Maftouh Mina, Belo Ana I, Avan Amir, Funel Niccola, Peters Godefridus J, Giovannetti Elisa, Van Die Irma
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Oncotarget. 2014 Jul 30;5(14):5335-49. doi: 10.18632/oncotarget.2104.
Galectin-4 (Gal-4) has been recently identified as a pivotal factor in the migratory capabilities of a set of defined pancreatic ductal adenocarcinoma (PDAC) cell lines using zebrafish as a model system. Here we evaluated the expression of Gal-4 in PDAC tissues selected according to their lymph node metastatic status (N0 vs. N1), and investigated the therapeutic potential of targeting the cross-link with the Wnt signaling pathway in primary PDAC cells. Analysis of Gal-4 expression in PDACs showed high expression of Gal-4 in 80% of patients without lymph node metastasis, whereas 70% of patients with lymph node metastases had low Gal-4 expression. Accordingly, in primary PDAC cells high Gal-4 expression was negatively associated with migratory and invasive ability in vitro and in vivo. Knockdown of Gal-4 in primary PDAC cells with high Gal-4 expression resulted in significant increase of invasion (40%) and migration (50%, P<0.05), whereas enforced expression of Gal-4 in primary cells with low Gal-4 expression reduced the migratory and invasive behavior compared to the control cells. Gal-4 markedly reduces β-catenin levels in the cell, counteracting the function of Wnt signaling, as was assessed by down-regulation of survivin and cyclin D1. Furthermore, Gal-4 sensitizes PDAC cells to the Wnt inhibitor ICG-001, which interferes with the interaction between CREB binding protein (CBP) and β-catenin. Collectively, our data suggest that Gal-4 lowers the levels of cytoplasmic β-catenin, which may lead to lowered availability of nuclear β-catenin, and consequently diminished levels of nuclear CBP-β-catenin complex and reduced activation of the Wnt target genes. Our findings provide novel insights into the role of Gal-4 in PDAC migration and invasion, and support the analysis of Gal-4 for rational targeting of Wnt/β-catenin signaling in the treatment of PDAC.
最近，以斑马鱼为模型系统，半乳糖凝集素-4（Gal-4）被确定为一组特定胰腺导管腺癌（PDAC）细胞系迁移能力的关键因素。在此，我们评估了根据淋巴结转移状态（N0 与 N1）选择的 PDAC 组织中 Gal-4 的表达，并研究了在原发性 PDAC 细胞中靶向与 Wnt 信号通路交联的治疗潜力。对 PDAC 中 Gal-4 表达的分析表明，80%无淋巴结转移的患者 Gal-4 高表达，而 70%有淋巴结转移的患者 Gal-4 低表达。因此，在原发性 PDAC 细胞中，Gal-4 高表达与体外和体内的迁移及侵袭能力呈负相关。在 Gal-4 高表达的原发性 PDAC 细胞中敲低 Gal-4 导致侵袭显著增加（40%）和迁移显著增加（50%，P<0.05），而在 Gal-4 低表达的原代细胞中强制表达 Gal-4 与对照细胞相比减少了迁移和侵袭行为。Gal-4 显著降低细胞中β-连环蛋白水平，通过下调生存素和细胞周期蛋白 D1 评估，这抵消了 Wnt 信号的功能。此外，Gal-4 使 PDAC 细胞对 Wnt 抑制剂 ICG-001 敏感，ICG-001 干扰 CREB 结合蛋白（CBP）与β-连环蛋白之间的相互作用。总体而言，我们的数据表明 Gal-4 降低了细胞质β-连环蛋白水平，这可能导致核β-连环蛋白可用性降低，进而导致核 CBP-β-连环蛋白复合物水平降低以及 Wnt 靶基因激活减少。我们的研究结果为 Gal-4 在 PDAC 迁移和侵袭中的作用提供了新的见解，并支持在 PDAC 治疗中分析 Gal-4 以合理靶向 Wnt/β-连环蛋白信号通路。
