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Cancer Discov. 2013 Nov;3(11):1302-15. doi: 10.1158/2159-8290.CD-13-0159. Epub 2013 Sep 3.

Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment.

Author information

1
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
2
Department of Obstetrics and Gynecology, The University of Tokushima, Graduate School; Japan.
3
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
4
Department of Surgery, School of Medicine, Gyeongsang National University, Jin-ju, South Korea.
5
Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, USA.
6
The Center for RNA Interference and Non-coding RNAs, The University of Texas M.D. Anderson Center, Houston, TX; USA.
7
Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Batiment Genopode, Lausanne, Switzerland.
8
Department of Thoracic, Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
9
Division of Gynecologic Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
10
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
#
Contributed equally

Abstract

Development of improved RNA interference-based strategies is of utmost clinical importance. Although siRNA-mediated silencing of EphA2, an ovarian cancer oncogene, results in reduction of tumor growth, we present evidence that additional inhibition of EphA2 by a microRNA (miRNA) further "boosts" its antitumor effects. We identified miR-520d-3p as a tumor suppressor upstream of EphA2, whose expression correlated with favorable outcomes in two independent patient cohorts comprising 647 patients. Restoration of miR-520d-3p prominently decreased EphA2 protein levels, and suppressed tumor growth and migration/invasion both in vitro and in vivo. Dual inhibition of EphA2 in vivo using 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) nanoliposomes loaded with miR-520d-3p and EphA2 siRNA showed synergistic antitumor efficiency and greater therapeutic efficacy than either monotherapy alone. This synergy is at least in part due to miR-520d-3p targeting EphB2, another Eph receptor. Our data emphasize the feasibility of combined miRNA-siRNA therapy, and will have broad implications for innovative gene silencing therapies for cancer and other diseases.

SIGNIFICANCE:

This study addresses a new concept of RNA inhibition therapy by combining miRNA and siRNA in nanoliposomal particles to target oncogenic pathways altered in ovarian cancer. Combined targeting of the Eph pathway using EphA2-targeting siRNA and the tumor suppressor miR-520d-3p exhibits remarkable therapeutic synergy and enhanced tumor suppression in vitro and in vivo compared with either monotherapy alone.

Comment in

PMID:
24002999
PMCID:
PMC3855315
DOI:
10.1158/2159-8290.CD-13-0159
[Indexed for MEDLINE]
Free PMC Article

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