Abstract
Transforming growth factor-β (TGFβ) is enriched in the bone matrix and serves as a key factor in promoting bone metastasis in cancer. In addition, TGFβ signaling activates mammalian target of rapamycin (mTOR) functions, which is important for the malignant progression. Here, we demonstrate that TGFβ regulates the level of microRNA-96 (miR-96) through Smad-dependent transcription and that miR-96 promotes the bone metastasis in prostate cancer. The enhanced effects in cellular growth and invasiveness suggest that miR-96 functions as an oncomir/and metastamir. Supporting this idea, we identified a downstream target of the TGFβ-miR-96 signaling pathway to be AKT1S1 mRNA, whose translated protein is a negative regulator of mTOR kinase. Our findings provide a novel mechanism accounting for the TGFβ signaling and bone metastasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Adaptor Proteins, Signal Transducing / biosynthesis*
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Adaptor Proteins, Signal Transducing / genetics
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Animals
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Bone Neoplasms / genetics
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Bone Neoplasms / pathology
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Bone Neoplasms / secondary
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Cell Line, Tumor
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Cell Proliferation / genetics
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Male
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Mice
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MicroRNAs / biosynthesis
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MicroRNAs / genetics*
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / pathology
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Smad Proteins / genetics
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TOR Serine-Threonine Kinases / genetics*
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Transforming Growth Factor beta / biosynthesis*
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Transforming Growth Factor beta / genetics
Substances
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3' Untranslated Regions
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AKT1S1 protein, human
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Adaptor Proteins, Signal Transducing
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MIRN96 microRNA, human
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MicroRNAs
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Smad Proteins
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Transforming Growth Factor beta
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MTOR protein, human
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TOR Serine-Threonine Kinases