IGF-1-mediated PKM2/β-catenin/miR-152 regulatory circuit in breast cancer

Abstract

Dysregulation of miRNAs is important in breast cancer initiation and malignant progression. Recently we showed that miR-152 downregulation is associated with breast cancer development, yet the underlying mechanism of miR-152 remains to be well elucidated. In this study, we identified β-catenin as a new direct target of miR-152. MiR-152 inhibited cell proliferation by targeting and inhibiting both β-catenin and PKM2 expression. We found that miR-152 expression sensitized the breast cancer cells to paclitaxel treatment by inhibiting β-catenin and PKM2 expression. Intriguingly, IGF-1 induced β-catenin and PKM2 expression and enhanced β-catenin and PKM2 interaction. Subsequently, IGF-1-induced β-catenin and PKM2 complex translocated into the nucleus, which in turn activated expression of miR-152. These results suggested a regulatory circuit between miR-152, β-catenin and PKM2 in breast cancer. By using human clinical specimens, we also showed that miR-152 expression levels were negatively correlated with β-catenin and PKM2 levels in breast cancer tissues. Our findings provide new insights into a mechanism of miR-152 involved in β-catenin and PKM2 inhibition which would have clinical implication for the cancer development and new treatment option in the future.