title: Altered regulation of miR-34a and miR-483-3p in alcoholic hepatitis and DDC fed mice.
abstract: MicroRNAs are small noncoding RNAs that negatively regulate gene expression by binding to the untranslated regions of their target mRNAs. Deregulation of miRNAs is shown to play pivotal roles in tumorigenesis and progression. Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. By comparing AH livers where MDBs had formed with normal livers, there were significant changes of miR-34a and miR-483-3p by RNA sequencing (RNA-Seq) analyses. Real-time PCR further shows a 3- and 6-fold upregulation (respectively) of miR-34a in the AH livers and in the livers of DDC re-fed mice, while miR-483-3p was significantly downregulated in AH and DDC re-fed mice livers. This indicates that miR-34a and miR-483-3p may be crucial for liver MDB formation. P53 mRNA was found to be significantly downregulated both in the AH livers and in the livers of DDC re-fed mice, indicating that the upregulation of miR-34a is permitted by the decrease of p53 in AH since miR-34a is a main target of p53. Overexpression of miR-34a leads to an increase of p53 targets such as p27, which inhibits the cell cycle leading to cell cycle arrest. Importantly, BRCA1 is a target gene of miR-483-3p by RNA-Seq analyses and the downregulation of miR-483-3p may be the mechanism for liver MDB formation since the BRCA1 signal was markedly upregulated in AH livers. These results constitute a demonstration of the altered regulation of miR-34a and miR-483-3p in the livers of AH and mice fed DDC where MDBs formed, providing further insight into the mechanism of MDB formation mediated by miR-34a and miR-483-3p in AH.
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: French
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Tillman
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA. Electronic address: sfrench@labiomed.org.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006519:Hepatitis, Alcoholic / Q000235:genetics / Q000473:pathology*; D006801:Humans; D059609:Mallory Bodies / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C522425:MIRN34 microRNA, human; C551848:MIRN34a microRNA, mouse; C548912:MIRN483 microRNA, human; D035683:MicroRNAs; C548913:Mirn483 microRNA, mouse
keywords: Alcoholic hepatitis; Mallory–Denk bodies; miR-34a; miR-483-3p; p53