In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2
In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2
复制标题
DOI：
10.1002/path.3995
复制
发表时间：
2012-07-01
影响因子：
7.3
通讯作者：
Gramantieri, Laura
中科院分区：
文献类型：
--
作者：
Fornari, Francesca;Milazzo, Maddalena;Gramantieri, Laura
miR-519 d属于19号染色体miRNA簇（C19 MC），这是最大的人类miRNA簇。其成员之一，miR-519 d，在肝细胞癌（HCC）中过表达，我们表征了其对肝癌发生的贡献。在HCC细胞中，miR-519 d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。这些功能至少部分地通过直接靶向CDKN 1A/p21、PTEN、AKT 3和TIMP 2来发挥。通过基因组DNA扩增、甲基化分析和ChIP检测，探讨miR-519 d在HCC中异常表达的机制。C19 MC和TP 53的异常低甲基化分别被鉴定为允许miR-519 d异常表达的表观遗传变化，并且是能够激活其转录的因子之一。总之，我们通过表征其生物学功能，包括对抗癌治疗反应的调节，并通过鉴定其靶点中的CDKN 1A/p21、PTEN、AKT 3和TIMP 2，评估了miR-519 d在HCC中的致癌作用。版权所有（c）2012大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
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 (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.