title: MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma.
abstract: MicroRNAs (miRNA) aberrantly expressed in tumors may offer novel therapeutic approaches to treatment. miR-145 is downregulated in various cancers including colon carcinoma in which in vitro studies have established proapoptotic and antiproliferative roles. miR-33a was connected recently to cancer through its capacity to downregulate the oncogenic kinase Pim-1. To date, miRNA replacement therapy has been hampered by the lack of robust nonviral delivery methods for in vivo administration. Here we report a method of miRNA delivery by using polyethylenimine (PEI)-mediated delivery of unmodified miRNAs, using miR-145 and miR-33a to preclinically validate the method in a mouse model of colon carcinoma. After systemic or local application of low molecular weight PEI/miRNA complexes, intact miRNA molecules were delivered into mouse xenograft tumors, where they caused profound antitumor effects. miR-145 delivery reduced tumor proliferation and increased apoptosis, with concomitant repression of c-Myc and ERK5 as novel regulatory target of miR-145. Similarly, systemic injection of PEI-complexed miR-33a was validated as a novel therapeutic targeting method for Pim-1, with antitumor effects comparable with PEI/siRNA-mediated direct in vivo knockdown of Pim-1 in the model. Our findings show that chemically unmodified miRNAs complexed with PEI can be used in an efficient and biocompatible strategy of miRNA replacement therapy, as illustrated by efficacious delivery of PEI/miR-145 and PEI/miR-33a complexes in colon carcinoma.
authors.affiliation: Institute of Pharmacology, Philipps-University, Marburg, Germany.
authors.forename: Ahmed Fawzy
authors.initials: AF
authors.lastname: Ibrahim
authors.forename: Ulrike
authors.initials: U
authors.lastname: Weirauch
authors.forename: Maren
authors.initials: M
authors.lastname: Thomas
authors.forename: Arnold
authors.initials: A
authors.lastname: Grünweller
authors.forename: Roland K
authors.initials: RK
authors.lastname: Hartmann
authors.forename: Achim
authors.initials: A
authors.lastname: Aigner
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D048054:Mitogen-Activated Protein Kinase 7 / Q000096:biosynthesis / Q000235:genetics; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011094:Polyethyleneimine / Q000008:administration & dosage; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; C541010:MIRN145 microRNA, human; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D011094:Polyethyleneimine; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D048054:Mitogen-Activated Protein Kinase 7