Abstract
BackgroundThe 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).MethodsThe 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.ResultsRBP2 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.ConclusionsThe 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.
Highlights
The molecular mechanisms responsible for angiogenesis and abnormal expression of angiogenic factors in gastric cancer, including vascular endothelial growth factor (VEGF), remain unclear
Association of retinoblastoma binding protein 2 (RBP2) overexpression with increased VEGF expression and microvessel density (MVD) in human gastric cancer As compared with normal human tissues, gastric cancer specimens showed overexpression of RBP2 and VEGF mRNA and the correlation of mRNA expression, which supports the role of RBP2 and VEGF in tumorgenesis and their co-expression in vivo (Figure 1A, B and C)
The marker of cell proliferation, Ki67, was overexpressed in human gastric cancer specimens (Figure 1D, E). This clinical evidence supports the association of RBP2 and VEGF expression and increased angiogenesis in gastric cancer
Summary
The molecular mechanisms responsible for angiogenesis and abnormal expression of angiogenic factors in gastric cancer, including vascular endothelial growth factor (VEGF), remain unclear. Carcinogenesis is a multistep process involving the transformation, survival, proliferation, invasion, angiogenesis, and metastasis of tumor. During this process, the accumulation of genetic and epigenetic alterations leads to progressive transformation [4]. Vascular endothelial growth factor (VEGF) is a key mediator in the neovascularization of cancers [6]. VEGF overexpression involves abnormal expression of growth factors and their receptors [8]. Epigenetic regulation is important for VEGF expression. To better understand the mechanism of angiogenesis, the regulation of VEGF expression is a key point
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