@article{4848b25af7694d26882aacc3cb6a3993,
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.",
keywords = "Animals, Cell Line, Cyclin-Dependent Kinase Inhibitor p16/metabolism, Disease Progression, Genes, p16, Humans, Interleukin-6/genetics, Male, Mice, Mice, Transgenic, Neoplasms, Experimental, PTEN Phosphohydrolase/genetics, Prostatic Neoplasms/metabolism, Proto-Oncogene Proteins c-mdm2/metabolism, STAT3 Transcription Factor/genetics, Tumor Suppressor Protein p53/metabolism",
author = "Jan Pencik and Michaela Schlederer and Wolfgang Gruber and Christine Unger and Walker, {Steven M} and Athena Chalaris and Mari{\'e}, {Isabelle J} and Hassler, {Melanie R} and Tahereh Javaheri and Osman Aksoy and Blayney, {Jaine K} and Nicole Prutsch and Anna Skucha and Merima Herac and Kr{\"a}mer, {Oliver H} and Peter Mazal and Florian Grebien and Gerda Egger and Valeria Poli and Wolfgang Mikulits and Robert Eferl and Harald Esterbauer and Richard Kennedy and Falko Fend and Marcus Scharpf and Martin Braun and Sven Perner and Levy, {David E} and Tim Malcolm and Turner, {Suzanne D} and Andrea Haitel and Martin Susani and Ali Moazzami and Stefan Rose-John and Fritz Aberger and Olaf Merkel and Richard Moriggl and Zoran Culig and Helmut Dolznig and Lukas Kenner",
note = "Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",
year = "2015",
month = jul,
day = "22",
doi = "10.1038/ncomms8736",
language = "English",
volume = "6",
pages = "7736",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}