title: miR-133b Regulation of Connective Tissue Growth Factor: A Novel Mechanism in Liver Pathology.
abstract: miRNAs are involved in liver regeneration, and their expression is dysregulated in hepatocellular carcinoma (HCC). Connective tissue growth factor (CTGF), a direct target of miR-133b, is crucial in the ductular reaction (DR)/oval cell (OC) response for generating new hepatocyte lineages during liver injury in the context of hepatotoxin-inhibited hepatocyte proliferation. Herein, we investigate whether miR-133b regulation of CTGF influences HCC cell proliferation and migration, and DR/OC response. We analyzed miR-133b expression and found it to be down-regulated in HCC patient samples and induced in the rat DR/OC activation model of 2-acetylaminofluorene with partial hepatectomy. Furthermore, overexpression of miR-133b via adenoviral system in vitro led to decreased CTGF expression and reduced proliferation and Transwell migration of both HepG2 HCC cells and WBF-344 rat OCs. In vivo, overexpression of miR-133b in DR/OC activation models of 2-acetylaminofluorene with partial hepatectomy in rats, and 3,5-diethoxycarbonyl-1,4-dihydrocollidine in mice, led to down-regulation of CTGF expression and OC proliferation. Collectively, these results show that miR-133b regulation of CTGF is a novel mechanism critical for the proliferation and migration of HCC cells and OC response.
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Altin
authors.initials: A
authors.lastname: Gjymishka
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Liya
authors.initials: L
authors.lastname: Pi
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Seh-Hoon
authors.initials: SH
authors.lastname: Oh
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Marda
authors.initials: M
authors.lastname: Jorgensen
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Yianni
authors.initials: Y
authors.lastname: Protopapadakis
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Ashnee
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida. Electronic address: bryonpetersen@peds.ufl.edu.
authors.forename: Bryon E
authors.initials: BE
authors.lastname: Petersen
mesh_terms: D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D005822:Genetic Vectors; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000503:physiopathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D051381:Rats; D014162:Transfection
chemical_list: D002273:Carcinogens; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; D055513:Connective Tissue Growth Factor; D015073:2-Acetylaminofluorene