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Therapeutic Synergy between microRNA and siRNA in Ovarian Cancer Treatment

2013; American Association for Cancer Research; Volume: 3; Issue: 11 Linguagem: Inglês

10.1158/2159-8290.cd-13-0159

2159-8290

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

RNA Interference and Gene Delivery

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.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.