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Research article - Peer-reviewed, 2015

STAT3 regulated ARF expression suppresses prostate cancer metastasis

Pencik, Jan; Moazzami, Ali; Kenner, Lukas

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.

Published in

Nature Communications
2015, Volume: 6, article number: 7736
Publisher: NATURE PUBLISHING GROUP

      SLU Authors

    • Moazzami, Ali

      • The Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences

    Sustainable Development Goals

    SDG3 Good health and well-being

    UKÄ Subject classification

    Cell and Molecular Biology

    Publication identifier

    DOI: https://doi.org/10.1038/ncomms8736

    Permanent link to this page (URI)

    https://res.slu.se/id/publ/73443