Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
Mol Cancer Ther. 2012 Feb;11(2):298-307. doi: 10.1158/1535-7163.MCT-11-0682. Epub 2011 Nov 18.
Wnt5a is a representative ligand that activates the β-catenin-independent pathway in Wnt signaling. It was reported that the expression of Wnt5a in human gastric cancer is associated with aggressiveness and poor prognosis and that knockdown of Wnt5a reduces the ability of gastric cancer cells to metastasize in nude mice. Therefore, Wnt5a and its signaling pathway might be important targets for the therapy of gastric cancer. The aim of this study was to examine whether an anti-Wnt5a antibody affects metastasis of gastric cancer cells. One anti-Wnt5a polyclonal antibody (pAb5a-5) inhibited migration and invasion activities in vitro of gastric cancer cells with a high expression level of Wnt5a. Previously, it was shown that Wnt5a induces the internalization of receptors, which is required for Wnt5a-dependent activation of Rac1. pAb5a-5 inhibited Wnt5a-dependent internalization of receptors, thereby suppressed Wnt5a-dependent activation of Rac1. Laminin γ2 is one of target genes of Wnt5a signaling and Rac1 was involved in its expression. pAb5a-5 also inhibited Wnt5a-dependent expression of laminin γ2. In an experimental liver metastasis assay, gastric cancer cells were introduced into the spleens of nude mice. Laminin γ2 was required for liver metastatic ability of gastric cancer cells in vivo. Furthermore, intraperitoneal injection of pAb5a-5 inhibited the metastatic ability of gastric cancer cells. These results suggest that an anti-Wnt5a antibody was capable of suppressing Wnt5a-dependent internalization of receptors, resulting in the prevention of metastasis of gastric cancer cells by inhibiting the activation of Rac1 and the expression of laminin γ2.
Wnt5a 是一种代表性配体，可激活 Wnt 信号转导中的 β-连环蛋白非依赖性途径。据报道，人类胃癌中 Wnt5a 的表达与侵袭性和预后不良有关，并且敲低 Wnt5a 可降低胃癌细胞在裸鼠中转移的能力。因此，Wnt5a 及其信号通路可能是胃癌治疗的重要靶点。本研究旨在研究抗 Wnt5a 抗体是否影响胃癌细胞的转移。一种抗 Wnt5a 多克隆抗体 (pAb5a-5) 抑制了高表达 Wnt5a 的胃癌细胞的体外迁移和侵袭活性。先前表明，Wnt5a 诱导受体内化，这是 Wnt5a 依赖性 Rac1 激活所必需的。pAb5a-5 抑制了 Wnt5a 依赖性受体内化，从而抑制了 Wnt5a 依赖性 Rac1 激活。层粘连蛋白 γ2 是 Wnt5a 信号的靶基因之一，而 Rac1 参与其表达。pAb5a-5 还抑制了 Wnt5a 依赖性层粘连蛋白 γ2 的表达。在实验性肝转移测定中，将胃癌细胞引入裸鼠的脾脏中。层粘连蛋白 γ2 是胃癌细胞在体内肝转移能力所必需的。此外，腹腔内注射 pAb5a-5 抑制了胃癌细胞的转移能力。这些结果表明，抗 Wnt5a 抗体能够抑制 Wnt5a 依赖性受体内化，从而通过抑制 Rac1 的激活和层粘连蛋白 γ2 的表达来预防胃癌细胞的转移。
