microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells.
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.
Wang
Peng
P
Departments of Pathology and Pharmacology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Zou
Fangdong
F
Zhang
Xiaodong
X
Li
Hua
H
Dulak
Austin
A
Tomko
Robert J
RJ
Lazo
John S
JS
Wang
Zhenghe
Z
Zhang
Lin
L
Yu
Jian
J
D017209:Apoptosis; D001973:Bromodeoxyuridine; D002453:Cell Cycle; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004249:DNA Damage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000502:physiology*; D008940:Mitotic Index; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020687:cdc25 Phosphatases
C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D008156:Luciferases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D001973:Bromodeoxyuridine