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STAT3 regulated ARF expression suppresses prostate cancer metastasis
AuthorPencik, Jan ; Schlederer, Jan ; Gruber, Wolfgang ; Unger, Christine ; Walker, Steven M. ; Chalaris, Athena ; Marié, Isabelle J. ; Hassler, Melanie R. ; Javaheri, Tahereh ; Aksoy, Osman ; Blayney, Jaine K. ; Prutsch, Nicole ; Skucha, Anna ; Herac, Merima ; Krämer, Oliver H. ; Mazal, Peter ; Grebien, Florian ; Egger, Gerda ; Poli, Valeria ; Mikulits, Wolfgang ; Eferl, Robert ; Esterbauer, Harald ; Kennedy, Richard ; Fend, Falko
Published in
Nature Communications, London, 2015, Vol. 6, Issue article number 7736, page 1-15
PublishedNature Publishing Group, 2015
Document typeJournal Article
Keywords (EN)Cell signalling / Metastasis / Prognostic markers / Prostate cancer
URNurn:nbn:at:at-ubs:3-3724 Persistent Identifier (URN)
 The work is publicly available
STAT3 regulated ARF expression suppresses prostate cancer metastasis [3.48 mb]
Abstract (English)

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 ARFMdm2p53 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.

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