School of Anatomy and Human Biology, Faculty of Life and Physical Sciences, The University of Western Australia, Crawley, Western Australia.
Oncol Res. 2012;20(1):1-6. doi: 10.3727/096504012x13425470196010.
Secreted frizzled-related protein 4 (sFRP4) is a Wnt signaling antagonist. Classically, sFRP4 antagonizes the canonical Wnt signaling pathway, resulting in decreased cellular proliferation and increased apoptosis. Recent research from our laboratory has established that sFRP4 inhibits angiogenesis by decreasing proliferation, migration, and tube formation of endothelial cells. The objective of this study was to examine the role of sFRP4's cysteine-rich domain (CRD) and netrin-like domain (NLD) in angiogenesis inhibition. Experiments were carried out to examine cell death and tube formation of endothelial cells after treatment with the CRD and the NLD. The CRD was seen to inhibit tube formation of endothelial cells, which suggests that this domain is important to sFRP4's antiangiogenesis property. In addition, the NLD promoted endothelial cell death and may also inhibit angiogenesis. Furthermore, treatment with the CRD and the NLD increased endothelial intracellular calcium levels. Our findings implicate a role for both the CRD and NLD in angiogenesis inhibition by sFRP4. It is suggestive of alternative antiangiogenic downstream targets of canonical Wnt signaling and a possible importance of the noncanonical Ca2+ Wnt signaling pathway in sFRP4-mediated angiogenesis inhibition.
分泌型卷曲相关蛋白 4（sFRP4）是一种 Wnt 信号通路拮抗剂。经典地，sFRP4 拮抗经典的 Wnt 信号通路，导致细胞增殖减少和细胞凋亡增加。我们实验室最近的研究表明，sFRP4 通过减少内皮细胞的增殖、迁移和管腔形成来抑制血管生成。本研究的目的是研究 sFRP4 的富含半胱氨酸结构域（CRD）和神经导向因子样结构域（NLD）在血管生成抑制中的作用。进行了实验以研究内皮细胞在用 CRD 和 NLD 处理后细胞死亡和管腔形成的情况。CRD 被发现抑制内皮细胞的管腔形成，这表明该结构域对 sFRP4 的抗血管生成特性很重要。此外，NLD 促进内皮细胞死亡，也可能抑制血管生成。此外，用 CRD 和 NLD 处理可增加内皮细胞内的钙水平。我们的发现提示 CRD 和 NLD 都参与了 sFRP4 对血管生成的抑制作用。这表明经典 Wnt 信号的下游抗血管生成靶点存在替代性，并且非经典的 Ca2+ Wnt 信号通路在 sFRP4 介导的血管生成抑制中可能具有重要性。
