Wang Peng, Zou Fangdong, Zhang Xiaodong, Li Hua, Dulak Austin, Tomko Robert J, Lazo John S, Wang Zhenghe, Zhang Lin, Yu Jian
Departments of Pathology and Pharmacology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Cancer Res. 2009 Oct 15;69(20):8157-65. doi: 10.1158/0008-5472.CAN-09-1996. Epub 2009 Oct 13.
microRNAs (miRNA) are small noncoding 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 into 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'-untranslated region. We found that miR-21 is induced by serum starvation and DNA damage, negatively regulates G(1)-S transition, and participates in DNA damage-induced G(2)-M checkpoint through down-regulation 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 show 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.
微小RNA（miRNA）是一类小的非编码RNA，通过抑制靶基因表达参与多种生物学过程。已有报道称miR-21在癌症中表达改变。为深入了解其在肿瘤发生中的潜在作用，我们通过基因靶向技术构建了miR-21基因敲除的结肠癌细胞。无偏倚的微阵列分析结合生物信息学鉴定出细胞周期调节因子Cdc25A是miR-21的一个靶标。miR-21通过其3'非翻译区的特定序列抑制Cdc25A的表达。我们发现miR-21受血清饥饿和DNA损伤诱导，负向调节G1-S期转换，并通过下调Cdc25A参与DNA损伤诱导的G2-M期检查点。相反，在正常细胞培养条件下，miR-21缺陷并不影响多种常用抗癌药物诱导的细胞凋亡或细胞增殖。此外，在一部分Cdc25A过表达的结肠癌中发现miR-21表达下调。我们的数据表明miR-21在应激后调节细胞周期进程中发挥作用，为Cdc25A的调控提供了新机制，并对miR-21在肿瘤发生中的作用给出了潜在解释。
