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 half maximal inhibitory concentration (IC50) more than 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.

journal_name

Mol Ther Nucleic Acids

authors

Guo S,Fesler A,Huang W,Wang Y,Yang J,Wang X,Zheng Y,Hwang GR,Wang H,Ju J

doi

10.1016/j.omtn.2019.11.010

subject

Has Abstract

pub_date

2020-03-06 00:00:00

pages

228-239

issn

2162-2531

pii

S2162-2531(19)30363-4

journal_volume

19

pub_type

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