STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Jan Pěnčík ,Robert Eferl,Gerda Egger,Suzanne D Turner,Wolfgang Mikulits,Steven M Walker,Melanie R Hassler,Michaela Schlederer,Harald Esterbauer,Stefan Rose-John,Andrea Haitel,Marcus Scharpf,Valeria Poli,Lukas Kenner,Olaf Merkel,Richard Moriggl,Tahereh Javaheri,Christine Unger,Athena Chalaris,Fritz Aberger,Anna Skucha,Jaine K Blayney,Nicole Prutsch,Martin Susani,Merima Herac,Falko Fend,David E Levy,Oliver H Krämer,Florian Grebien,Wolfgang Gruber,Osman Aksoy,Sven Perner,Martin Braun,Helmut Dolznig,Peter R Mazal ,Isabelle Marié ,Richard D Kennedy ,Ali A Moazzami ,Zoran Čulig ,Timothy Malcolm

doi:10.1038/ncomms8736

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.

Highlights

Prostate cancer (PCa) is the most prevalent cancer in men
We show that loss of IL-6/Stat[3] signalling in a Pten-deficient PCa model accelerates cancer progression leading to metastasis
We observed an increase in IL-6Ra levels in tumour cells and soluble IL-6R serum levels (Supplementary Fig. 1a–c) as well as increased Stat[3], IL-6Ra and IL-6 mRNA levels (Supplementary Fig. 1d) in Ptenpc À / À PCa compared with WT controls

Summary

Introduction

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. Loss of Stat[3] promoted PCa formation in Pten heterozygous prostate tissue (Ptenpc þ / À Stat3pc À / À ) at 19 weeks of age, whereas Ptenpc þ / À mice developed only prostatic intraepithelial neoplasia[17] (PIN) (Supplementary Fig. 3a). Our data demonstrate that Stat[3] suppresses malignant progression of Pten-deficient PCa. We found reduced p53 protein expression in Ptenpc þ / À Stat3pc À / À prostates (Supplementary Fig. 3b).

Results

Conclusion