Centro di Ricerca Biomedica Applicata, Policlinico S. Orsola-Malpighi e Università di Bologna, Italy.
J Pathol. 2012 Jul;227(3):275-85. doi: 10.1002/path.3995. Epub 2012 Apr 18.
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.
miR-519d 属于染色体 19 miRNA 簇（C19MC），是人类最大的 miRNA 簇。其成员之一 miR-519d 在肝细胞癌（HCC）中过度表达，我们研究了其对肝癌发生的贡献。在 HCC 细胞中，miR-519d 的过表达促进细胞增殖、侵袭，并损害抗癌治疗后的细胞凋亡。这些功能至少部分是通过直接靶向 CDKN1A/p21、PTEN、AKT3 和 TIMP2 来实现的。通过基因组 DNA 扩增、甲基化分析和 ChIP 分析检测到 HCC 中 miR-519d 异常表达的机制。C19MC 和 TP53 的异常低甲基化分别被鉴定为允许 miR-519d 异常表达的表观遗传变化，以及能够激活其转录的因素之一。总之，我们通过研究其生物学功能，包括对抗癌治疗反应的调节，以及鉴定其靶标中的 CDKN1A/p21、PTEN、AKT3 和 TIMP2，评估了 miR-519d 在 HCC 中的致癌作用。
