title: Dickkopf-3 maintains the PANC-1 human pancreatic tumor cells in a dedifferentiated             state.
abstract: Pancreatic cancer (PaCa) is the fourth leading cause of cancer deaths in             Western societies, with pancreatic ductal adenocarcinomas (PDACs) accounting for             >90% of such cases. PDAC is a heterogeneous disease that includes a subset             showing overexpression of the secreted glycoprotein Dickkopf-related protein 3             (Dkk-3), a protein shown to be downregulated in various cancers of different tissues.             The biological function of Dkk-3 in this subset was studied using the Dkk-3 expressing             PANC-1 cell line as a model for PDACs. The influence of Dkk-3 overexpression and             knockdown on cellular differentiation and proliferation of PANC-1 was investigated.             Confocal microscopy showed that Dkk-3 was expressed in a fraction of PANC-1 cells.             While lentiviral-mediated overexpression of DKK3 did not alter cellular proliferation,             knockdown of DKK3 resulted in significant reduction of cellular proliferation             and concomitant induction of cell cycle inhibitors CDKN2B (p15INK4b), CDKN1A (p21CIP1)             and CDKN1B (p27KIP1). In parallel, pancreatic epithelial cell differentiation             markers AMY2A, CELA1, CTRB1, GCG, GLB1 and INS were significantly upregulated.             PANC-1 cells differentiated using exendin-4 showed analogous induction of cell             cycle inhibitors and differentiation markers. Thus, we conclude that Dkk-3 is             required to maintain a highly dedifferentiated and consequently proliferative             state in PANC-1, indicating a similar function in the Dkk-3 overexpressing subset             of PDACs. Therefore, Dkk-3 represents a potential target for the treatment of             Dkk-3-positive subtypes of PaCa to drive cells into cell cycle arrest and differentiation.
authors: Institute for Biomedical Aging Research, Austrian Academy of                     Sciences, A-6020 Innsbruck, Austria.
authors: Christoph
authors: C
authors: Zenzmaier
authors: Martin
authors: M
authors: Hermann
authors: Paul
authors: P
authors: Hengster
authors: Peter
authors: P
authors: Berger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D018925:Chemokines; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016086:Lentivirus / Q000235:genetics; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C436291:CDKN1B protein, human; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27