Abstract
Despite existing chemotherapy and surgical resection strategies, pancreatic cancer is one of the major causes of mortality in the United States with a 5-year mean survival rate of less than 5%. The activation of the urokinase-type plasminogen activator receptor-urokinase-type plasminogen activator (uPAR-uPA) system in the development of pancreatic ductal adenocarcinoma has been well established. In the present study, we used 2 pancreatic cancer cell lines, MIA PaCa-2 and PANC-1 to show the effects of uPAR and uPA downregulation. From the results, we observed that RNAi expressing plasmids efficiently downregulated mRNA and protein expression of uPAR and uPA. In vitro and in vivo angiogenic assays revealed a significant decrease in the angiogenic potential of MIA PaCa-2 and PANC-1 cells that were downregulated for both uPAR and uPA. From the angiogenesis antibody array analysis, we observed that the simultaneous downregulation of uPAR and uPA resulted in the downregulation of angiogenin and overexpression of RANTES. Further, FACS analysis showed that the simultaneous downregulation of uPAR and uPA caused the accumulation of cells in the sub-G(0/1) phase in both MIA PaCa-2 and PANC-1 cells. In addition, Western blot analysis revealed that downregulation of uPAR and uPA caused the activation of caspase 8 and CAD, which is indicative of apoptosis, and in vivo TUNEL assay confirmed these results. Finally, we observed the nuclear localization of uPA and that uPA interacts with the transcription factor Lhx-2. Taken together, the results of the present study show that the targeting of the uPAR-uPA system has therapeutic potential.
Highlights
Each year about 37,000 individuals in the United States are diagnosed with pancreatic cancer, and more than 30,000 die from the disease
From the human tissue array analysis, we observed that both uPA receptor (uPAR) and urokinase-type plasminogen activator (uPA) were highly expressed in human pancreatic cancer tissues, and the expression of uPAR was always correlated with the expression of its ligand uPA
Researchers have demonstrated that activation of the uPAR-uPA system is an early event in the development of pancreatic ductal adenocarcinoma and that uPAR gene amplifications identify a subgroup of aggressive tumors, thereby making the uPARuPA system a critical and highly promising target for therapeutic interventions [10]
Summary
Each year about 37,000 individuals in the United States are diagnosed with pancreatic cancer, and more than 30,000 die from the disease. Patients diagnosed with pancreatic cancer typically have a poor prognosis partly because the cancer usually does not cause symptoms at earlier stages, which leads to locally advanced or metastatic disease by the time of diagnosis. Median survival is 3 to 6 months after diagnosis and as mentioned earlier, the five-year survival rate is less than 5 percent [3]. It accounts for only 2.5 percent of new cases, pancreatic cancer is responsible for 6 percent of cancer deaths each year [4]. The survival rate [3] and high recurrence after surgery clearly demonstrate the need for novel therapies [5]
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