期刊
CANCER LETTERS
卷 386, 期 -, 页码 12-23出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.11.003
关键词
GPER; G-1; Angiogenesis; TNBC; NF-kappa B
类别
资金
- National Natural Science Foundation of China [81673454, 81672608, 81472470, 81302317, 81572270]
- Guangdong Natural Science Funds for Distinguished Young Scholar [2014A030306025]
- Pearl River S&T Nova Program of Guangzhou [201506010039]
- Opening Project Program of State Key Laboratory of Oncology in South China [HN2014-09]
- Science & Technology Planning Project of Guangdong Province [2013B060300005]
Triple-negative breast cancer (TNBC) is characterized by high vascularity and frequent metastasis. Here, we found that activation of G protein-coupled estrogen receptor (GPER) by its specific agonist G-1 can significantly inhibit interleulcin 6 (IL-6) and vascular endothelial growth factor A (VEGF-A). TNBC tissue microarrays from 100 TNBC patients revealed GPER is negatively associated with IL-6 levels and higher grade and stage. Activation of GPER or anti-IL-6 antibody can inhibit both in vitro tube formation of human umbilical vein endothelial cells (HUVECs) and migration of TNBC cells. While recombinant IL-6 supplementary can significantly reverse the inhibitory effects of G-1, suggesting the essential role of IL-6 in G-1 induced suppression of angiogenesis and invasiveness of TNBC cells. G-1 treatment decreased the phosphorylation, nuclear localization, transcriptional activities of NF-kappa B and suppressed its binding with IL-6 promoter. BAY11-7028, the inhibitor of NF-kappa B, can mimic the effect of G-1 to suppression of IL-6 and VEGF-A. While over expression of p65 can attenuate the inhibitory effects of G-1 on IL-6 and VEGF expression. The suppression of IL-6 by G-1 can further inhibit HIF-1 alpha and STAT3 signals in TNBC cells by inhibition their expression, phosphorylation and/or nuclear localization. Moreover, G-1 also inhibited the in vivo NF-kappa B/IL-6 signals and angiogenesis and metastasis of MDA-MB-231 xenograft tumors. In conclusion, our study demonstrated that activation of GPER can suppress migration and angiogenesis of TNBC via inhibition of NF-kappa B/IL-6 signals, therefore it maybe act as an important target for TNBC treatment. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据