Antisense to cyclin D1 inhibits vascular endothelial growth factor-stimulated growth of vascular endothelial cells: Implication of tumor vascularization
Antisense to cyclin D1 inhibits vascular endothelial growth factor-stimulated growth of vascular endothelial cells: Implication of tumor vascularization
复制标题
DOI：
10.1158/1078-0432.ccr-05-1213
复制
发表时间：
2006-08-01
影响因子：
11.5
通讯作者：
Monden, Morito
中科院分区：
文献类型：
--
作者：
Yasui, Masayoshi;Yamamoto, Hirofumi;Monden, Morito
目的：我们的目的是确定细胞周期蛋白D1抑制肿瘤相关的新生血管和内皮细胞growth.Experimental设计的影响：我们已经产生了腺病毒系统的反义细胞周期蛋白D1（AS CyD1）和评价在体外和体内的影响。针对细胞周期蛋白D1的小干扰RNA也被用来分析细胞周期蛋白D1抑制相关的血管内皮生长因子（VEGF）regulation.Results：用腺病毒AS CyD1处理的异种移植物显示出更少的血管密度和显示更小的肿瘤大小在结肠癌细胞系HCT 116和DLD 1。体外研究表明，AS CyD1降低DLD 1中的VEGF蛋白表达，但在HCT 116中不降低。细胞周期蛋白D1小干扰RNA导致DLD 1中VEGF表达在蛋白和RNA水平上降低。VEGF启动子活性适度降低，STAT3转录因子通过去磷酸化失活。另一方面，细胞周期蛋白D1抑制剂加STAT3抑制剂显著降低了HCT 116中的VEGF表达，尽管单独使用STAT3抑制剂并没有改变VEGF。在培养的人脐静脉内皮细胞（HUVEC）中，VEGF增强细胞周期蛋白D1的表达和细胞生长。AS CyD1显着抑制HUVEC的生长，即使在VEGF的存在下。AS CyD1也显着抑制在体外管形成VEGF处理的HUVEC和在体内大动脉瘤形成VEGF处理Matrigel plug.Conclusions：我们的研究结果表明，细胞周期蛋白D1可能发挥作用，维持VEGF的表达，AS CyD1可能是潜在的有用的靶向癌细胞和肿瘤血管的微环境。
Purpose: Our aim was to determine the effects of cyclin D1 inhibition on tumor-associated neovascularization and endothelial cell growth.Experimental Design: We have generated adenovirus system for antisense to cyclin D1 (AS CyD1) and evaluated in vitro and in vivo effects. Small interfering RNA against cyclin D1 was also used to analyze cyclin D1 inhibition-associated vascular endothelial growth factor (VEGF) regulation.Results: The xenografts treated with adenoviral AS CyD1 showed less vessel density and displayed smaller tumor size in colon cancer cell lines HCT116 and DLD1. In vitro studies indicated that AS CyD1 decreased VEGF protein expression in DLD1 but not in HCT116. Cyclin D1 small interfering RNA caused a decrease in VEGF expression at protein and RNA levels in DLD1. A modest decrease was noted in the VEGF promoter activity, with inactivation of the STAT3 transcription factor through dephosphorylation. On the hand, the cyclin D1 inhibition plus STAT3 inhibitor markedly decreased VEGF expression in HCT116, although VEGF did not change by the STAT3 inhibitor alone. In cultures of human umbilical vein endothelial cells (HUVEC), VEGF augmented cyclin D1 expression and cell growth. AS CyD1 significantly inhibited HUVEC growth even in the presence of VEGF. AS CyD1 also significantly suppressed in vitro tube formation in VEGF-treated HUVEC and in vivo macroaneurysm formation in VEGF-treated Matrigel plug.Conclusions: Our results suggest that cyclin D1 may play a role in the maintenance of VEGF expression and that AS CyD1 could be potentially useful for targeting both cancer cells and their microenvironment of tumor vessels.