Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment

Masato Nishimura, Eun Jung Jung, Maitri Y. Shah, Chunhua Lu, Riccardo Spizzo, Masayoshi Shimizu, Hee Dong Han, Cristina Ivan, Simona Rossi, Xinna Zhang, Milena S. Nicoloso, Sherry Y. Wu, Maria Ines Almeida, Justin Bottsford-Miller, Chad V. Pecot, Behrouz Zand, Koji Matsuo, Mian M. Shahzad, Nicholas B. Jennings, Cristian Rodriguez-AguayoGabriel Lopez-Berestein, Anil K. Sood, George A. Calin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1302-1315
Number of pages14
JournalCancer Discovery
Volume3
Issue number11
DOIs
Publication statusPublished - Nov 2013

ASJC Scopus subject areas

  • Oncology

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