Smad4 is a
common Smad and is a key downstream regulator of the
transforming growth factor-β signaling pathway, in which Smad4 often acts as a potent
tumor suppressor and functions in a highly context-dependent manner, particularly in
pancreatic cancer. However, little is known regarding whether Smad4 regulates other signaling pathways involved in
pancreatic cancer. The present study demonstrated that Smad4 downregulates
c-Jun N-terminal kinase (JNK) activity using a Smad4 loss-of-function or gain-of-function analysis. Additionally, stable overexpression of Smad4 clearly affected the migration of human pancreatic epithelioid
carcinoma PANC-1 cells, but did not affect cell growth. In addition, the present study revealed that upregulation of
mitogen-activated protein kinase phosphatase-1 is required for the reduction of JNK activity by Smad4, leading to a decrease in
vascular endothelial growth factor expression and inhibiting cell migration. Overall, the present findings indicate that Smad4 may suppress JNK activation and inhibit the
tumor characteristics of
pancreatic cancer cells.