Amplification of hsa-miR-191/425 locus promotes breast cancer proliferation and metastasis by targeting DICER1.

Abstract

The dysregulation of micro RNAs (miRNAs) is a crucial characteristic of human cancers. Herein, we observed frequent amplification of the MIR191/425 locus in breast cancer, which is correlated with poor survival outcome. We demonstrated that the miR-191/425 cluster binds the 3' untranslated region of the DICER1 transcript and posttranscriptionally represses DICER1 expression, thereby impairing global miRNAs biogenesis. Functionally, the forced expression of miR-191 or miR-425 stimulated the proliferation, survival, migration and invasion of breast cancer cells, whereas the inhibition of miR-191 or miR-425 suppressed these oncogenic behaviors of breast cancer cells, in a manner dependent on miR-191/425-mediated downregulation of DICER1. Furthermore, the miR-191/425 cluster promoted breast tumor growth, invasion and metastasis in vivo. The let-7 family of miRNAs was downregulated upon forced expression of miR-191 or miR-425, with a corresponding increase in the levels of let-7 target, high-mobility group AT-hook 2 (HMGA2). The forced expression of let-7 partially abrogated the miR-191/425-mediated oncogenic effects in breast cancer cells, suggestive of let-7 as a downstream effector of the miR-191/425-DICER1 axis. Collectively, we proposed that the inhibition of global miRNA processing, through miR-191/425-mediated downregulation of DICER1, promotes breast cancer progression.