The miR200 Family of MicroRNAs Regulates WAVE3-dependent Cancer Cell Invasion

MicroRNAs are small non-coding RNAs that are directly involved in the regulation of gene expression by either translational repression or degradation of target mRNAs. Because of the high level of conservation of the target motifs, known as seed sequences, within the 3'-untranslated regions, a single microRNA can regulate numerous target genes simultaneously, making this class of RNAs a powerful regulator of gene expression. The miR200 family of microRNAs has recently been shown to regulate the process of epithelial to mesenchymal transition during tumor progression and metastasis. Here, we report that the expression of WAVE3, an actin cytoskeleton remodeling and metastasis promoter protein, is regulated by miR200 microRNAs. We show a clear inverse correlation between expression levels of WAVE3 and miR200 microRNAs in invasive versus non-invasive cancer cells. miR200 directly targets the 3'-untranslated regions of the WAVE3 mRNA and inhibits its expression. The miR200-mediated down-regulation of WAVE3 results in a significant reduction in the invasive phenotype of cancer cells, which is specific to the loss of WAVE3 expression. Re-expression of a miR200-resistant WAVE3 reverses miR200-mediated inhibition of cancer cell invasion. Loss of WAVE3 expression downstream of miR200 also results in a dramatic change in cell morphology resembling that of a mesenchymal to epithelial transition. In conclusion, a novel mechanism for the regulation of WAVE3 expression in cancer cells has been identified, which controls the invasive properties and morphology of cancer cells associated with their metastatic potential.