Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer.
Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer.
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DOI：
10.1093/nar/gkp002
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发表时间：
2009-04
影响因子：
14.9
通讯作者：
Kim VN
中科院分区：
文献类型：
--
作者：
Kim YK;Yu J;Han TS;Park SY;Namkoong B;Kim DH;Hur K;Yoo MW;Lee HJ;Yang HK;Kim VN
microRNA（miRNAs）在包括肿瘤发生在内的多种过程中发挥着不可或缺的作用。miRNA基因座通常紧密连接，并且这种成簇的miRNA基因从共同的启动子转录以产生多顺反子初级转录物。初级转录物（pri-miRNA）然后被两种RNase III蛋白加工以释放成熟的miRNA。虽然已经推测同一簇中的miRNAs可能发挥相关的生物学功能，但这尚未在实验上得到解决。在这里，我们报告了两个簇中的miRNAs（miR-106 b → 93 → 25和miR-222 → 221）抑制Cdk抑制剂的Cip/Kip家族成员（p57 Kip 2、p21 Cip 1和p27 Kip 1）。我们发现miR-25通过3′-UTR靶向p57。此外，miR-106 b和miR-93控制p21，而miR-222和miR-221调节p27和p57。这些miRNAs的异位表达导致Cdk 2的激活和G1/S期转变的促进。与这些结果一致，与相应的正常组织相比，两个簇在胃癌组织中异常上调。miR-222簇的异位表达增强了小鼠异种移植模型中的肿瘤生长。我们的研究证明了成簇的miRNA之间的功能关联，并进一步暗示有效的癌症治疗可能需要组合方法来靶向多个致癌miRNA簇。
microRNAs (miRNAs) play integral roles in diverse processes including tumorigenesis. miRNA gene loci are often found in close conjunction, and such clustered miRNA genes are transcribed from a common promoter to generate polycistronic primary transcript. The primary transcript (pri-miRNA) is then processed by two RNase III proteins to release the mature miRNAs. Although it has been speculated that the miRNAs in the same cluster may play related biological functions, this has not been experimentally addressed. Here we report that the miRNAs in two clusters (miR-106b∼93 ∼ 25 and miR-222 ∼ 221) suppress the Cip/Kip family members of Cdk inhibitors (p57Kip2, p21Cip1 and p27Kip1). We show that miR-25 targets p57 through the 3′-UTR. Furthermore, miR-106b and miR-93 control p21 while miR-222 and miR-221 regulate both p27 and p57. Ectopic expression of these miRNAs results in activation of Cdk2 and facilitation of G1/S phase transition. Consistent with these results, both clusters are abnormally upregulated in gastric cancer tissues compared to the corresponding normal tissues. Ectopic expression of miR-222 cluster enhanced tumor growth in the mouse xenograft model. Our study demonstrates the functional associations between clustered miRNAs and further implicates that effective cancer treatment may require a combinatorial approach to target multiple oncogenic miRNA clusters.
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影响因子：
11.8
作者：
Nakayama, K;Nagahama, H;Nakayama, KI
通讯作者：
Nakayama, KI
影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
DOI：
10.1146/annurev.pathol.4.110807.092222
发表时间：
2009
期刊：
Annual review of pathology
影响因子：
--
作者：
Lee YS;Dutta A
通讯作者：
Dutta A
影响因子：
8
作者：
Si, M.-L.;Zhu, S.;Mo, Y.-Y.
通讯作者：
Mo, Y.-Y.
影响因子：
4.3
作者：
Gillies, Jana K.;Lorimer, Ian A. J.
通讯作者：
Lorimer, Ian A. J.