MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes.
MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes.
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DOI：
10.1002/hep.23381
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发表时间：
2010-03
期刊：
影响因子：
13.5
通讯作者：
Patel, Tushar
中科院分区：
文献类型：
--
作者：
Braconi, Chiara;Huang, Nianyuan;Patel, Tushar
虽然炎症相关细胞因子白细胞介素-6（IL-6）与胆管癌的生长有关，但IL-6与致癌变化之间的关系尚不清楚。IL-6可以增加DNA甲基转移酶1（DNMT-1）的表达，并在表观遗传学上调节包括microRNA（miRNAs）在内的几种基因的表达。DNMT-1上调发生在肝胆癌中，并且与不良预后相关。为了了解IL-6依赖性miRNAs对DNMT-1的潜在调节作用，我们检测了一组与DNMT-1的3′-UTR具有序列互补性的miRNAs，即miR-148 a、miR-152和miR-301的表达。这些miRNAs在胆管癌细胞中的表达降低。此外，所有三种miRNA的表达在体外IL-6过表达的恶性胆管细胞和肿瘤细胞异种移植物中均降低。甲基化敏感的肿瘤抑制基因Rassf 1a和p16 INK 4a的表达也随之减少。使用荧光素酶报告基因构建体，DNMT-1被验证为miR-148 a和miR-152的靶标。miR-148 a和miR-152的前体降低DNMT-1蛋白表达，增加Rassf 1a和p16 INK 4a表达并降低细胞增殖。这些数据表明，IL-6可以通过调节miR-148 a和miR-152来调节DNMT-1的活性和甲基化依赖性肿瘤抑制基因的表达，并提供了这种炎症相关细胞因子与胆管癌发生之间的联系。
Although the inflammation-associated cytokine Interleukin-6 (IL-6) has been implicated in cholangiocarcinoma growth, the relationship between IL-6 and oncogenic changes is unknown. IL-6 can increase expression of DNA methyltransferase 1 (DNMT-1) and epigenetically regulate the expression of several genes, including microRNAs (miRNAs). DNMT-1 up-regulation occurs in hepatobiliary cancers and is associated with a poor prognosis. To understand the potential regulation of DNMT-1 by IL-6 dependent miRNAs, we examined the expression of a group of miRNAs which have sequence complementarity to the 3′-UTR of DNMT-1, namely miR-148a, miR-152 and miR-301. The expression of these miRNAs was decreased in cholangiocarcinoma cells. Moreover, the expression of all three miRNAs was decreased in IL-6 over-expressing malignant cholangiocytes in vitro and in tumor cell xenografts. There was a concomitant decrease in expression of the methylation-sensitive tumor suppressor genes Rassf1a, and p16INK4a. Using luciferase reporter constructs, DNMT-1 was verified as a target for miR-148a and miR-152. Precursors to miR-148a and miR-152 decreased DNMT-1 protein expression, increased Rassf1a and p16INK4a expression and reduced cell proliferation. These data indicate that IL-6 can regulate the activity of DNMT-1 and expression of methylation-dependent tumor suppressor genes by modulation of miR-148a and miR-152, and provide a link between this inflammation-associated cytokines and oncogenesis in cholangiocarcinoma.
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影响因子：
30.8
作者：
Dammann, R;Li, C;Pfeifer, GP
通讯作者：
Pfeifer, GP
microRNA表达模式在人肝内胆管癌中的作用。
影响因子：
25.7
作者：
Chen, Lei;Yan, He-Xin;Wang, Hong-Yang
通讯作者：
Wang, Hong-Yang
胆管癌：发病机理，诊断和治疗的进展。
影响因子：
13.5
作者：
Blechacz, Boris;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
3.5
作者：
Bestor, TH
通讯作者：
Bestor, TH
影响因子：
11.4
作者：
BESTOR, TH
通讯作者：
BESTOR, TH