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Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer

Oncogene volume 33, pages 4097–4106 (2014)Cite this article

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Abstract

Prostate cancer cells escape growth inhibition from transforming growth factor β (TGFβ) by downregulating TGFβ receptors. However, the mechanism by which cancer cells downregulate TGFβ receptors in prostate is not clear. Here, we showed that coordinated action of miR-21 and androgen receptor (AR) signaling had a critical role in inhibiting TGFβ receptor II (TGFBR2) expression in prostate cancer cells. Our results revealed that miR-21 suppresses TGFBR2 levels by binding to its 3′-UTR and AR signaling further potentiates this effect in both untransformed and transformed human prostate epithelial cells as well as in human prostate cancers. Analysis of primary prostate cancers showed that increased miR-21/AR expression parallel a significantly reduced expression of TGFBR2. Manipulation of androgen signaling or the expression levels of AR or miR-21 negatively altered TGFBR2 expression in untransformed and transformed human prostate epithelial cells, human prostate cancer xenografts and mouse prostate glands. Importantly, we demonstrated that miR-21 and AR regulated each other’s expression resulting in a positive feedback loop. Our results indicated that miR-21/AR mediate its tumor-promoting function by attenuating TGFβ-mediated Smad2/3 activation, cell growth inhibition, cell migration and apoptosis. Together, these results suggest that the AR and miR-21 axis exerts its oncogenic effects in prostate tumors by downregulating TGFBR2, hence inhibiting the tumor-suppressive activity of TGFβ pathway. Targeting miR-21 alone or in combination with AR may restore the tumor inhibitory activity of TGFβ in prostate cancer.

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Acknowledgements

This work was supported in part by funding from NIH Grants R01CA75253 and R01CA79683 to LuZhe Sun, William and Ella Owens Foundation and Thrive Well foundation to Manjeet Rao, U54 CA113001 (Integrative Cancer Biology Program) to Tim Huang and the Cancer Therapy and Research Center at University of Texas Health Science Center at San Antonio through the NCI Cancer Center Support Grant 2P30CA054174-17 to the optical imaging core facility. We thank Dr Clifford G Tepper and Dr Paramita Ghosh at UC Davis Cancer Center for the CWR22 xenograft tissue and PSA-luciferase plasmid, respectively, and Dr Scott Lucia at University of Colorado Health Science Center for providing us with BPH-1 cells.

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Authors and Affiliations

  1. Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA

    S Mishra, J J Deng, P S Gowda, M K Rao & L-Z Sun

  2. Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA

    C-L Lin, C L Chen & T Huang

  3. Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA

    T Huang & L-Z Sun

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Correspondence to L-Z Sun.

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Mishra, S., Deng, J., Gowda, P. et al. Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer. Oncogene 33, 4097–4106 (2014). https://doi.org/10.1038/onc.2013.374

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