title: Dicer-dependent production of microRNA221 in hepatocytes inhibits p27 and is required for liver regeneration in mice.
abstract: Dicer processes microRNAs (miRs) into active forms in a wide variety of tissues, including the liver. To determine the role of Dicer in liver regeneration, we performed a series of in vivo and in vitro studies in a murine 2/3 hepatectomy model. Dicer was downregulated after 2/3 hepatectomy, and loss of Dicer inhibited liver regeneration associated with decreased cyclin A2 and miR-221, as well as increased levels of the cell cycle inhibitor p27. In vitro, miR-221 inhibited p27 production in primary hepatocytes and increased hepatocyte proliferation. Specific reconstitution of miR-221 in hepatocyte-specific Dicer-null mice inhibited p27 and restored liver regeneration. In wild type mice, targeted inhibition of miR-221 using a cholesterol-conjugated miR-221 inhibited hepatocyte proliferation after 2/3 hepatectomy. These results identify Dicer production of miR-221 as an essential component of a miRNA-dependent mechanism for suppression of p27 that controls the rate of hepatocyte proliferation after partial hepatectomy.NEW & NOTEWORTHYOur findings demonstrate a direct role for microRNAs in controlling the rate of liver regeneration after injury. By deleting Dicer, an enzyme responsible for processing microRNAs into mature forms, we determined miR-221 is a critical microRNA in the physiological process of restoration of liver mass after injury. miR-221 suppresses p27, releasing its inhibitory effects on hepatocyte proliferation. Pharmaceuticals based on miR-221 may be useful to modulate hepatocyte proliferation in the setting of liver injury.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Oya
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Ryota
authors.initials: R
authors.lastname: Masuzaki
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsugawa
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Ray
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; and seth.karp@vanderbilt.edu.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Karp
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000254:growth & development*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D043244:Ribonuclease III / Q000378:metabolism*
chemical_list: C546122:MIRN221 microRNA, mouse; D035683:MicroRNAs; D050760:Cyclin-Dependent Kinase Inhibitor p27; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: Dicer; liver; miR-221; p27; regeneration