Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma
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Mina Maftouh1,*, Ana I. Belo2,*, Amir Avan1,3, Niccola Funel4, Godefridus J. Peters1, Elisa Giovannetti1,4,* and Irma van Die2,*
1 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
2 Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
3 Biochemistry of Nutrition Research Center, and Department of New Sciences and Technology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
4 Start-Up Unit, University of Pisa, Pisa, Italy
* These Authors contributed equally to this work
Irma van Die, email:
Elisa Giovannetti, email:
Keywords: Pancreatic ductal adenocarcinoma, Galectin-4, migration, lymph node ratio, primary PDAC cells, Wnt/β-catenin pathway
Received: April 17, 2014 Accepted: June 12, 2014 Published: June 13, 2014
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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