Suppression of the uPAR-uPA system retards angiogenesis, invasion, and in vivo tumor development in pancreatic cancer cells.

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.

Gorantla B ，Asuthkar S ，Rao JS ，Patel J ，Gondi CS ... -  《-》

Targeting of urokinase plasminogen activator receptor in human pancreatic carcinoma cells inhibits c-Met- and insulin-like growth factor-I receptor-mediated migration and invasion and orthotopic tumor growth in mice.

Bauer TW ，Liu W ，Fan F ，Camp ER ，Yang A ，Somcio RJ ，Bucana CD ，Callahan J ，Parry GC ，Evans DB ，Boyd DD ，Mazar AP ，Ellis LM ... -  《CANCER RESEARCH》

Downregulation of uPA/uPAR inhibits intermittent hypoxia-induced epithelial-mesenchymal transition (EMT) in DAOY and D283 medulloblastoma cells.

Gupta R ，Chetty C ，Bhoopathi P ，Lakka S ，Mohanam S ，Rao JS ，Dinh DE ... -  《-》

Prognostic significance of growth factors and the urokinase-type plasminogen activator system in pancreatic ductal adenocarcinoma.

Xue A ，Scarlett CJ ，Jackson CJ ，Allen BJ ，Smith RC ... -  《-》

Interleukin-1alpha enhances the aggressive behavior of pancreatic cancer cells by regulating the alpha6beta1-integrin and urokinase plasminogen activator receptor expression.

Sawai H ，Okada Y ，Funahashi H ，Matsuo Y ，Takahashi H ，Takeyama H ，Manabe T ... -  《BMC CELL BIOLOGY》