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Transforming growth factor-β promotes prostate bone metastasis through induction of microRNA-96 and activation of the mTOR pathway

Oncogene volume 34, pages 4767–4776 (2015)Cite this article

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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.

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Acknowledgements

This work was jointly supported by grants from the Taipei Medical University-Wan Fang Hospital (102TMU-WFH-05) to Y-N Liu, Taipei Medical University (TMU102-AE1-B30) to Y-C Tsai, the Ministry of Science and Technology (NSC102-2320-B-038-001) of Taiwan to Y-N Liu, and the Ministry of Science and Technology (NSC103-2311-B-038-001) of Taiwan to Y-C Tsai. We also thank Dr Ji-Hshiung Chen (Tzu Chi University) for reading the manuscript and for his comments and helpful suggestions. We also thank Dr Orla Casey for reviewing our manuscript and discussion.

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Author notes

  1. M K Siu and Y-C Tsai: These authors contributed equally to this work.

Authors and Affiliations

  1. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan

    M K Siu, Y-C Tsai & Y-N Liu

  2. Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    M K Siu

  3. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

    Y-C Tsai, Y-S Chang & Y-N Liu

  4. Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    J J Yin & F Suau

  5. Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    W-Y Chen

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  1. M K Siu
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Correspondence to Y-C Tsai or Y-N Liu.

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Siu, M., Tsai, YC., Chang, YS. et al. Transforming growth factor-β promotes prostate bone metastasis through induction of microRNA-96 and activation of the mTOR pathway. Oncogene 34, 4767–4776 (2015). https://doi.org/10.1038/onc.2014.414

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  • DOI: https://doi.org/10.1038/onc.2014.414

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