An estrogen receptor alpha suppressor, microRNA-22, is downregulated in estrogen receptor alpha-positive human breast cancer cell lines and clinical samples.
Previous studies have suggested that microRNAs (miRNAs) may play important roles in tumorigenesis, but little is known about the functions of most miRNAs in cancer development. In the present study, we set up a cell-based screen using a luciferase reporter plasmid carrying the whole approximately 4.7 kb 3'-UTR of estrogen receptor alpha (ERalpha) mRNA cotransfected with a synthetic miRNA expression library to identify potential ERalpha-targeting miRNAs. Among all the miRNAs, miR-22 was found to repress robustly the luciferase signal in both HEK-293T and ERalpha-positive MCF-7 cells. Mutation of the target site was found to abrogate this repression effect of miR-22, whereas antagonism of endogenous miR-22 in MDA-MB-231 cells resulted in elevated reporter signals. We assessed the miR-22 expression patterns in five breast cancer cell lines and 23 clinical biopsies and revealed that there is a significant inverse association between the miR-22 levels and ERalpha protein expression. To evaluate the potential of miR-22 as a potential therapeutic intervention, we found that reduction of endogenous ERalpha protein levels and suppression of cancer cell growth could be achieved in MCF-7 cells by miR-22 overexpression in a way that can be recapitulated by the introduction of specific small interfering RNA against ERalpha. The phenomena can be rescued by the reintroduction of ERalpha. Taken together, our data indicate that miR-22 was frequently downregulated in ERalpha-positive human breast cancer cell lines and clinical samples. Direct involvement in the regulation of ERalpha may be one of the mechanisms through which miR-22 could play a pivotal role in the pathogenesis of breast cancer.
Xiong
Jianhua
J
Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University, Beijing, China.
Yu
Dianke
D
Wei
Na
N
Fu
Hanjiang
H
Cai
Tianjing
T
Huang
Yuanyu
Y
Wu
Chen
C
Zheng
Xiaofei
X
Du
Quan
Q
Lin
Dongxin
D
Liang
Zicai
Z
D020413:3' Untranslated Regions; D000368:Aged; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology / Q000379:methods; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D012689:Sequence Homology, Nucleic Acid
D020413:3' Untranslated Regions; D047628:Estrogen Receptor alpha; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides