Therapeutic Synergy between microRNA and siRNA in Ovarian Cancer Treatment

Abstract

Development of improved RNA interference based strategies is of utmost clinical importance. While 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 further ‘boosts’ its anti-tumor 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 of 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 DOPC nano-liposomes loaded with miR-520d-3p and EphA2-siRNA showed synergistic anti-tumor efficiency and greater therapeutic efficacy than either monotherapy alone. This synergy is atleast 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.

Cell‐to‐cell communication: microRNAs as hormones

“…Another novel approach is the combination of small interfering RNA (siRNA) and miRNA‐based treatment that can allow a ‘boosting’ effect for targeting oncogenic pathways and repressing cancer growth (Nishimura et al ., 2013). We proved that combined inhibition of EphA2, an ovarian cancer oncogene, with EphA2 siRNA and miR‐520d‐3p mimic exhibits synergistic effects (Nishimura et al ., 2013).…”

“…We proved that combined inhibition of EphA2, an ovarian cancer oncogene, with EphA2 siRNA and miR‐520d‐3p mimic exhibits synergistic effects (Nishimura et al ., 2013). We identified miR‐520d‐3p as a tumor suppressor upstream of EphA2, which is associated with longer overall and relapse‐free survival time in ovarian cancer patients (Nishimura et al ., 2013). In this study, miR‐520d‐3p was shown to directly target EphA2 and EphB2 and inhibit their protein expression in ovarian cancer cells.…”

“…Treatment with the combination of miR‐520d‐3p mimic and EphA2 siRNA resulted in less invasion/migration by HeyA8 and SKOV3ip1 cells than either miR‐520d‐3p or EphA2 siRNA alone or the controls. Moreover, in vivo therapeutic delivery of miR‐520d‐3p mimic and EphA2 siRNA induced potent synergy, resulting in substantial inhibition of tumor growth when compared with individual treatments in ovarian cancer tumor xenograft models (Nishimura et al ., 2013). …”

A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells

“…Combining RNAi to achieve a synergistic antitumor effect is an emerging therapeutic field for several cancer types, including ovarian and non-small lung cancers [50,51]. Nevertheless, to date the available delivery options are mostly confined to liposome-encapsulated RNAi that are selectively trapped in the liver.…”

Extracellular Micro-RNAs in Health and Disease: Basic Science, Biogenesis and Release

“…Turchinovich and colleagues [43], showed that the majority of miRNAs found in human plasma, are associated with Ago2 and that the high proportion of Ago-miRNA may represent by-products of dead cells, since Ago-miRNA complexes, which are known to be present within Exosomes, are known to be extremely stable within cells [59], and it may be derived from vesicles potentially damaged during purification [74].…”