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Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions

Oncogene volume 29, pages 811–821 (2010)Cite this article

Abstract

Runx2, a bone-specific transcriptional regulator, is abnormally expressed in highly metastatic prostate cancer cells. Here, we identified the functional activities of Runx2 in facilitating tumor growth and osteolysis. Our studies show that negligible Runx2 is found in normal prostate epithelial and non-metastatic LNCaP prostate cancer cells. In the intra-tibial metastasis model, high Runx2 levels are associated with development of large tumors, increased expression of metastasis-related genes (MMP9, MMP13, VEGF, Osteopontin) and secreted bone-resorbing factors (PTHrP, IL8) promoting osteolytic disease. Runx2 siRNA treatment of PC3 cells decreased cell migration and invasion through Matrigel in vitro, and in vivo shRunx2 expression in PC3 cells blocked their ability to survive in the bone microenvironment. Mechanisms of Runx2 function were identified in co-culture studies showing that PC3 cells promote osteoclastogenesis and inhibit osteoblast activity. The clinical significance of these findings is supported by human tissue microarray studies of prostate tumors at stages of cancer progression, in which Runx2 is expressed in both adenocarcinomas and metastatic tumors. Together these findings indicate that Runx2 is a key regulator of events associated with prostate cancer metastatic bone disease.

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Acknowledgements

We acknowledge the following for providing us with prostate cancer cell lines: RWPE, George Barnes (Boston University School of Medicine); PC3-H and C4-2B, Leland Chung (Emory University School of Medicine). This work was supported by NIH Grants PO1CA082834 (GSS); RO1CA89720 (LRL); RO1CA090917 (DCA); P01CA093900 and SPORE P50CA69568 (EK); R01CA069158 (TAG); and Our Danny Cancer Fund post-doctoral fellowship, ODCF 114357 (JA). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. The Cancer Center Prostate Cancer Discovery and Development Program, University of Massachusetts Medical School, Worcester, MA, USA

    J Akech, J J Wixted, K Bedard, M van der Deen, S Hussain, A J van Wijnen, J L Stein, L R Languino, D C Altieri, J Pratap, G S Stein & J B Lian

  2. Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA

    J Akech, K Bedard, M van der Deen, S Hussain, A J van Wijnen, J L Stein, J Pratap, G S Stein & J B Lian

  3. Department of Orthopedic Surgery and Rehabilitation, University of Massachusetts Medical School, Worcester, MA, USA

    J J Wixted

  4. Department of Internal Medicine, Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, IN, USA

    T A Guise

  5. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA

    L R Languino & D C Altieri

  6. Department of Urology, University of Michigan School of Medicine, Ann Arbor, MI, USA

    E Keller

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  1. J Akech
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Correspondence to J B Lian.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Akech, J., Wixted, J., Bedard, K. et al. Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene 29, 811–821 (2010). https://doi.org/10.1038/onc.2009.389

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