MiRNA Involved in Six1-Induced Breast Cancer.

摘要

The Six1 homeoprotein encodes a transcription factor that is critical during embryonic development. Six1 expression is normally limited to embryogenesis, however is found to be overexpressed in human breast cancers. Using cell culture and mouse models, we have previously shown that Six1 not only promotes proliferation and survival, contributing to tumorigenesis, but also upregulates the TGF pathway, brings about an EMT-like transformation, increases the cancer stem cell population, aand promotesmetastasis. To further investigate the mechanism by which Six1 mediates the switch in TGF signaling, we performed a miRNA microarray screen and identified a cluster of miRNAs, the miR106b-25 cluster, that is upregulated in response to Six1 overexpression. The miR106b-25 cluster consists of three miRNAs, miR-106b, miR-93, and miR-25, which reside together in the intron of the MCM7 gene. Importantly, overexpression and knockdown experiments demonstrate that Six1 regulates all three miRNAs within the cluster. Interestingly, these miRNA have previously been implicated in the impairment of TGF -mediated growth suppression through repression of the cell cycle inhibitor, p21, and pro-apoptotic factor, Bim. These data suggest that Six1-induced upregulation of these miRNA may mediate the switch in TGF signaling from tumor suppressive to tumor promotional. Surprinsingly, bioinformatic analysis revealed that the miR106b-25 cluster may also contribute to the activation of TGF signaling through repression of the TGF signaling inhibitor, Smad7, which mediates the degradation of T RI. Indeed, we now report that overexpression of the miR106b-25 cluster results in repression of the Smad7 3 UTR, with concominant upregulation of T RI.