STAT3 regulated ARF expression suppresses prostate cancer metastasis

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, Nicole Prutsch, Anna Skucha, Merima Herac, Oliver H. Krämer, Peter Mazal, Florian Grebien, Gerda Egger, Valeria Poli, Wolfgang Mikulits, Robert Eferl, Harald Esterbauer, Richard Kennedy, Falko Fend, Marcus Scharpf, Martin Braun, Sven Perner, David E. Levy, Tim Malcolm, Suzanne D. Turner, Andrea Haitel, Martin Susani, Ali Moazzami, Stefan Rose-John, Fritz Aberger, Olaf Merkel, Richard Moriggl, Zoran Culig, Helmut Dolznig and Lukas Kenner ()
Additional contact information
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
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
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
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
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

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8736

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