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In hepatocellular carcinoma miR‐519d is up‐regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2
Author(s) -
Fornari Francesca,
Milazzo Maddalena,
Chieco Pasquale,
Negrini Massimo,
Marasco Elena,
Capranico Giovanni,
Mantovani Vilma,
Marinello Jessica,
Sabbioni Silvia,
Callegari Elisa,
Cescon Matteo,
Ravaioli Matteo,
Croce Carlo M,
Bolondi Luigi,
Gramantieri Laura
Publication year - 2012
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.3995
Subject(s) - pten , microrna , dna methylation , cancer research , epigenetics , biology , hepatocellular carcinoma , apoptosis , gene expression , gene , pi3k/akt/mtor pathway , genetics
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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.