Ara Hosne, Takagishi Maki, Enomoto Atsushi, Asai Masato, Ushida Kaori, Asai Naoya, Shimoyama Yoshie, Kaibuchi Kozo, Kodera Yasuhiro, Takahashi Masahide
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Cancer Sci. 2016 Feb;107(2):133-9. doi: 10.1111/cas.12848. Epub 2015 Dec 23.
In gastric cancer, the non-canonical Wnt signaling pathway is activated by Wnt5a, which has a critical role in disease outcome. Previous studies have shown that Wnt5a mediates the expression of the extracellular matrix protein laminin γ2 through Rac and JNK activation to promote gastric cancer progression. However, the mechanism of this regulatory pathway has not been completely addressed. The scaffold protein Dvl is a major component of the Wnt signaling pathway. Here, we show that Dvl-associating protein with a high frequency of leucine residues (Daple) mediates Wnt5a-induced laminin γ2 expression. Immunohistochemical analysis showed marked expression of Daple in advanced clinical stages of gastric cancer, where it highly correlated with Wnt5a/b and laminin γ2 expression, the depth of wall invasion, and the frequency of lymph node metastasis. In cultured cancer cells, Daple depletion led to the suppression of Wnt5a-induced Rac and JNK activation, laminin γ2 expression, and cell migration and invasion. Accordingly, Daple depletion also suppressed liver metastasis in a mouse xenograft model of gastric cancer. These results suggest that the non-canonical Wnt signaling pathway contributes to gastric cancer progression at least in part via Daple, which provides a new therapeutic opportunity for the treatment of the disease.
在胃癌中，非经典Wnt信号通路由Wnt5a激活，Wnt5a在疾病转归中起关键作用。先前的研究表明，Wnt5a通过激活Rac和JNK介导细胞外基质蛋白层粘连蛋白γ2的表达，从而促进胃癌进展。然而，这一调控途径的机制尚未完全阐明。支架蛋白Dvl是Wnt信号通路的主要成分。在此，我们表明富含亮氨酸残基的Dvl结合蛋白（Daple）介导Wnt5a诱导的层粘连蛋白γ2表达。免疫组织化学分析显示，Daple在胃癌临床进展期有明显表达，且与Wnt5a/b、层粘连蛋白γ2表达、壁层浸润深度及淋巴结转移频率高度相关。在培养的癌细胞中，Daple缺失导致Wnt5a诱导的Rac和JNK激活、层粘连蛋白γ2表达以及细胞迁移和侵袭受到抑制。相应地，在胃癌小鼠异种移植模型中，Daple缺失也抑制了肝转移。这些结果表明，非经典Wnt信号通路至少部分通过Daple促进胃癌进展，这为该疾病的治疗提供了新的治疗机会。
