The ROS-mediated activation of STAT-3/VEGF signaling is involved in the 27-hydroxycholesterol-induced angiogenesis in human breast cancer cells
The ROS-mediated activation of STAT-3/VEGF signaling is involved in the 27-hydroxycholesterol-induced angiogenesis in human breast cancer cells
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ROS 介导的 STAT-3/VEGF 信号传导激活参与人乳腺癌细胞中 27-羟基胆固醇诱导的血管生成
DOI：
10.1016/j.toxlet.2016.11.006
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发表时间：
2016-12-15
影响因子：
3.5
通讯作者：
Li, Yuan
中科院分区：
文献类型：
--
作者：
Zhu, Dongmei;Shen, Zhaoxia;Li, Yuan
乳腺癌（BC）是全球女性癌症相关死亡的主要原因，血管生成在BC进展中起着至关重要的作用。27-羟基胆固醇（27 HC）是一种内源性选择性雌激素受体调节剂，可促进乳腺癌的生长和转移。在此，我们进一步发现，27 HC以VEGF依赖的方式提高BC的血管生成能力。分子机制方面，一方面，27 HC作为雌激素样因子，通过经典的ER α/VEGF信号通路促进ER阳性BC细胞VEGF的表达;另一方面，在ER阳性和ER阴性BC细胞中，27 HC均促进ROS的产生，进而以不依赖于ER的方式激活STAT-3/VEGF信号通路。无论是阻断ROS的产生还是敲低STAT-3都能减弱27 HC诱导的VEGF自分泌和血管生成。这些发现不仅提示了27 HC促进血管生成的机制，而且有助于认识到27 HC是BC中的新的潜在有害因子，特别是在绝经患者中。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Breast cancer (BC) is the leading cause of cancer-related mortality among females worldwide, and angiogenesis plays a crucial role in BC progression. 27-Hydroxycholesterol (27HC) is an endogenous selective estrogen receptor modulator, which promotes the growth and metastasis of BC. Here, we further found that, 27HC improved the angiogenic ability of BC in a VEGF-dependent manner. For the molecular mechanisms, on one hand, as an estrogen-like factor, 27HC enhanced the expression of VEGF by the classical ER alpha/VEGF signaling in ER-positive BC cells; on the other hand, in both ER-positive and ER-negative BC cells, 27HC enhanced the generation of ROS, which in turn activated the STAT-3/VEGF signaling in an ER independent manner. Either blocking the generation of ROS or knockdown of STAT-3 attenuated the 27HC-induced autocrine of VEGF and angiogenesis. These findings not only suggested a mechanism whereby 27HC enhanced the angiogenesis, but also helped to recognize the 27HC as a novel potential harmful factor in BC, especially in the menopause patients. (C) 2016 Elsevier Ireland Ltd. All rights reserved.