STAT3 regulated ARF expression suppresses prostate cancer metastasis

Nat Commun. 2015 Jul 22;6:7736. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Disease Progression
  • Genes, p16
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Neoplasms, Experimental
  • PTEN Phosphohydrolase / genetics
  • Prostatic Neoplasms / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Interleukin-6
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Tumor Suppressor Protein p53
  • interleukin-6, mouse
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • PTEN Phosphohydrolase
  • Pten protein, mouse