Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma

Abstract

Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge.There is an urgent need to develop novel strategies to enhance survival and improve patient prognosis. microRNAs (miRNAs) play critical roles as oncogenes or tumor suppressors in the regulation of cancer development and progression. In this study, we demonstrate that low expression of miR-15a is associated with poor prognosis of PDAC patients. miR-15a expression is reduced in PDAC while closely related miR-16 expression remains relatively unchanged. miR-15a suppresses several important targets such as Wee1, Chk1, Yap-1, and BMI-1 causing cell cycle arrest and inhibiting cell proliferation. Ectopic expression of miR-15a sensitizes PDAC cells to gemcitabine reducing the IC 50 over 6.5-fold. To investigate the therapeutic potential of miR-15a, we used a modified miR-15a (5-FU-miR-15a) with uracil (U) residues in the guide strand replaced with 5-fluorouracil (5-FU). We demonstrated enhanced inhibition of PDAC cell proliferation by 5-FU-miR-15a compared to native miR-15a. In vivo we showed the therapeutic power of 5-FU-miR-15a alone or in combination with gemcitabine with near complete elimination of PDAC lung metastatic tumor growth. These results support the future development of 5-FU-miR-15a as a novel therapeutic agent as well as a prognostic biomarker in the clinical management of PDAC. Introduction:

Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics

“…30 We have previously demonstrated in colon cancer, pancreatic, and breast cancer that 5-FU modification of miRNAs have several key features such as retaining target specificity, vehicle-free delivery, enhanced potency, and increased intracellular stability. 28,30,31,48 To demonstrate the general applicability of this approach to other tumor suppressor miRNAs, we chose 12 well-studied tumor suppressor miRNAs and applied our 5-FU modification strategy.…”

Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics

“…30 We have previously demonstrated in colon cancer, pancreatic, and breast cancer that 5-FU modification of miRNAs have several key features such as retaining target specificity, vehicle-free delivery, enhanced potency, and increased intracellular stability. 28,30,31,48 To demonstrate the general applicability of this approach to other tumor suppressor miRNAs, we chose 12 well-studied tumor suppressor miRNAs and applied our 5-FU modification strategy. We screened these 12 different 5-FU-modified miRNA mimetics in several other major cancer types including breast cancer, gastric cancer, leukemia, lung cancer, and pancreatic cancer.…”

The involvement of exosomes in the diagnosis and treatment of pancreatic cancer

“…It has been reported that miR-15a makes PC resistant to gemcitabine, to overcome this situation, they modified the exosomal micro RNA in question to 5-FU-miR-15a, which stopped PC cell proliferation. The combination significantly suppressed pancreatic cancer lung metastatic development [81]. Pancreatic cancer is one of a malignant disease that resists to some of the available chemotherapies, as the battle continues to eliminate this burden, the researchers found that exosomes may be excellent tools to prevent this problem, for example, it has been reported that microRNA-410-3p significantly reduced the PC cancer resistance to gemcitabine by inhibiting HMGB1mediated autophagy this made the exosomes to be considered as good candidates to be used in treating pancreatic cancer [82].…”