STAT3 regulated ARF expression suppresses prostate cancer metastasis.

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 p19(ARF) 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 p14(ARF) 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.

Nature communications. 2015 Jul 22*** epublish ***

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, Lukas Kenner

Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria. , 1] Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria [2] Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria. , Department of Molecular Biology, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria. , Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria. , Center for Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN Belfast, UK. , Institute of Biochemistry, University of Kiel, 24098 Kiel, Germany. , 1] Department of Pathology and NYU Cancer Institute, NYU School of Medicine, New York 10016, USA [2] Department of Microbiology and NYU Cancer Institute, NYU School of Medicine, New York 10016, USA. , Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria. , Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria. , Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria. , NI Stratified Medicine Research Group, University of Ulster, BT47 6SB Londonderry, UK. , Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria. , CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. , Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria. , Department of Toxicology, University Medical Center, 55131 Mainz, Germany. , Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria. , Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria. , Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria. , Molecular Biotechnology Center (MBC), Department of Genetics, Biology and Biochemistry, University of Turin, Turin 10126, Italy. , Department of Medicine I, Division: Institute for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. , Department of Medicine I, Division: Institute for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. , Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria. , Center for Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN Belfast, UK. , Institute of Pathology and Neuropathology, University Hospital Tuebingen, 72076 Tuebingen, Germany. , Institute of Pathology and Neuropathology, University Hospital Tuebingen, 72076 Tuebingen, Germany. , Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, 53127 Bonn, Germany. , Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, 53127 Bonn, Germany. , 1] Department of Pathology and NYU Cancer Institute, NYU School of Medicine, New York 10016, USA [2] Department of Microbiology and NYU Cancer Institute, NYU School of Medicine, New York 10016, USA. , Department of Pathology, University of Cambridge, CB2 0QQ Cambridge, UK. , Department of Pathology, University of Cambridge, CB2 0QQ Cambridge, UK. , Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria. , Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria. , Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences, 75007 Uppsala, Sweden. , Institute of Biochemistry, University of Kiel, 24098 Kiel, Germany. , Department of Molecular Biology, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria. , Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria. , 1] Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria [2] Unit for Translational Methods in Cancer Research, University of Veterinary Medicine Vienna, 1210 Vienna, Austria. , Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria. , Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria. , 1] Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria [2] Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria [3] Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine Vienna, 1210 Vienna, Austria.

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