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 p19ARF 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 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.
| Original language | English |
|---|---|
| Article number | 7736 |
| Journal | Nature Communications |
| Volume | 6 |
| ISSN | 1751-8628 |
| DOIs | |
| Publication status | Published - 22.07.2015 |
Funding
L.K and J.P. are supported by FWF, P26011 and the Genome Research-Austria project ‘Inflammobiota’ grants. H.D. is supported by the Herzfelder Family Foundation and the Niederösterr. Forschungs-und Bildungsges.m.b.H (nfb). R.M. is supported by grant SFB-F2807 and SFB-F4707 from the Austrian Science Fund (FWF); A.M. is supported by Infrastructure for biosciences-Strategic fund, SciLifeLab and Formas, Z.C. is supported by FWF, P24428; A.C. and S.R.-J. are supported by the Deutsche Forschungsgemeinschaft (Grant SFB 877, Project A1and the Cluster of Excellence–‘Inflammation at Interfaces’). A.S. is supported by the European FP7 Marie-Curie Initial Training Network HEM_ID. Work of the Aberger lab was supported by the Austrian Science Fund FWF (Projects P25629 and W1213), the European FP7 Marie-Curie Initial Training Network HEALING and the priority program Biosciences and Health of the Paris-Lodron University of Salzburg. V.P. is supported by the Italian Association for Cancer Research (AIRC, No IG13009). R.K. and S.M.W. are supported by the McClay Foundation and the Movember Centre of Excellence (PC-UK and Movember). O.H. K. is supported by Wilhelm-Sander Stiftung (grant 2010.078.2), Deutsche Krebshilfe (grant 110909), Deutsche Forschungsgemeinschaft (grant KR2291/4-1) and intramural funding from the University Medical Center Mainz. G.E. is supported by FWF, P27616. T.M. and S.D.T. are supported by Leukaemia and Lymphoma Research. We thank Markus Mair, Harini Nivarthi, Tina Brachett and Jelena Marjanovic for their excellent technical support. We also thank Gerardo Ferbeyre for providing the PML antibody. We thank Andrew Pospisilik for critically reading the manuscript.
