S1PR1 regulates the switch of two angiogenic modes by VE-cadherin phosphorylation in breast cancer
S1PR1 regulates the switch of two angiogenic modes by VE-cadherin phosphorylation in breast cancer
复制标题
S1PR1通过VE-钙粘蛋白磷酸化调节乳腺癌中两种血管生成模式的转换
DOI：
10.1038/s41419-019-1411-x
复制
发表时间：
2019-02-27
影响因子：
9
通讯作者：
Sun, Baocun
中科院分区：
文献类型：
--
作者：
Liu, Shuang;Ni, Chunsheng;Sun, Baocun
实体瘤中的血管生成分为两种模式：内皮依赖性血管（EDV）和血管生成拟态（VM）。 1-磷酸鞘氨醇受体 1 (S1PR1) 在多种人类肿瘤的 EDV 中发挥着至关重要的作用。但S1PR1与VM之间的关系尚不清楚。本研究的目的是探讨 S1PR1 对乳腺癌 EDV 和拟态形成的调节作用。在这里，我们发现 S1PR1 磷酸化 VE-钙粘蛋白复合物来调节 EDV 和拟态形成的转换。 S1PR1 的抑制会损害 EDV，但会促进 VM 的产生、体内和体外的侵袭和转移。通过抑制 RhoA 激活，S1PR1/VE-钙粘蛋白信号传导被阻断。 S1PR1 通过 RhoA 激活控制 VE-钙粘蛋白表达和 EDV。此外，S1PR1的低表达与乳腺癌患者VM和不良预后相关。结果表明，S1PR1 调节 RhoA 激活，加速 VE-钙粘蛋白磷酸化 (Y731)，导致乳腺癌中 EDV 增加、VM 减少。 S1PR1可能为乳腺癌患者的抗血管生成治疗提供新的思路方向。
Angiogenesis in solid tumors is divided into two modes: endothelium-dependent vessel (EDV) and vasculogenic mimicry (VM). Sphingosine-1-phosphate receptor 1 (S1PR1) plays a vital role on EDV in a variety of human tumors. However, the relationship between S1PR1 and VM is not clear. The aim of this study is to investigate S1PR1 on the regulation of EDV and mimicry formation in breast cancer. Here we show that S1PR1 phosphorylates the complex of VE-cadherin to regulate the switch of EDV and mimicry formation. Suppression of S1PR1 impairs EDV, but contributes to the generation of VM, invasion, and metastasis in vivo and vitro. By inhibiting RhoA activation, the S1PR1/VE-cadherin signaling is blocked. S1PR1 controls VE-cadherin expression and EDV via RhoA activation. Moreover, the low expression of S1PR1 correlates with VM and poor prognosis in breast cancer patient. The results show that S1PR1 regulated RhoA activation to accelerate VE-cadherin phosphorylation (Y731), leading to increased EDV and reduced VM in breast cancer. S1PR1 may provide a new thinking direction for antiangiogenic therapy for patients with breast cancer.