LEF 1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR - 34

ThemicroRNA-34a (miR-34a), a tumor-suppressivemicroRNA (miRNA), is implicated in epithelial–mesenchymal transition (EMT) and cancer stem cells. Lymphoid enhancer-binding factor-1 (LEF1) is a key transcription factor in the Wnt signaling pathway, and has been suggested to be involved in regulation of cell proliferation and invasion.Here, themolecularmechanismof miR-34a and LEF1 in cooperatively regulating prostate cancer cell invasion is described. Molecular profiling analysis of miRNA levels in prostate cancer cells revealed a negative correlation between miR-34a and LEF1 expression, and the downregulation of LEF1 by miR-34a was confirmed by luciferase assays. Furthermore, miR-34a specifically repressed LEF1 expression through direct binding to its 30-untranslated regions (30-UTR). miR-34a modulated the levels of LEF1 to regulate EMT in prostate cancer cells. Functionally, miR-34a negatively correlated with the migration and invasion of prostate cancer cells through LEF1. An analysis of miR-34a expression levels in matched human tumor and benign tissues demonstrated consistent and statistically significant downregulation of miR-34a in primary prostate cancer specimens. These data strongly suggest that miR-34a/LEF1 regulationof EMTplays an important role in prostate cancermigration and invasion. Implications: The miR-34a–LEF1 axis represents a potential molecular target for novel therapeutic strategies in prostate cancer. Mol Cancer Res; 13(4); 681–8. 2015 AACR.