RT Journal Article
SR Electronic
T1 Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 716738
DO 10.1101/716738
A1 Shixiang Guo
A1 Andrew Fesler
A1 Wenjie Huang
A1 Yunchao Wang
A1 Jiali Yang
A1 Xianxing Wang
A1 Yao Zheng
A1 Ga-Ram Hwang
A1 Huaizhi Wang
A1 Jingfang Ju
YR 2019
UL http://biorxiv.org/content/early/2019/07/27/716738.abstract
AB 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 IC50 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.