Critical role of histone demethylase RBP2 in human gastric cancer angiogenesis

Molecular Cancer

Research

Jiping Zeng¹  Ping Song¹  Lupeng Li¹  Chunyan Chen²  Minran Zhou²  Jihui Jia³  Xiuming Liang³  Xue Geng⁴  Lixiang Wang⁴  Yangyang Wang⁴ 

[1] Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 250012, Jinan, P. R., China;Department of Hematology, Qilu Hospital, Shandong University School of Medicine, 250012, Jinan, P.R., China;Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, 250010, Jinan, P. R., China;Department of Pharmacology, Shandong University School of Medicine, 250012, Jinan, P. R., China;

关键词: RBP2;    VEGF;    Gastric cancer;    Angiogenesis;   

DOI  :  10.1186/1476-4598-13-81

 received in 2014-01-31, accepted in 2014-04-04,  发布年份 2014

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Li et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.