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 MikulitsRobert 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, Richard Kennedy

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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.

Original languageEnglish
Article number7736
Number of pages15
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 22 Jul 2015

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    Pencik, J., Schlederer, M., Gruber, W., Unger, C., Walker, S. M., Chalaris, A., Marié, I. J., Hassler, M. R., Javaheri, T., Aksoy, O., Blayney, J. K., Prutsch, N., Skucha, A., Herac, M., Krämer, O. H., Mazal, P., Grebien, F., Egger, G., Poli, V., ... Kennedy, R. (2015). STAT3 regulated ARF expression suppresses prostate cancer metastasis. Nature Communications, 6, [7736]. https://doi.org/10.1038/ncomms8736