Niu Guilian, Wright Kenneth L, Huang Mei, Song Lanxi, Haura Eric, Turkson James, Zhang Shumin, Wang Tianhong, Sinibaldi Dominic, Coppola Domenico, Heller Richard, Ellis Lee M, Karras James, Bromberg Jacqueline, Pardoll Drew, Jove Richard, Yu Hua
Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Oncology, University of South Florida College of Medicine, Tampa, Florida, FL 33612, USA.
Oncogene. 2002 Mar 27;21(13):2000-8. doi: 10.1038/sj.onc.1205260.
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 oligonucleotide 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.
非受体酪氨酸激酶和受体酪氨酸激酶，如Src和表皮生长因子受体（EGFR），是血管内皮生长因子（VEGF）的主要诱导因子，VEGF是血管生成最有效的介质之一。虽然酪氨酸激酶通过多种途径发出信号，但信号转导子和转录激活因子3（Stat3）是其中许多途径的汇聚点，并且在多种癌细胞中高频组成性激活。在此，我们表明VEGF表达与多种人类癌细胞系中的Stat3活性相关。活化的Stat3突变体（Stat3C）上调VEGF表达并刺激肿瘤血管生成。当VEGF启动子中的Stat3结合位点发生突变时，Stat3C诱导的VEGF上调被消除。此外，在肿瘤细胞中用显性负性Stat3蛋白或Stat3反义寡核苷酸中断Stat3信号传导可下调VEGF表达。与Stat3在各种致癌酪氨酸激酶诱导的VEGF上调中的重要作用一致，当Stat3信号传导被阻断时，v-Src介导的VEGF表达受到抑制。此外，染色质免疫沉淀分析表明Stat3蛋白在体内与VEGF启动子结合，并且VEGF启动子中Stat3结合位点的突变消除了v-Src诱导的VEGF启动子活性。这些研究提供了证据表明VEGF基因直接受Stat3蛋白调控，并表明Stat3是阻断人类癌症中多种信号通路诱导的血管生成的共同分子靶点。
