Stabilization of VEGF G-quadruplex and inhibition of angiogenesis by quindoline derivatives.
Stabilization of VEGF G-quadruplex and inhibition of angiogenesis by quindoline derivatives.
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DOI：
10.1016/j.bbagen.2014.06.002
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发表时间：
2014-09
期刊：
影响因子：
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通讯作者：
Yue Wu;Li-Peng Zan;Xiao-dong Wang;Yu-jing Lu;Tian-Miao Ou;Jing Lin;Zhishu Huang;L. Gu
中科院分区：
文献类型：
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作者：
Yue Wu;Li-Peng Zan;Xiao-dong Wang;Yu-jing Lu;Tian-Miao Ou;Jing Lin;Zhishu Huang;L. Gu
血管生成被认为在肿瘤的发生和发展中起着重要作用。血管内皮生长因子(VEGF)是一种多能细胞因子和血管生成生长因子，在胚胎发育和肿瘤进展中发挥重要作用。在许多类型的癌症中，血管内皮生长因子过度表达，通常与肿瘤进展和生存率有关。位于人血管内皮生长因子基因启动子区上游的多嘌呤/多嘧啶序列可以形成特定的平行G-四链体结构，从而增加了通过G-四链体配体调控转录的可能性。方法通过聚合酶链式反应、圆二色谱、RNA提取和RT-PCR、酶联免疫吸附试验、荧光素酶分析、细胞刮除试验、实时细胞分析和鸡胚绒毛尿囊膜(CAM)分析。结果与结论我们发现喹哚碱衍生物能够与该启动子的富含G的DNA序列相互作用，稳定该G-四链体，抑制其转录和表达。我们的新发现不仅对理解G-四链配体介导的血管生成抑制的机制具有重要意义，而且对于探索一种新的抗肿瘤策略，阻断血管内皮生长因子的转录，抑制肿瘤细胞的血管生成也具有重要意义。
BackgroundAngiogenesis is thought to be important in tumorigenesis and tumor progress. Vascular endothelial growth factor (VEGF) is a pluripotent cytokine and angiogenic growth factor that plays crucial roles in embryonic development and tumor progression. In many types of cancer, VEGF is overexpressed and is generally associated with tumor progression and survival rate. The polypurine/polypyrimidine sequence located upstream of the promoter region in the human VEGF gene can form specific parallel G-quadruplex structures, raising the possibility for transcriptional control of VEGF through G-quadruplex ligands.MethodsPCR stop assay, circular dichroism (CD) spectra, RNA extraction and RT-PCR, enzyme-linked immunosorbent assay (ELISA), luciferase Assays, cell scrape test, xCELLigence real-time cell analysis (RTCA), and chick embryo chorioallantoic membrane (CAM) assay.Results and conclusionsWe found that quindoline derivatives can interact with the G-rich DNA sequences of the VEGF promoter to stabilize this G-quadruplex and suppress the transcription and expression of the VEGF protein. We also demonstrated that these derivatives exhibit potential anti-angiogenic activity in chick embryos and antitumor activity, including the inhibition of cell proliferation and migration.General significanceOur new findings have significances not only for understanding the mechanism of the G-quadruplex ligands mediating the VEGF transcription inhibition, but also for exploring a new anti-tumor strategy to blocking the transcription of VEGF to inhibit the angiogenesis in cancer cells.