title: Inhibition of microRNA-214 ameliorates hepatic fibrosis and tumor incidence in platelet-derived growth factor C transgenic mice.
abstract: Differentially regulated microRNA (miRNA) are associated with hepatic fibrosis; however, their potential usefulness for blocking hepatic fibrosis has not been exploited fully. We examined the expression of miRNA in the liver of a transgenic mouse model in which platelet-derived growth factor C (PDGF-C) is overexpressed (Pdgf-c Tg), resulting in hepatic fibrosis and steatosis and the eventual development of hepatocellular carcinoma (HCC). Robust induction of miR-214 correlated with fibrogenesis in the liver of Pdgf-c Tg mice, atherogenic high-fat diet-induced NASH mice, and patients with chronic hepatitis B or C. Pdgf-c Tg mice were injected with locked nucleic acid (LNA)-antimiR-214 via the tail vein using Invivofectamine 2.0 and the degree of hepatic fibrosis and tumor incidence were evaluated. Pdgf-c Tg mice treated with LNA-antimiR-214 showed a marked reduction in fibrosis and tumor incidence compared with saline or LNA-miR-control-injected control mice. In vitro, LNA-antimiR-214 significantly ameliorated TGF-β1-induced pro-fibrotic gene expression in Lx-2 cells. MiR-214 targets a negative regulator of EGFR signaling, Mig-6. Mimic-miR-214 decreased the expression of Mig-6 and increased the levels of EGF-mediated p-EGFR (Y1173 and Y845) and p-Met (Tyr1234/1235) in Huh-7 cells. Conversely, LNA-antimiR-214 repressed the expression of these genes. In conclusion, miR-214 appears to participate in the development of hepatic fibrosis by modulating the EGFR and TGF-β signaling pathways. LNA-antimiR-214 is a potential therapy for the prevention of hepatic fibrosis.
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Hikari
authors.initials: H
authors.lastname: Okada
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.|Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Takegoshi
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Shirasaki
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Riuta
authors.initials: R
authors.lastname: Takabatake
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: The Tohkai Cytopathology Institute: Cancer Research and Prevention, Gifu, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D015994:Incidence; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D009841:Oligonucleotides / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D008222:Lymphokines; D035683:MicroRNAs; D009841:Oligonucleotides; D010982:Platelet-Derived Growth Factor; D053773:Transforming Growth Factor beta1; C477371:locked nucleic acid; C411423:platelet-derived growth factor C; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met
keywords: Hepatic fibrosis; hepatocellular carcinoma; locked nucleic acid; microRNA; platelet-derived growth factor C