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Type of publication: Journal Article
Type of document: Full Paper

Year: 2015

Authors: Pencik, J; Schlederer, M; Gruber, W; Unger, C; Walker, SM; Chalaris, A; Marié, IJ; Hassler, MR; Javaheri, T; Aksoy, O; Blayney, JK; Prutsch, N; Skucha, A; Herac, M; Krämer, OH; Mazal, P; Grebien, F; Egger, G; Poli, V; Mikulits, W; Eferl, R; Esterbauer, H; Kennedy, R; Fend, F; Scharpf, M; Braun, M; Perner, S; Levy, DE; Malcolm, T; Turner, SD; Haitel, A; Susani, M; Moazzami, A; Rose-John, S; Aberger, F; Merkel, O; Moriggl, R; Culig, Z; Dolznig, H; Kenner, L

Title: STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Source: Nat Commun. 2015; 6:7736



Authors Vetmeduni Vienna:

Grebien Florian
Kenner Lukas
Moriggl Richard
Prutsch Nicole

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics


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.

Keywords Pubmed: 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


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