Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma.
Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma.
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DOI：
10.18632/oncotarget.2104
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发表时间：
2014-07-30
期刊：
影响因子：
--
通讯作者：
Van Die I
中科院分区：
文献类型：
--
作者：
Maftouh M;Belo AI;Avan A;Funel N;Peters GJ;Giovannetti E;Van Die I
半乳糖凝集素-4（Gal-4）最近已被确定为一组确定的胰腺导管腺癌（PDAC）细胞系的迁移能力的关键因素，使用斑马鱼作为模型系统。在这里，我们评估了Gal-4在根据其淋巴结转移状态（N 0 vs. N1）选择的PDAC组织中的表达，并研究了在原代PDAC细胞中靶向与Wnt信号传导通路的交联的治疗潜力。对PDAC中Gal-4表达的分析显示，80%的无淋巴结转移的患者中Gal-4高表达，而70%的有淋巴结转移的患者中Gal-4低表达。因此，在原代PDAC细胞中，高Gal-4表达与体外和体内的迁移和侵袭能力呈负相关。与对照组相比，Gal-4高表达的原代PDAC细胞中Gal-4的敲低导致侵袭（40%）和迁移（50%，P<0.05）的显著增加，而Gal-4低表达的原代细胞中Gal-4的增强表达降低了迁移和侵袭行为。Gal-4显著降低细胞中的β-连环蛋白水平，抵消Wnt信号传导的功能，如通过下调生存素和细胞周期蛋白D1所评估的。此外，Gal-4使PDAC细胞对Wnt抑制剂ICG-001敏感，其干扰CREB结合蛋白（CBP）和β-连环蛋白之间的相互作用。总的来说，我们的数据表明，Gal-4降低了细胞质β-连环蛋白的水平，这可能导致细胞核β-连环蛋白的可用性降低，从而降低了细胞核CBP-β-连环蛋白复合物的水平，并降低了Wnt靶基因的激活。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，并支持分析Gal-4在PDAC治疗中合理靶向Wnt/β-catenin信号传导。
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.
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影响因子：
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作者：
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通讯作者：
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