microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells.
microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells.
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DOI：
10.1158/0008-5472.can-09-1996
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发表时间：
2009-10-15
期刊：
影响因子：
11.2
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Wang P;Zou F;Zhang X;Li H;Dulak A;Tomko RJ Jr;Lazo JS;Wang Z;Zhang L;Yu J
MicroRNA是一类小的非编码RNA，通过抑制靶基因的表达参与多种生物学过程。已经报道了癌症中miR-21的表达改变。为了深入了解其在肿瘤发生中的潜在作用，我们通过基因靶向产生了miR-21敲除的结肠癌细胞。无偏微阵列分析结合生物信息学鉴定细胞周期调控因子Cdc 25 A为miR-21靶点。miR-21通过其3′UTR中的特定序列抑制Cdc 25 A的表达。我们发现miR-21受血清饥饿和DNA损伤诱导，负调控G1-S期转换，并通过下调Cdc 25 A参与DNA损伤诱导的G2-M期检查点。相比之下，miR-21缺陷不影响由各种常用抗癌剂诱导的凋亡或在正常细胞培养条件下的细胞增殖。此外，发现miR-21在Cdc 25 A过表达的结肠癌亚组中表达不足。我们的数据表明miR-21在应激后调节细胞周期进程中的作用，提供了Cdc 25 A调节的新机制和miR-21在肿瘤发生中的潜在解释。
MicroRNAs are small non-coding RNAs that participate in diverse biological processes by suppressing target gene expression. Altered expression of miR-21 has been reported in cancer. To gain insights in its potential role in tumorigenesis, we generated miR-21 knockout colon cancer cells through gene targeting. Unbiased microarray analysis combined with bioinformatics identified cell cycle regulator Cdc25A as a miR-21 target. miR-21 suppressed Cdc25A expression through a defined sequence in its 3′UTR. We found that miR-21 is induced by serum starvation and DNA damage, negatively regulates G1-S transition, and participates in DNA damage-induced G2-M checkpoint through downregulation of Cdc25A. In contrast, miR-21 deficiency did not affect apoptosis induced by a variety of commonly used anticancer agents or cell proliferation under normal cell culture conditions. Furthermore, miR-21 was found to be underexpressed in a subset of Cdc25A overexpressing colon cancers. Our data demonstrated a role of miR-21 in modulating cell cycle progression following stress, providing a novel mechanism of Cdc25A regulation and a potential explanation of miR-21 in tumorigenesis.