Pancreatic stellate cells (PSCs) are a subset of
pancreatic cancer-associated fibroblasts, which play a critical role in pancreatic
fibrosis, a characteristic feature of
pancreatic cancer. The interplay between PSCs and
pancreatic cancer cells is vital for promotion of
tumor progression and
metastasis. BAG3 is correlated with poor prognostics in patients with pancreatic ductal
adenocarcinoma (PDAC), however, the exact mechanisms remain largely unknown. In this study, we demonstrated that BAG3 downregulation decreased
IL6 release by PDACs, and
IL6 reduction was, at least partially, responsible for suppression of PSCs activation by PDACs with BAG3 downmodulation. Importantly, BAG3 expression positively correlated with
fibrosis in
pancreatic cancer tissue. With regard to the underlying mechanism, we demonstrated that BAG3 knockdown facilitated recruitment of Agonaute 2 (Ago2) to
IL6 mRNA, resulting in destabilization of
IL6 mRNA. In addition, the current study demonstrated that phosphorylation at
Serine (Ser) 387 site was required for recruitment of Ago2-containing miRISC to
IL6 mRNA and BAG3 knockdown facilitated Ago2 loading to
IL6 mRNA via increasing its phosphorylation at Ser 387. This study shed new light on the
tumor-promoting role of BAG3 in PDAC
tumors, suggesting BAG3 might represent an interesting therapeutic opportunity to PDAC patients.