title: Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma.
abstract: 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.
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Mina
authors: M
authors: Maftouh
authors: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Ana I
authors: AI
authors: Belo
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. Biochemistry of Nutrition Research Center, and Department of New Sciences and Technology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors: Amir
authors: A
authors: Avan
authors: Start-Up Unit, University of Pisa, Pisa, Italy.
authors: Niccola
authors: N
authors: Funel
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Godefridus J
authors: GJ
authors: Peters
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Start-Up Unit, University of Pisa, Pisa, Italy.
authors: Elisa
authors: E
authors: Giovannetti
authors: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Irma
authors: I
authors: Van Die
mesh_terms: D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D015398:Signal Transduction; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin