5-FU-miR-15a Inhibits Activation of Pancreatic Stellate Cells by Reducing YAP1 and BCL-2 Levels In Vitro

Chronic pancreatitis is characterized by chronic inflammation and fibrosis, processes heightened by activated pancreatic stellate cells (PSCs). Recent publications have demonstrated that miR-15a, which targets YAP1 and BCL-2, is significantly downregulated in patients with chronic pancreatitis compared to healthy controls. We have utilized a miRNA modification strategy to enhance the therapeutic efficacy of miR-15a by replacing uracil with 5-fluorouracil (5-FU). We demonstrated increased levels of YAP1 and BCL-2 (both targets of miR-15a) in pancreatic tissues obtained from Ptf1aCre(ERTM) and Ptf1aCre(ERTM);LSL-Kras(G12D) mice after chronic pancreatitis induction as compared to controls. In vitro studies showed that delivery of 5-FU-miR-15a significantly decreased viability, proliferation, and migration of PSCs over six days compared to 5-FU, TGF beta 1, control miR, and miR-15a. In addition, treatment of PSCs with 5-FU-miR-15a in the context of TGF beta 1 treatment exerted a more substantial effect than TGF beta 1 alone or when combined with other miRs. Conditioned medium obtained from PSC cells treated with 5-FU-miR-15a significantly inhibits the invasion of pancreatic cancer cells compared to controls. Importantly, we demonstrated that treatment with 5-FU-miR-15a reduced the levels of YAP1 and BCL-2 observed in PSCs. Our results strongly suggest that ectopic delivery of miR mimetics is a promising therapeutic approach for pancreatic fibrosis and that 5-FU-miR-15a shows specific promise.

Automated summary

Chronic pancreatitis is characterized by inflammation and fibrosis, which are worsened by activated pancreatic stellate cells (PSCs). Recent research shows that miR-15a, which targets YAP1 and BCL-2, is significantly downregulated in patients with chronic pancreatitis. We demonstrated that 5-FU-miR-15a can effectively inhibit PSC viability, proliferation, and migration, as well as reduce the invasion of pancreatic cancer cells.