The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer
| Autor: | Anna L Smith, Douglas S. Micalizzi, Aik Choon Tan, David J. Drasin, Rebecca L. Vartuli, Ritsuko Iwanaga, Heide L. Ford |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
TGF-β
Six1 Cancer Research Epithelial-Mesenchymal Transition Receptor Transforming Growth Factor-beta Type I Regulator Breast Neoplasms Context (language use) Protein Serine-Threonine Kinases Biology medicine.disease_cause Article Smad7 Protein tumor initiating cell 03 medical and health sciences 0302 clinical medicine Transforming Growth Factor beta Cell Line Tumor microRNA Genetics medicine Humans Epithelial–mesenchymal transition Molecular Biology miRNA 030304 developmental biology Homeodomain Proteins 0303 health sciences R-SMAD Transforming growth factor beta Up-Regulation 3. Good health Gene Expression Regulation Neoplastic MicroRNAs Cell Transformation Neoplastic 030220 oncology & carcinogenesis Immunology MCF-7 Cells Cancer research biology.protein Female epithelial-to-mesenchymal transition Signal transduction Carcinogenesis Receptors Transforming Growth Factor beta Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2012.11 |
| Popis: | The role of TGF-β signaling in tumorigenesis is paradoxical: it can be tumor suppressive or tumor promotional, depending on context. The metastatic regulator, Six1, was recently shown to mediate this switch, providing a novel means to explain this elusive “TGF-β paradox”. Herein, we identify a mechanism by which Six1 activates the tumor promotional arm of TGF-β signaling, via its ability to upregulate the miR-106b-25 microRNA cluster, and further identify a novel function for this cluster of microRNAs. While expression of the miR-106b-25 cluster is known to overcome TGF-β-mediated growth suppression via targeting p21 and BIM, we demonstrate for the first time that this same cluster can additionally target the inhibitory Smad7 protein, resulting in increased levels of the TGF-β type I receptor (TβRI) and downstream activation of TGF-β signaling. We further show that the miR-106b-25 cluster is sufficient to induce an epithelial to mesenchymal transition and a tumor initiating cell phenotype, and that it is required downstream of Six1 to induce these phenotypes. Finally, we demonstrate a significant correlation between miR-106b, Six1, and activated TGF-β signaling in human breast cancers, and further show that high levels of miR-106b and miR-93 in breast tumors significantly predicts shortened time to relapse. These findings expand the spectrum of oncogenic functions of miR-106b-25, and may provide a novel molecular explanation, through the Six1 regulated miR-106b-25 cluster, by which TGF-β signaling shifts from tumor suppressive to tumor promoting. |
| Databáze: | OpenAIRE |
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