Abstract
It is not yet understood how the enhanced expression of pancreatic adenocarcinoma up-regulated factor (PAUF; a novel oncogene identified in our recent studies), contributes to the oncogenesis of pancreatic cells. We herein report that PAUF up-regulates the expression and transcriptional activity of β-catenin while the suppression of PAUF by shRNA down-regulates β-catenin. The induction of b-catenin by PAUF is mediated by the activities of Akt and GSK-3β, but inhibition of downstream ERK does not reduce β-catenin expression. To test whether PAUF emulates either the Wnt3a-mediated or the protein kinase A-mediated signaling pathway for the stabilization of β-catenin, we examined the phosphorylation status of β-catenin in the presence of PAUF compared with that of β-catenin during treatment with Wnt3a or dibutyryl cAMP, a cell permeable cyclic AMP analogue. PAUF expression induces phosphorylation at Ser-33/37/Thr-41 and Ser-675 of β-catenin but no phosphorylation at Ser-45, indicating that a unique phosphorylation pattern of b-catenin is caused by PAUF. Finally, the expression of PAUF up-regulates both cyclin-D1 and c-Jun, target genes of β-catenin, leading to a rapid proliferation of pancreatic cells; conversely decreased PAUF expression (by shRNA) results in the reduced proliferation of pancreatic cells. Treatment with hexachlorophene (an inhibitor of β-catenin) reduces the proliferation of pancreatic cells despite the presence of PAUF. Taken together, we propose that PAUF can up-regulate and stabilize β-catenin via a novel pattern of phosphorylation, thereby contributing to the rapid proliferation of pancreatic cancer cells.
Highlights
Pancreatic cancer has an extremely poor prognosis with a 5-yr survival rate of less than 5% (Ghaneh et al, 2007; Maitra and Hruban, 2008)
This study led us to discover a novel gene that we named pancreatic adenocarcinoma up-regulated factor (PAUF), which was highly expressed in human pancreatic cancer
Further study revealed that PAUF plays important roles in cancer progression such as oncogenic activity and metastasis (Kim et al, 2009; Lee et al, 2010), and we have argued that PAUF may be a novel diagnostic marker as well as a therapeutic target in pancreatic cancer
Summary
Pancreatic cancer has an extremely poor prognosis with a 5-yr survival rate of less than 5% (Ghaneh et al, 2007; Maitra and Hruban, 2008). The only potential curative treatment for pancreatic cancer is surgery, but only 10-20% of patients are candidates for surgery at the time of presentation. To overcome obstacles such as late diagnosis, the aggressive nature of the tumor, and resistance to existing therapeutic regimens (Hawes et al, 2000), novel tumor-specific biomarkers and genetic pathways that may lead to potential diagnostic and therapeutic targets are desperately needed. We demonstrated that PAUF expression enhances migration and invasion by up-regulating CXCR4, which eventually facilitates the metastasis of pancreatic cancer (Lee et al, 2010)
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