title: In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2.
abstract: MiR-519d belongs to the chromosome 19 miRNA cluster (C19MC), the largest human miRNA cluster. One of its members, miR-519d, is over-expressed in hepatocellular carcinoma (HCC) and we characterized its contribution to hepatocarcinogenesis. In HCC cells, the over-expression of miR-519d promotes cell proliferation, invasion and impairs apoptosis following anticancer treatments. These functions are, at least in part, exerted through the direct targeting of CDKN1A/p21, PTEN, AKT3 and TIMP2. The mechanisms underlying miR-519d aberrant expression in HCC were assayed by genomic DNA amplification, methylation analysis and ChIP assay. The aberrant hypomethylation of C19MC and TP53 were respectively identified as an epigenetic change allowing the aberrant expression of miR-519d and one of the factors able to activate its transcription. In conclusion, we assessed the oncogenic role of miR-519d in HCC by characterizing its biological functions, including the modulation of response to anticancer treatments and by identifying CDKN1A/p21, PTEN, AKT3 and TIMP2 among its targets.
authors.affiliation: Centro di Ricerca Biomedica Applicata, Policlinico S. Orsola-Malpighi e Università di Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fornari
authors.forename: Maddalena
authors.initials: M
authors.lastname: Milazzo
authors.forename: Pasquale
authors.initials: P
authors.lastname: Chieco
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.forename: Elena
authors.initials: E
authors.lastname: Marasco
authors.forename: Giovanni
authors.initials: G
authors.lastname: Capranico
authors.forename: Vilma
authors.initials: V
authors.lastname: Mantovani
authors.forename: Jessica
authors.initials: J
authors.lastname: Marinello
authors.forename: Silvia
authors.initials: S
authors.lastname: Sabbioni
authors.forename: Elisa
authors.initials: E
authors.lastname: Callegari
authors.forename: Matteo
authors.initials: M
authors.lastname: Cescon
authors.forename: Matteo
authors.initials: M
authors.lastname: Ravaioli
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Luigi
authors.initials: L
authors.lastname: Bolondi
authors.forename: Laura
authors.initials: L
authors.lastname: Gramantieri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000903:Antibiotics, Antineoplastic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C546194:MIRN519 microRNA, human; D035683:MicroRNAs; C560823:TIMP2 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019716:Tissue Inhibitor of Metalloproteinase-2; D004317:Doxorubicin; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human