title: Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model.
abstract: Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies.
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Janaiah
authors.initials: J
authors.lastname: Kota
authors.forename: Raghu R
authors.initials: RR
authors.lastname: Chivukula
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: O'Donnell
authors.forename: Erik A
authors.initials: EA
authors.lastname: Wentzel
authors.forename: Chrystal L
authors.initials: CL
authors.lastname: Montgomery
authors.forename: Hun-Way
authors.initials: HW
authors.lastname: Hwang
authors.forename: Tsung-Cheng
authors.initials: TC
authors.lastname: Chang
authors.forename: Perumal
authors.initials: P
authors.lastname: Vivekanandan
authors.forename: Michael
authors.initials: M
authors.lastname: Torbenson
authors.forename: K Reed
authors.initials: KR
authors.lastname: Clark
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000628:therapy*; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005822:Genetic Vectors; D008113:Liver Neoplasms / Q000235:genetics* / Q000628:therapy*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics
chemical_list: D056742:Cyclin D2; D016213:Cyclins; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; C080336:CCND2 protein, human; C503688:CCNE2 protein, human; C528163:MIRN26 microRNA, human; C489427:MYC protein, human