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STAT3 regulated ARF expression suppresses prostate cancer metastasis.

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 - Nat Commun (2015)

Bottom Line: However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit.STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases.Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria.

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.

No MeSH data available.


Related in: MedlinePlus

Loss of STAT3 and ARF in metastases of PCa patients.(a) Three representative images of PTEN expression determined by IHC analyses in matched patient samples with primary and metastatic PCa (n=5). Scale bars, 100 μm. (b) Representative IHC images of STAT3 and p14ARF expression from primary (n=41) and metastatic (n=23) PCa samples. Scale bars, 100 μm. (c,d) STAT3 and p14ARF staining intensity ranging from undetectable (Negative) to maximal expression levels (+++) in cohorts of primary and metastatic PCa. (e) Graphical representation of TP53, PTEN, STAT3 and CDKN2A mutations in 529 patients with primary PCa71. (f) Graphical representation of TP53, PTEN, STAT3, CDKN2A deletions in 14 metastatic PCa55. Data were processed by Affymetrix Genome-Wide Human SNP Array 6.0. (g) Graphic representation of gene deletion analysis of TP53, PTEN, STAT3 and CDKN2A in an independent data set of 37 metastatic PCa samples35.
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f8: Loss of STAT3 and ARF in metastases of PCa patients.(a) Three representative images of PTEN expression determined by IHC analyses in matched patient samples with primary and metastatic PCa (n=5). Scale bars, 100 μm. (b) Representative IHC images of STAT3 and p14ARF expression from primary (n=41) and metastatic (n=23) PCa samples. Scale bars, 100 μm. (c,d) STAT3 and p14ARF staining intensity ranging from undetectable (Negative) to maximal expression levels (+++) in cohorts of primary and metastatic PCa. (e) Graphical representation of TP53, PTEN, STAT3 and CDKN2A mutations in 529 patients with primary PCa71. (f) Graphical representation of TP53, PTEN, STAT3, CDKN2A deletions in 14 metastatic PCa55. Data were processed by Affymetrix Genome-Wide Human SNP Array 6.0. (g) Graphic representation of gene deletion analysis of TP53, PTEN, STAT3 and CDKN2A in an independent data set of 37 metastatic PCa samples35.

Mentions: We next tested whether expression of STAT3 and p14ARF can serve as novel prognostic markers predicting the risk of BCR and metastatic disease progression. STAT3 and p14ARF levels were independently evaluated by five pathologists in 204 human PCa specimens from patients who underwent radical prostatectomy. Patient samples were categorized into low or high expression groups based on staining intensities and number of positive cells (Methods) using validated antibodies (Supplementary Fig. 9a,b). Classification was verified by quantitative histopathological image analysis36 (Supplementary Fig. 10a). Indeed, increased Gleason score (GSC) correlated with low STAT3 or p14ARF protein expression levels. In addition, we found a strong direct correlation between STAT3 and p14ARF in accordance with p14ARF being a direct target of STAT3 (Fig. 7c,d). STAT3 expression was significantly decreased in PCa (GCS≤7) compared with PIN areas of 67 matched patient samples (Supplementary Fig. 10b,c). Strikingly, both low STAT3 expression (P<0.007; log-rank test) and low p14ARF (P<0.000001; log-rank test) expression were associated with poor outcome (Fig. 7e,f). Moreover, combined loss of p14ARF and STAT3 expression in tumours of PCa patients predicted the worst outcome (P=0.000007, log-rank test) (Fig. 7g). Using multivariate analysis, we identified p14ARF as a reliable, independent prognostic marker for PCa, which has a twofold higher hazard ratio compared with GSC (Fig. 7h). In accordance with the literature2537, we found increased AR expression in metastases compared with primary human PCa (Supplementary Fig. 11a,b). IHC analysis of matched primary and metastatic human PCa revealed significant loss of PTEN expression in metastatic PCa (Fig. 8a and Supplementary Fig. 11c), suggesting an important role of PTEN loss in PCa metastasis. PTEN levels showed no significant correlation with STAT3 or p14ARF protein expression in a cohort of >200 patients (Supplementary Fig. 11d,e). Moreover, we demonstrated that loss of STAT3 and/or p14ARF is associated with progression to metastatic disease (Fig. 8b–d). This is supported by expression data from matched primary and metastatic PCa samples (Supplementary Fig. 12a–c), where in all seven cases a significant loss of STAT3 and p14ARF expression occurred in the metastases.


STAT3 regulated ARF expression suppresses prostate cancer metastasis.

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 - Nat Commun (2015)

Loss of STAT3 and ARF in metastases of PCa patients.(a) Three representative images of PTEN expression determined by IHC analyses in matched patient samples with primary and metastatic PCa (n=5). Scale bars, 100 μm. (b) Representative IHC images of STAT3 and p14ARF expression from primary (n=41) and metastatic (n=23) PCa samples. Scale bars, 100 μm. (c,d) STAT3 and p14ARF staining intensity ranging from undetectable (Negative) to maximal expression levels (+++) in cohorts of primary and metastatic PCa. (e) Graphical representation of TP53, PTEN, STAT3 and CDKN2A mutations in 529 patients with primary PCa71. (f) Graphical representation of TP53, PTEN, STAT3, CDKN2A deletions in 14 metastatic PCa55. Data were processed by Affymetrix Genome-Wide Human SNP Array 6.0. (g) Graphic representation of gene deletion analysis of TP53, PTEN, STAT3 and CDKN2A in an independent data set of 37 metastatic PCa samples35.
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Related In: Results  -  Collection

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f8: Loss of STAT3 and ARF in metastases of PCa patients.(a) Three representative images of PTEN expression determined by IHC analyses in matched patient samples with primary and metastatic PCa (n=5). Scale bars, 100 μm. (b) Representative IHC images of STAT3 and p14ARF expression from primary (n=41) and metastatic (n=23) PCa samples. Scale bars, 100 μm. (c,d) STAT3 and p14ARF staining intensity ranging from undetectable (Negative) to maximal expression levels (+++) in cohorts of primary and metastatic PCa. (e) Graphical representation of TP53, PTEN, STAT3 and CDKN2A mutations in 529 patients with primary PCa71. (f) Graphical representation of TP53, PTEN, STAT3, CDKN2A deletions in 14 metastatic PCa55. Data were processed by Affymetrix Genome-Wide Human SNP Array 6.0. (g) Graphic representation of gene deletion analysis of TP53, PTEN, STAT3 and CDKN2A in an independent data set of 37 metastatic PCa samples35.
Mentions: We next tested whether expression of STAT3 and p14ARF can serve as novel prognostic markers predicting the risk of BCR and metastatic disease progression. STAT3 and p14ARF levels were independently evaluated by five pathologists in 204 human PCa specimens from patients who underwent radical prostatectomy. Patient samples were categorized into low or high expression groups based on staining intensities and number of positive cells (Methods) using validated antibodies (Supplementary Fig. 9a,b). Classification was verified by quantitative histopathological image analysis36 (Supplementary Fig. 10a). Indeed, increased Gleason score (GSC) correlated with low STAT3 or p14ARF protein expression levels. In addition, we found a strong direct correlation between STAT3 and p14ARF in accordance with p14ARF being a direct target of STAT3 (Fig. 7c,d). STAT3 expression was significantly decreased in PCa (GCS≤7) compared with PIN areas of 67 matched patient samples (Supplementary Fig. 10b,c). Strikingly, both low STAT3 expression (P<0.007; log-rank test) and low p14ARF (P<0.000001; log-rank test) expression were associated with poor outcome (Fig. 7e,f). Moreover, combined loss of p14ARF and STAT3 expression in tumours of PCa patients predicted the worst outcome (P=0.000007, log-rank test) (Fig. 7g). Using multivariate analysis, we identified p14ARF as a reliable, independent prognostic marker for PCa, which has a twofold higher hazard ratio compared with GSC (Fig. 7h). In accordance with the literature2537, we found increased AR expression in metastases compared with primary human PCa (Supplementary Fig. 11a,b). IHC analysis of matched primary and metastatic human PCa revealed significant loss of PTEN expression in metastatic PCa (Fig. 8a and Supplementary Fig. 11c), suggesting an important role of PTEN loss in PCa metastasis. PTEN levels showed no significant correlation with STAT3 or p14ARF protein expression in a cohort of >200 patients (Supplementary Fig. 11d,e). Moreover, we demonstrated that loss of STAT3 and/or p14ARF is associated with progression to metastatic disease (Fig. 8b–d). This is supported by expression data from matched primary and metastatic PCa samples (Supplementary Fig. 12a–c), where in all seven cases a significant loss of STAT3 and p14ARF expression occurred in the metastases.

Bottom Line: However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit.STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases.Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria.

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.

No MeSH data available.


Related in: MedlinePlus