Silencing of miR-370 in human cholangiocarcinoma by allelic loss and interleukin-6 induced maternal to paternal epigenotype switch.
Silencing of miR-370 in human cholangiocarcinoma by allelic loss and interleukin-6 induced maternal to paternal epigenotype switch.
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DOI：
10.1371/journal.pone.0045606
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Selaru FM
中科院分区：
文献类型：
--
作者：
An F;Yamanaka S;Allen S;Roberts LR;Gores GJ;Pawlik TM;Xie Q;Ishida M;Mezey E;Ferguson-Smith AC;Mori Y;Selaru FM
胆管癌（CCA）是一种起源于胆道上皮的高度致命的恶性肿瘤。白细胞介素 6 (IL-6) 是炎症的主要介质，也是胆管系统癌变的重要因素。先前的研究表明，强制IL-6通过与CCA有关的几个基因的高甲基化而促进胆管癌的发生。然而，IL-6 在 CCA 中作用的确切机制仍不清楚。我们现在证明，与正常肝组织相比，microRNA (miR)-370 在一大群人类 CCA 中表达不足。此外，我们发现 IL-6 会诱导 miR-370 的时间依赖性沉默。此外，CCA 细胞的去甲基化导致 miR-370 上调。此外，我们证明 miR-370 是印记的，并且负责该基因组位点印记调节的基因间差异甲基化区域（IG-DMR）响应 IL-6 处理而高度甲基化。此外，与正常匹配对照相比，人类 CCA 样本中的 IG-DMR 高度甲基化，其位置与 IL-6 诱导的高度甲基化相同。最后，发现 miR-370 在荧光素酶和蛋白质印迹实验中调节 WNT10B。我们的数据表明，miR-370 的父系等位基因通常通过基因组印记沉默，并且 CCA 中 IL-6 的过表达有效抑制母系等位基因 miR-370 的表达，这为人类 CCA 中 miR-370 沉默遵循经典的二次打击机制的理论提供了支持。
Cholangiocarcinoma (CCA) is a highly lethal malignant tumor arising from the biliary tract epithelium. Interleukin-6 (IL-6) is a major mediator of inflammation and contributor to carcinogenesis within the biliary tree. Previous studies suggested that enforced IL-6 contributes to cholangiocarcinogenesis through hypermethylation of several genes implicated in CCA. However, the precise mechanisms of IL-6 effects in CCA remain unclear. We now demonstrate that microRNA (miR)-370 is underexpressed in a large cohort of human CCA vs. normal liver tissues. In addition, we show that IL-6 induces a time-dependent silencing of miR-370. In addition, demethylation of CCA cells results in upregulation of miR-370. Furthermore, we demonstrate that miR-370 is imprinted, and that the Intergenic Differentially Methylated Region (IG-DMR) responsible for imprinting regulation of this genomic locus is hypermethylated in response to IL-6 treatment. In addition, the IG-DMR is hypermethylated in human CCA specimens compared to normal matched controls, in the same location as the IL-6 induced hypermethylation. Finally, miR-370 was found to regulate WNT10B in luciferase as well as western blotting experiments. Our data indicate that the paternal allele of miR-370 is normally silenced through genomic imprinting and that the overexpression of IL-6 in CCA effectively suppresses the expression of miR-370 from the maternal allele, lending support to the theory that miR-370 silencing in human CCA follows a classic two-hit mechanism.
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影响因子：
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影响因子：
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作者：
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通讯作者：
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