Interleukin-1α enhances the aggressive behavior of pancreatic cancer cells by regulating the α6β1-integrin and urokinase plasminogen activator receptor expression

Background: In human pancreatic cancer progression, the alpha(6)beta(1)-integrin is expressed on cancer cell surface during invasion and metastasis formation. In this study, we investigated whether interleukin (IL)-1 alpha induces the alterations of integrin subunits and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) expression in pancreatic cancer cells. We hypothesize that the alterations of integrin subunits and uPA/uPAR expression make an important role in signaling pathways responsible for biological behavior of pancreatic cancer cells. Results: IL-1 alpha upregulated the expression of alpha(6) and beta(1) integrins without any alterations of alpha(5) and alpha(v) integrins expression. IL-1 alpha also induced enhancement in the expression of uPA/uPAR in pancreatic cancer cells. IL-1 alpha enhanced the proliferation, adhesion, and migration in pancreatic cancer cells, and IL-1 alpha-induced alterations of uPA/uPAR expression correlated with the increased the migration of pancreatic cancer cells. Upregulation of alpha(6) integrin subunit and uPA/uPAR correlated with the activation of Ras and downstream extracellular signal-egulated kinase (ERK) pathways. IL-1 alpha-induced activation of Ras and downstream ERK can be inhibited by using inhibitory antibodies against alpha(6) and beta(1) integrin and uPAR, consistent with the inhibition of proliferation, adhesion and migration of pancreatic cancer cells. Immunohistochemical analysis demonstrated a significant association between strong expressions of alpha(6) integrin with uPAR in pancreatic cancer specimens. Furthermore, the strong expression of alpha(6) integrin and uPAR was found to be independent prognosticator in pancreatic cancer patients. Conclusion: Based on these findings, we conclude that IL-1 alpha can induce selective upregulation of alpha(6)beta(1)-integrin and uPA/uPAR in pancreatic cancer cells and these changes may modulate the aggressive functions of pancreatic cancer.