Epithelial-mesenchymal transition via TGF-β in pancreatic cancer is potentiated by the inflammatory glycoprotein LRG.

We previously showed that an inflammation-related, molecule leucine-rich alpha-2 glycoprotein (LRG) enhances the transforming growth factor (TGF)-beta 1-induced phosphorylation of Smad proteins and is elevated in patients with pancreatic ductal adenocarcinoma (PDAC). As TGF-beta/Smad signaling is considered to play a key role in epithelial-mesenchymal transition (EMT), we attempted to clarify the mechanism underlying LRG-related EMT in relation to metastasis in PDAC. We cultured LRG-overexpressing PDAC cells (Panc1/LRG) and evaluated the morphology, EMT-related molecules and TGF-beta/Smad signaling pathway in these cells. We also assessed the LRG levels in plasma and resected specimens from patients with PDAC. Inflammatory cytokines induced LRG production in PDAC cells. A spindle-like shape was visualized more frequently than other shapes in Panc1/LRG with TGF-beta 1 exposure. The expression of E-cadherin in Panc1/LRG was decreased with TGF-beta 1 exposure. Invasion increased with TGF-beta 1 stimulation of Panc1/LRG. The phosphorylation of smad2 in Panc1/LRG was increased in comparison with parental Panc1 under TGF-beta 1 stimulation. In the plasma LRG-high group, the recurrence rate tended to be higher and the recurrence-free survival (RFS) tended to be worse in comparison with the plasma LRG-low group. LRG enhanced EMT induced by TGF-beta signaling, thus indicating that LRG has a significant effect on the metastasis of PDAC.