Abstract
Pancreatic cancer (PDAC) is a lethal disease with a five-year survival of 3–5%. Mutations in K-Ras are found in nearly all cases, but K-Ras mutations alone are not sufficient for the development of PDAC. Additional factors contribute to activation of Ras signaling and lead to tumor formation. Galectin-3 (Gal-3), a multifunctional β-galactoside-binding protein, is highly expressed in PDAC. We therefore investigated the functional role of Gal-3 in pancreatic cancer progression and its relationship to Ras signaling. Expression of Gal-3 was determined by immunohistochemistry, Q-PCR and immunoblot. Functional studies were performed using pancreatic cell lines genetically engineered to express high or low levels of Gal-3. Ras activity was examined by Raf pull-down assays. Co-immunoprecipitation and immunofluorescence were used to assess protein-protein interactions. In this study, we demonstrate that Gal-3 was highly up-regulated in human tumors and in a mutant K-Ras mouse model of PDAC. Down-regulation of Gal-3 by lentivirus shRNA decreased PDAC cell proliferation and invasion in vitro and reduced tumor volume and size in an orthotopic mouse model. Gal-3 bound Ras and maintained Ras activity; down-regulation of Gal-3 decreased Ras activity as well as Ras down-stream signaling including phosphorylation of ERK and AKT and Ral A activity. Transfection of Gal-3 cDNA into PDAC cells with low-level Gal-3 augmented Ras activity and its down-stream signaling. These results suggest that Gal-3 contributes to pancreatic cancer progression, in part, by binding Ras and activating Ras signaling. Gal-3 may therefore be a potential novel target for this deadly disease.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related death, with an estimated 43,140 new cases and 36,800 deaths in the United States [1]
We systematically evaluated the expression of Gal3 in 120 paired human pancreatic tissues from normal pancreas, pancreatitis and pancreatic tumors, and for the first time determined the expression of Gal-3 in tissues and tumor cells derived from of a mutant K-Ras mouse model of pancreatic cancer
We found that Gal-3 expression progressively increased in the sequence of disease progression normal (Figure 1A, a, b), pancreatitis (c,d) and pancreatic ductal adenocarcinoma (e,f)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related death, with an estimated 43,140 new cases and 36,800 deaths in the United States [1]. Considerable effort has been made to understand the molecular events which may drive the pathogenesis of PDAC. Among the numerous molecular alterations identified in PDAC, mutations in the pro-oncogene KRas are found in most cases [3] and is an early event for the development of PDAC [4]. K-Ras mutations alone are not sufficient for the development of PDAC. It has been proposed that it is the activity of K-Ras rather than the presence of mutation per se which is the biologically relevant parameter associated with the pathogenesis of pancreatic cancer [2]. Additional factors are required that contribute to Ras activity; the mechanisms by which Ras activity is further activated are largely unknown
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