Harper Jay, Yan Li, Loureiro Robyn M, Wu Iinmin, Fang Jianmin, D'Amore Patricia A, Moses Marsha A
Vascular Biology Program, Children's Hospital Boston, Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
Cancer Res. 2007 Sep 15;67(18):8736-41. doi: 10.1158/0008-5472.CAN-07-1617.
Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis. Although many positive regulators of VEGF have been identified, relatively little is known regarding the negative regulation of VEGF expression. We identified a zinc finger transcription factor, ZNF24, that may repress VEGF transcription. An inverse correlation between expression of VEGF and ZNF24 was observed in a series of independent studies. ZNF24 was up-regulated in angiogenic tumor nodules where VEGF expression is significantly decreased compared with preangiogenic nodules. In human breast carcinoma cells cultured under normoxic conditions, ZNF24 levels were significantly up-regulated whereas VEGF levels were low. In contrast, VEGF was significantly increased in hypoxic cells whereas ZNF24 was down-regulated. The same inverse correlation between ZNF24 and VEGF was also observed in 70% of matched cDNA pairs of normal and malignant tissues from human colon and breast biopsies. Overexpression of ZNF24 resulted in a significant down-regulation of VEGF, whereas silencing of ZNF24 with small interfering RNA led to increased VEGF expression. Cotransfection of ZNF24 and a VEGF promoter luciferase reporter construct in MDA-MB-231 cells resulted in a significant decrease in VEGF promoter activity. Taken together, these data suggest that ZNF24 is involved in negative regulation of VEGF and may represent a novel repressor of VEGF transcription.
血管内皮生长因子（VEGF）是一种强大的血管生成刺激因子。尽管已经鉴定出许多VEGF的正调控因子，但关于VEGF表达的负调控却知之甚少。我们鉴定出一种锌指转录因子ZNF24，它可能抑制VEGF转录。在一系列独立研究中观察到VEGF和ZNF24表达之间呈负相关。在血管生成性肿瘤结节中ZNF24上调，与血管生成前结节相比，VEGF表达显著降低。在常氧条件下培养的人乳腺癌细胞中，ZNF24水平显著上调而VEGF水平较低。相反，在缺氧细胞中VEGF显著增加而ZNF24下调。在70%的来自人结肠和乳腺活检的正常和恶性组织配对cDNA对中也观察到ZNF24和VEGF之间存在相同的负相关。ZNF24的过表达导致VEGF显著下调，而用小干扰RNA沉默ZNF24导致VEGF表达增加。在MDA-MB-231细胞中共转染ZNF24和VEGF启动子荧光素酶报告构建体导致VEGF启动子活性显著降低。综上所述，这些数据表明ZNF24参与VEGF的负调控，可能是VEGF转录的一种新型抑制因子。
