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Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion.
Publication Type:Journal Article
Source:J Biol Chem, Volume 284, Issue 27, p.18515-24 (2009)
Keywords:Apoptosis Regulatory Proteins, Breast Neoplasms, Female, Gene Expression Regulation, Neoplastic, HeLa Cells, Humans, MAP Kinase Kinase 1, MAP Kinase Signaling System, MicroRNAs, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Neoplasm Invasiveness, Receptor, erbB-2, RNA-Binding Proteins, Up-Regulation
<p>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.</p>