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

Abstract

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 Ptf1aCreERTM and Ptf1aCreERTM;LSL-KrasG12D 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, TGFβ1, control miR, and miR-15a. In addition, treatment of PSCs with 5-FU-miR-15a in the context of TGFβ1 treatment exerted a more substantial effect than TGFβ1 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.

Development of gemcitabine-modified miRNA mimics as cancer therapeutics for pancreatic ductal adenocarcinoma

“…Given the important regulatory function of miR-15a in immune response, other cancer types, and diseases, the therapeutic potential of Gem-miR-15a may extend beyond being an anticancer treatment for PDAC. 11 , 37 , 67 , 68 , 69 As a general platform strategy, when utilizing this Gem modification on tumor suppressor miRNAs, the tumor suppressor miRNA candidate must be carefully selected based on their targets to reflect the complex nature of resistance in PDAC. However, modified miRNA-based therapies with purine and pyrimidine-based chemotherapeutic analogs can be conceptualized as a new class of multi-targeted biomimicry therapy with enhanced potency and minimal toxicity for future cancer care that can improve the quality of life for cancer patients.…”

Development of Gemcitabine-Modified miRNA Mimics as Cancer Therapeutics for Pancreatic Ductal Adenocarcinoma

“…Our results also demonstrate the potential for Gem-miR-15a as an anticancer treatment for patients with PDAC. Given the important regulatory function of miR-15a in immune response, other cancer types, and diseases, the therapeutic potential of Gem-miR-15a may extend beyond being an anticancer treatment for PDAC (11,37,(66)(67)(68). As a general platform strategy, when utilizing this Gem modification on tumor suppressor miRNAs, the tumor suppressor miRNA candidate must be carefully selected based on their targets to reflect the complex nature of resistance in PDAC.…”

Functional and Potential Therapeutic Implication of MicroRNAs in Pancreatic Cancer

“…Notably, 5-FU-miR-15a was found to be potent in inhibiting PDAC metastatic tumor growth and sensitizing PDAC to gemcitabine in vivo, showcasing its therapeutic promise [38]. 5-FU-miR-15a was also shown to significantly inhibit the expression of Yap1, Bcl2, Il6, and Mmp9, both alone and during treatment with TGFβ1 in murine and human Pancreatic Stellate Cells, suggesting the reduced proliferation and migration of pancreatic stellate and cancer cells [171].…”