TY - JOUR
T1 - Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment
AU - Nishimura, Masato
AU - Jung, Eun Jung
AU - Shah, Maitri Y.
AU - Lu, Chunhua
AU - Spizzo, Riccardo
AU - Shimizu, Masayoshi
AU - Han, Hee Dong
AU - Ivan, Cristina
AU - Rossi, Simona
AU - Zhang, Xinna
AU - Nicoloso, Milena S.
AU - Wu, Sherry Y.
AU - Almeida, Maria Ines
AU - Bottsford-Miller, Justin
AU - Pecot, Chad V.
AU - Zand, Behrouz
AU - Matsuo, Koji
AU - Shahzad, Mian M.
AU - Jennings, Nicholas B.
AU - Rodriguez-Aguayo, Cristian
AU - Lopez-Berestein, Gabriel
AU - Sood, Anil K.
AU - Calin, George A.
PY - 2013/11
Y1 - 2013/11
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-13-0159
DO - 10.1158/2159-8290.CD-13-0159
M3 - Article
C2 - 24002999
AN - SCOPUS:84887467125
SN - 2159-8274
VL - 3
SP - 1302
EP - 1315
JO - Cancer discovery
JF - Cancer discovery
IS - 11
ER -