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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-death, and has the worst prognosis of any major malignancy, with less than 5% of patients alive 5-years after diagnosis [1]
In this study we focus on the role of Galectin 4 (Gal4) in PDAC
Our data establish a role of Gal-4 as tumor suppressor in PDAC, since we showed that elevated Gal-4 levels correlated significantly with a reduced in vitro migratory and invasive behavior in primary PDAC cultures, as well as with a reduced lymph node metastasis in PDAC patients
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-death, and has the worst prognosis of any major malignancy, with less than 5% of patients alive 5-years after diagnosis [1]. One of the major hallmarks of PDAC is its early systemic dissemination, which can be coupled to extensive local www.impactjournals.com/oncotarget tumor spread [2]. These features explain why more than 80% of patients diagnosed with this disease cannot be offered surgical treatment and are among the main causes of the high mortality rate among PDAC patients. Loss of junctional contact between adjacent epithelial cells and cellextracellular matrix association constitute fundamental prerequisites for cancer cell detachment from the primary tumor. Adhesion molecules on the cell surface and regulators of transmembrane signaling play a determinant role in tumor cell migration and regulate the potential for epithelial cells to metastasize [3]
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