Critical role of histone demethylase RBP2 in human gastric cancer angiogenesis.
Critical role of histone demethylase RBP2 in human gastric cancer angiogenesis.
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组蛋白去甲基化酶 RBP2 在人胃癌血管生成中的关键作用
DOI：
10.1186/1476-4598-13-81
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发表时间：
2014-04-09
期刊：
影响因子：
37.3
通讯作者：
Zeng J
中科院分区：
文献类型：
--
作者：
Li L;Wang L;Song P;Geng X;Liang X;Zhou M;Wang Y;Chen C;Jia J;Zeng J
胃癌中血管生成和血管生成因子（包括血管内皮生长因子（VEGF））异常表达的分子机制仍不清楚。组蛋白去甲基酶视网膜母细胞瘤结合蛋白 2 (RBP2) 通过抑制细胞周期蛋白依赖性激酶抑制剂 (CDKI) 的表达参与胃肿瘤发生。在 30 例人胃癌样本和正常对照样本中评估了 RBP2、VEGF、CD31、CD34 和 Ki67 的表达。我们使用定量 RT-PCR、蛋白质印迹分析、ELISA、管形成实验和集落形成实验来表征 RBP2 沉默或过表达诱导的 VEGF 表达和相关生物活性的变化。采用荧光素酶测定和 ChIP 探讨 RBP2 对 VEGF 启动子活性的直接调节。采用裸鼠和RBP2靶向突变小鼠检测RBP2在体内VEGF表达和血管生成中的作用。 RBP2和VEGF在人胃癌组织中均过表达，与正常组织相比，具有更高的微血管密度（MVD）和细胞增殖。在胃上皮细胞系中，RBP2过表达显着促进VEGF的表达以及细胞的生长和血管生成，而RBP2敲低则具有相反的作用。 RBP2直接与VEGF的启动子结合，通过组蛋白H3K4去甲基化来调节其表达。转染RBP2敲低的BGC-823细胞的裸鼠皮下组织中VEGF表达和MVD降低，癌变和细胞增殖减少。此外，H3K4 三甲基化增加的 RBP2 突变小鼠的胃上皮显示 VEGF 表达和 MVD 降低。 RBP2 促进胃肿瘤发生与 VEGF 表达反式激活和血管生成增加显着相关。 RBP2的过度表达和VEGF的激活可能在人胃癌的发生和进展中发挥重要作用。
The molecular mechanisms responsible for angiogenesis and abnormal expression of angiogenic factors in gastric cancer, including vascular endothelial growth factor (VEGF), remain unclear. The histone demethylase retinoblastoma binding protein 2 (RBP2) is involved in gastric tumorgenesis by inhibiting the expression of cyclin-dependent kinase inhibitors (CDKIs). The expression of RBP2, VEGF, CD31, CD34 and Ki67 was assessed in 30 human gastric cancer samples and normal control samples. We used quantitative RT-PCR, western blot analysis, ELISA, tube-formation assay and colony-formation assay to characterize the change in VEGF expression and associated biological activities induced by RBP2 silencing or overexpression. Luciferase assay and ChIP were used to explore the direct regulation of RBP2 on the promoter activity of VEGF. Nude mice and RBP2-targeted mutant mice were used to detect the role of RBP2 in VEGF expression and angiogenesis in vivo. RBP2 and VEGF were both overexpressed in human gastric cancer tissue, with greater microvessel density (MVD) and cell proliferation as compared with normal tissue. In gastric epithelial cell lines, RBP2 overexpression significantly promoted the expression of VEGF and the growth and angiogenesis of the cells, while RBP2 knockdown had the reverse effect. RBP2 directly bound to the promoter of VEGF to regulate its expression by histone H3K4 demethylation. The subcutis of nude mice transfected with BGC-823 cells with RBP2 knockdown showed reduced VEGF expression and MVD, with reduced carcinogenesis and cell proliferation. In addition, the gastric epithelia of RBP2 mutant mice with increased H3K4 trimethylation showed reduced VEGF expression and MVD. The promotion of gastric tumorigenesis by RBP2 was significantly associated with transactivation of VEGF expression and elevated angiogenesis. Overexpression of RBP2 and activation of VEGF might play important roles in human gastric cancer development and progression.
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