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PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer

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Abstract

The non-canonical Wnt pathway, a regulator of cellular motility and morphology, is increasingly implicated in cancer metastasis. In a quantitative PCR array analysis of 84 Wnt pathway associated genes, both non-canonical and canonical pathways were activated in primary and metastatic tumors relative to normal prostate. Expression of the Wnt target gene PITX2 in a prostate cancer (PCa) bone metastasis was strikingly elevated over normal prostate (over 2,000-fold) and primary prostate cancer (over 200-fold). The elevation of PITX2 protein was also evident on tissue microarrays, with strong PITX2 immunostaining in PCa skeletal and, to a lesser degree, soft tissue metastases. PITX2 is associated with cell migration during normal tissue morphogenesis. In our studies, overexpression of individual PITX2A/B/C isoforms stimulated PC-3 PCa cell motility, with the PITX2A isoform imparting a specific motility advantage in the presence of non-canonical Wnt5a stimulation. Furthermore, PITX2 specific shRNA inhibited PC-3 cell migration toward bone cell derived chemoattractant. These experimental results support a pivotal role of PITX2A and non-canonical Wnt signaling in enhancement of PCa cell motility, suggest PITX2 involvement in homing of PCa to the skeleton, and are consistent with a role for PITX2 in PCa metastasis to soft and bone tissues. Our findings, which significantly expand previous evidence that PITX2 is associated with risk of PCa biochemical recurrence, indicate that variation in PITX2 expression accompanies and may promote prostate tumor progression and metastasis.

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Acknowledgments

We would like to thank the patients and their families who were willing to participate in the Prostate Cancer Donor Program, for without them research of this nature would not be possible. We would like to acknowledge Robert Vessella, and Lisha Brown and the rapid autopsy teams in the Urology Department at the University of Washington. This material is the result of work supported by resources from the VA Puget Sound Health Care System, Seattle, Washington, by the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1CA085859), and the Richard M. Lucas Foundation. CM is a recipient of the Career Development Award from the Pacific Northwest Prostate Cancer SPORE (P50CA097186). These studies were supported by the Australian National Health and Medical Research Council (Project Grant 455854), the UQ Diamantina Institute, Queensland Health, the Australasian Urologic Foundation, the Queensland Government Smart State PhD Funding Program.

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  1. I. Vela

    Present address: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

  2. D. L. Nicol

    Present address: Royal Marsden Hospital, London, UK

  3. E. M. Gardiner

    Present address: Department of Orthopaedics and Sports Medicine, Harborview Medical Center, University of Washington, Seattle, WA, USA

Authors and Affiliations

  1. Department of Urology, Princess Alexandra Hospital, Brisbane, QLD, Australia

    I. Vela & D. L. Nicol

  2. School of Medicine, University of Queensland, Brisbane, QLD, Australia

    I. Vela & D. L. Nicol

  3. Department of Urology, School of Medicine, University of Washington, Seattle, WA, USA

    C. Morrissey, X. Zhang & E. Corey

  4. Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S. Chen

  5. Department of Anatomical Pathology, Pathology Queensland Princess Alexandra Hospital, Brisbane, QLD, Australia

    G. M. Strutton

  6. Australian Prostate Cancer Research Centre-QLD, Institute of Health and Biomedical Innovation, Queensland University of Technology at the Translational Research Institute, Brisbane, QLD, Australia

    C. C. Nelson & J. A. Clements

  7. Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia

    E. M. Gardiner

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Vela, I., Morrissey, C., Zhang, X. et al. PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer. Clin Exp Metastasis 31, 199–211 (2014). https://doi.org/10.1007/s10585-013-9620-7

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