MicroRNA-140 acts as a liver tumor suppressor by controlling NF-κB activity by directly targeting DNA methyltransferase 1 (Dnmt1) expression.
MicroRNA-140 acts as a liver tumor suppressor by controlling NF-κB activity by directly targeting DNA methyltransferase 1 (Dnmt1) expression.
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DOI：
10.1002/hep.26011
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发表时间：
2013-01
期刊：
影响因子：
13.5
通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
--
作者：
Takata, Akemi;Otsuka, Motoyuki;Yoshikawa, Takeshi;Kishikawa, Takahiro;Hikiba, Yohko;Obi, Shuntaro;Goto, Tadashi;Kang, Young Jun;Maeda, Shin;Yoshida, Haruhiko;Omata, Masao;Asahara, Hiroshi;Koike, Kazuhiko
MicroRNA (miRNA) 是调节特定靶基因表达的小RNA。虽然在许多肿瘤中检测到 miRNA 表达水平失调，但 miRNA 功能损伤是否也与癌症发生有关仍不清楚。我们研究了 miRNA 机械组件的失调和随后的 miRNA 功能损伤是否与肝癌发生有关。在含有 miRNA 的核糖核蛋白复合物成分中，在人肝细胞癌中经常观察到 DDX20 表达降低，其中 NF-κB 活性增强被认为与癌发生密切相关。由于 DDX20 通常通过优先调节抑制 NF-κB 的 miRNA-140 的功能来抑制 NF-κB 活性，因此我们推测 miRNA-140 功能的损伤可能与肝癌发生有关。 Dnmt1 被确定为 miRNA-140 的直接靶标，DDX20 缺陷细胞中 Dnmt1 表达的增加使金属硫蛋白基因的启动子超甲基化，导致金属硫蛋白表达减少，从而增强 NF-κB 活性。 miRNA-140 敲除小鼠容易发生肝癌，并且具有与 DDX20 缺陷相似的表型，表明 miRNA-140 在 DDX20 缺陷相关发病机制中发挥核心作用。这些结果表明 miRNA-140 充当肝脏肿瘤抑制因子，并且由于 miRNA 机械成分 DDX20 的缺乏而导致 miRNA-140 功能受损，可能导致肝癌发生。
MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA-containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced NF-κB activity is believed to be closely linked to carcinogenesis. Because DDX20 normally suppresses NF-κB activity by preferentially regulating the function of the NF-κB-suppressing miRNA-140, we hypothesized that impairment of miRNA-140 function may be involved in hepatocarcinogenesis. Dnmt1 was identified as a direct target of miRNA-140, and increased Dnmt1 expression in DDX20-deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF-κB activity. MiRNA-140-knockout mice were prone to hepatocarcinogenesis and had a phenotype similar to that of DDX20 deficiency, suggesting that miRNA-140 plays a central role in DDX20 deficiency-related pathogenesis. These results indicate that miRNA-140 acts as a liver tumor suppressor, and that impairment of miRNA-140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis.
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影响因子：
12.4
作者：
Lambertz, I.;Nittner, D.;Mestdagh, P.;Denecker, G.;Vandesompele, J.;Dyer, M. A.;Marine, J-C
通讯作者：
Marine, J-C
影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
4.8
作者：
Ghoshal, K;Majumder, S;Jacob, ST
通讯作者：
Jacob, ST
影响因子：
25.7
作者：
Liu, P;Kimmoun, E;Bernuau, D
通讯作者：
Bernuau, D
DOI：
10.1056/nejmoa0901282
发表时间：
2009-10-08
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ji J;Shi J;Budhu A;Yu Z;Forgues M;Roessler S;Ambs S;Chen Y;Meltzer PS;Croce CM;Qin LX;Man K;Lo CM;Lee J;Ng IO;Fan J;Tang ZY;Sun HC;Wang XW
通讯作者：
Wang XW