title: Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|Department of Obstetrics and Gynecology, The University of Tokushima, Graduate School; Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|Department of Surgery, School of Medicine, Gyeongsang National University, Jin-ju, South Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Jung
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Maitri Y
authors.initials: MY
authors.lastname: Shah
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Spizzo
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Han
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|The Center for RNA Interference and Non-coding RNAs, The University of Texas M.D. Anderson Center, Houston, TX; USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Batiment Genopode, Lausanne, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|The Center for RNA Interference and Non-coding RNAs, The University of Texas M.D. Anderson Center, Houston, TX; USA.
authors.forename: Xinna
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Milena S
authors.initials: MS
authors.lastname: Nicoloso
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sherry Y
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Maria Ines
authors.initials: MI
authors.lastname: Almeida
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Bottsford-Miller
authors.affiliation: Department of Thoracic, Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chad V
authors.initials: CV
authors.lastname: Pecot
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Behrouz
authors.initials: B
authors.lastname: Zand
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|Division of Gynecologic Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Mian M
authors.initials: MM
authors.lastname: Shahzad
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Jennings
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|The Center for RNA Interference and Non-coding RNAs, The University of Texas M.D. Anderson Center, Houston, TX; USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|The Center for RNA Interference and Non-coding RNAs, The University of Texas M.D. Anderson Center, Houston, TX; USA.|Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|The Center for RNA Interference and Non-coding RNAs, The University of Texas M.D. Anderson Center, Houston, TX; USA.|Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.|The Center for RNA Interference and Non-coding RNAs, The University of Texas M.D. Anderson Center, Houston, TX; USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000494:pharmacology / Q000627:therapeutic use*; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010713:Phosphatidylcholines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use*; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D036183:Receptor, EphB2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C575048:MIRN520 microRNA, human; D035683:MicroRNAs; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; D036104:Receptor, EphA2; D036183:Receptor, EphB2; C017251:1,2-oleoylphosphatidylcholine