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STAT3 regulated ARF expression suppresses prostate cancer metastasis

Author

Listed:
  • Jan Pencik

    (Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria)

  • Michaela Schlederer

    (Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria
    Clinical Institute of Pathology, Medical University of Vienna)

  • Wolfgang Gruber

    (Paris-Lodron University of Salzburg)

  • Christine Unger

    (Institute of Medical Genetics, Medical University of Vienna)

  • Steven M. Walker

    (Center for Cancer Research and Cell Biology, Queen's University Belfast)

  • Athena Chalaris

    (Institute of Biochemistry, University of Kiel)

  • Isabelle J. Marié

    (NYU School of Medicine
    NYU School of Medicine)

  • Melanie R. Hassler

    (Clinical Institute of Pathology, Medical University of Vienna)

  • Tahereh Javaheri

    (Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria)

  • Osman Aksoy

    (Clinical Institute of Pathology, Medical University of Vienna)

  • Jaine K. Blayney

    (NI Stratified Medicine Research Group, University of Ulster)

  • Nicole Prutsch

    (Clinical Institute of Pathology, Medical University of Vienna)

  • Anna Skucha

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Merima Herac

    (Clinical Institute of Pathology, Medical University of Vienna)

  • Oliver H. Krämer

    (University Medical Center)

  • Peter Mazal

    (Clinical Institute of Pathology, Medical University of Vienna)

  • Florian Grebien

    (Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria)

  • Gerda Egger

    (Clinical Institute of Pathology, Medical University of Vienna)

  • Valeria Poli

    (Molecular Biotechnology Center (MBC), Biology and Biochemistry, University of Turin)

  • Wolfgang Mikulits

    (Comprehensive Cancer Center, Medical University of Vienna)

  • Robert Eferl

    (Comprehensive Cancer Center, Medical University of Vienna)

  • Harald Esterbauer

    (Medical University of Vienna)

  • Richard Kennedy

    (Center for Cancer Research and Cell Biology, Queen's University Belfast)

  • Falko Fend

    (Institute of Pathology and Neuropathology, University Hospital Tuebingen)

  • Marcus Scharpf

    (Institute of Pathology and Neuropathology, University Hospital Tuebingen)

  • Martin Braun

    (Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn)

  • Sven Perner

    (Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn)

  • David E. Levy

    (NYU School of Medicine
    NYU School of Medicine)

  • Tim Malcolm

    (University of Cambridge)

  • Suzanne D. Turner

    (University of Cambridge)

  • Andrea Haitel

    (Clinical Institute of Pathology, Medical University of Vienna)

  • Martin Susani

    (Clinical Institute of Pathology, Medical University of Vienna)

  • Ali Moazzami

    (Swedish University of Agricultural Sciences)

  • Stefan Rose-John

    (Institute of Biochemistry, University of Kiel)

  • Fritz Aberger

    (Paris-Lodron University of Salzburg)

  • Olaf Merkel

    (Clinical Institute of Pathology, Medical University of Vienna)

  • Richard Moriggl

    (Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria
    Unit for Translational Methods in Cancer Research, University of Veterinary Medicine Vienna)

  • Zoran Culig

    (Medical University of Innsbruck)

  • Helmut Dolznig

    (Institute of Medical Genetics, Medical University of Vienna)

  • Lukas Kenner

    (Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria
    Clinical Institute of Pathology, Medical University of Vienna
    Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine Vienna)

Abstract

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19ARF as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF–Mdm2–p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14ARF expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

Suggested Citation

  • Jan Pencik & Michaela Schlederer & Wolfgang Gruber & Christine Unger & Steven M. Walker & Athena Chalaris & Isabelle J. Marié & Melanie R. Hassler & Tahereh Javaheri & Osman Aksoy & Jaine K. Blayney &, 2015. "STAT3 regulated ARF expression suppresses prostate cancer metastasis," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8736
    DOI: 10.1038/ncomms8736
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    Cited by:

    1. Mehdi Sadeghi & Bijan Ranjbar & Mohamad Reza Ganjalikhany & Faiz M. Khan & Ulf Schmitz & Olaf Wolkenhauer & Shailendra K Gupta, 2016. "MicroRNA and Transcription Factor Gene Regulatory Network Analysis Reveals Key Regulatory Elements Associated with Prostate Cancer Progression," PLOS ONE, Public Library of Science, vol. 11(12), pages 1-19, December.

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