Tanshinone IIA inhibits β-catenin/VEGF-mediated angiogenesis by targeting TGF-β1 in normoxic and HIF-1α in hypoxic microenvironments in human colorectal cancer
Tanshinone IIA inhibits β-catenin/VEGF-mediated angiogenesis by targeting TGF-β1 in normoxic and HIF-1α in hypoxic microenvironments in human colorectal cancer
复制标题
丹参酮 IIA 通过靶向人结直肠癌常氧微环境中的 TGF-β 1 和缺氧微环境中的 HIF-1 α 来抑制 β-连环蛋白/VEGF 介导的血管生成
DOI：
10.1016/j.canlet.2017.05.013
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发表时间：
2017-09-10
期刊：
影响因子：
9.7
通讯作者：
Li, Qi
中科院分区：
文献类型：
--
作者：
Sui, Hua;Zhao, Jihui;Li, Qi
在先前的研究中，我们证明了丹参酮IIA在体内有效地抑制CRC血管生成，但其潜在的机制尚未阐明。在这份报告中，我们描述了实验中，HIF-1 α水平被操纵，以探测缺氧对CRC细胞血管生成的影响。我们研究了谭IIA对CRC促血管生成因子和人脐静脉内皮细胞在常氧和缺氧条件下血管生成的影响。结果表明，丹参Ⅱ A不仅能降低HIF-1 α水平，抑制VEGF和bFGF的分泌，而且能有效抑制HUVECs的增殖、管腔形成和转移。HIF-1 α/β-cateniniTCF 3/LEF 1信号通路的中断发生在缺氧微环境中。其机制涉及HIF-1a抑制TGF-β 1分泌，TGF-β 1分泌通过促进B-连环蛋白核定位和TCF/LEF激活来驱动血管生成。为了测试Tan IIA的改进的递送系统，我们将药物加载到介孔二氧化硅纳米颗粒（MSN-NH 2）中，并发现它有效地靶向小鼠结肠肿瘤模型中的HIF-1a过表达。最后，Tan IIA磺酸钠通过降低血管生成素、VEGF和bFGF表达水平在CRC患者中表现出抗血管生成活性。我们的研究提供了一种新的抗血管生成策略，并加强了对使用Tan IIA作为血管生成抑制剂的支持。(C)2017爱思唯尔B. V.保留所有权利。
In a previous study, we demonstrated that Tanshinone IIA effectively inhibits CRC angiogenesis in vivo, but the underlying mechanisms were not elucidated. In this report, we describe experiments in which HIF-1 alpha levels were manipulated to probe the effect of hypoxia on CRC cell angiogenesis. We studied the effects of Tan IIA on CRC pro-angiogenic factor and on human umbilical vein endothelial cell angiogenesis in normoxia and hypoxia. Our results show that Tan IIA not only lowers HIF-1 alpha levels and inhibits secretion of VEGF and bFGF, but also efficiently suppresses the proliferation, tube formation and metastasis of HUVECs. Interruption of the HIF-1 alpha/beta-cateniniTCF3/LEF1 signaling pathway occurs in the hypoxic microenvironment. The mechanism involves HIF-1a inhibition of TGF-beta 1 secretion, which drives angiogenesis by promoting B-catenin nuclear localization and TCF/LEF activation. To test an improved delivery system for Tan IIA, we loaded the drug into mesoporous silica nanoparticles (MSN-NH2) and found that it effectively targets HIF-1a overexpression in a mouse colon tumor model. Finally, Tan IIA sodium sulfonate exhibits anti-angiogenesis activity in CRC patients by reducing levels of angiogenin, VEGF and bFGF expression. Our research provides a new anti-angiogenesis strategy and strengthens support for the use of Tan IIA as an angiogenesis inhibitor. (C) 2017 Elsevier B.V. All rights reserved.