover, chromatin immunoprecipitation assays indicate that Stat3 protein binds to the VEGF promoter in vivo and mutation of a Stat3-binding site in the VEGF promoter abrogates v-Src-induced VEGF promoter activity. These studies provide evidence that the VEGF gene is regulated directly by Stat3 protein, and indicate that Stat3 represents a common molecular target for blocking angiogenesis induced by multiple signaling pathways in human cancers.