title: STAT3 regulated ARF expression suppresses prostate cancer metastasis.
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 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.
authors.affiliation: 1] Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria. [2] Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Jan
authors.initials: J
authors.lastname: Pencik
authors.affiliation: 1] Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria [2] Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.affiliation: Department of Molecular Biology, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gruber
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Unger
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN Belfast, UK.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Walker
authors.affiliation: Institute of Biochemistry, University of Kiel, 24098 Kiel, Germany.
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.affiliation: 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.
authors.forename: Isabelle J
authors.initials: IJ
authors.lastname: Marié
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Hassler
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria.
authors.forename: Tahereh
authors.initials: T
authors.lastname: Javaheri
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Osman
authors.initials: O
authors.lastname: Aksoy
authors.affiliation: NI Stratified Medicine Research Group, University of Ulster, BT47 6SB Londonderry, UK.
authors.forename: Jaine K
authors.initials: JK
authors.lastname: Blayney
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Prutsch
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Skucha
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Merima
authors.initials: M
authors.lastname: Herac
authors.affiliation: Department of Toxicology, University Medical Center, 55131 Mainz, Germany.
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Mazal
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Grebien
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Gerda
authors.initials: G
authors.lastname: Egger
authors.affiliation: Molecular Biotechnology Center (MBC), Department of Genetics, Biology and Biochemistry, University of Turin, Turin 10126, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Poli
authors.affiliation: Department of Medicine I, Division: Institute for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
authors.affiliation: Department of Medicine I, Division: Institute for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Eferl
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN Belfast, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Kennedy
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Scharpf
authors.affiliation: Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, 53127 Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Braun
authors.affiliation: Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, 53127 Bonn, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: 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.
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
authors.affiliation: Department of Pathology, University of Cambridge, CB2 0QQ Cambridge, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Malcolm
authors.affiliation: Department of Pathology, University of Cambridge, CB2 0QQ Cambridge, UK.
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Turner
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haitel
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Susani
authors.affiliation: Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences, 75007 Uppsala, Sweden.
authors.forename: Ali
authors.initials: A
authors.lastname: Moazzami
authors.affiliation: Institute of Biochemistry, University of Kiel, 24098 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Department of Molecular Biology, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Aberger
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Olaf
authors.initials: O
authors.lastname: Merkel
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Dolznig
authors.affiliation: 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.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
mesh_terms: D000818:Animals; D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D018450:Disease Progression; D019942:Genes, p16; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016159:Tumor Suppressor Protein p53; C577686:interleukin-6, mouse; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse