Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 24, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/ijms24043954
Keywords
pancreatic stellate cells; chronic pancreatitis; microRNA
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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.
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.
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