Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion.
The cell surface receptor tyrosine kinase HER2/neu enhances tumor metastasis. Recent studies suggest that deregulated microRNA (miRNA) expression promotes invasion and metastasis of cancer cells; we therefore explored the possibility that HER2/neu signaling induces the expression of specific miRNAs involved in this process. We identified a putative oncogenic miRNA, miR-21, whose expression is correlated with HER2/neu up-regulation and is functionally involved in HER2/neu-induced cell invasion. We show that miR-21 is up-regulated via the MAPK (ERK1/2) pathway upon stimulation of HER2/neu signaling in breast cancer cells, and overexpression of other ERK1/2 activators such as RASV12 or ID-1 is sufficient to induce miR-21 up-regulation in HER2/neu-negative breast cancer cells. Furthermore, the metastasis suppressor protein PDCD4 (programmed cell death 4) is down-regulated by miR-21 in breast cancer cells expressing HER2/neu. Our data reveal a mechanism for HER2/neu-induced cancer cell invasion via miRNA deregulation. In addition, our results identify miR-21 as a potential therapeutic target for the prevention of breast cancer invasion and metastasis.
Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA.
Tzu-Hsuan
TH
Huang
Fangting
F
Wu
Gabriel B
GB
Loeb
Ruby
R
Hsu
Amy
A
Heidersbach
Allison
A
Brincat
Dai
D
Horiuchi
Robert J
RJ
Lebbink
Yin-Yuan
YY
Mo
Andrei
A
Goga
Michael T
MT
McManus
D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics*; D035683:MicroRNAs / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D016601:RNA-Binding Proteins / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D048369:MAP Kinase Kinase 1; D035683:MicroRNAs; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C524940:MIRN21 microRNA, human; C114487:PDCD4 protein, human; C508053:ERBB2 protein, human; C482125:MAP2K1 protein, human