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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/or p14ARF expression predicts early BCR in patients with PCa.(a,b) Kaplan–Meier analysis including number at risk of patients stratified into high or low lL6- and STAT3 mRNA expression predicting biochemical recurrence (BCR) of the Taylor data set35. (c) Distribution of STAT3 and p14ARF protein expression with low (≤7) or high (8–10) GSC in tumour specimens from men diagnosed with PCa. (d) Fisher's exact test of data shown in c and correlation of STAT3 to p14ARF expression. (e) Kaplan–Meier analysis of BCR-free survival ratio based on STAT3 protein expression in a panel of 204 PCa patients. (f) Kaplan–Meier analysis of BCR-free survival ratio based on p14ARF protein expression in a panel of 204 PCa patients. (g) Co-expression analyses of BCR-free survival of STAT3 and p14ARF. (h) Univariate and multivariate analyses of GSC, STAT3 or p14ARF protein levels. Data from a,b,e,f and g were analysed by log-rank test.
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f7: Loss of STAT3 and/or p14ARF expression predicts early BCR in patients with PCa.(a,b) Kaplan–Meier analysis including number at risk of patients stratified into high or low lL6- and STAT3 mRNA expression predicting biochemical recurrence (BCR) of the Taylor data set35. (c) Distribution of STAT3 and p14ARF protein expression with low (≤7) or high (8–10) GSC in tumour specimens from men diagnosed with PCa. (d) Fisher's exact test of data shown in c and correlation of STAT3 to p14ARF expression. (e) Kaplan–Meier analysis of BCR-free survival ratio based on STAT3 protein expression in a panel of 204 PCa patients. (f) Kaplan–Meier analysis of BCR-free survival ratio based on p14ARF protein expression in a panel of 204 PCa patients. (g) Co-expression analyses of BCR-free survival of STAT3 and p14ARF. (h) Univariate and multivariate analyses of GSC, STAT3 or p14ARF protein levels. Data from a,b,e,f and g were analysed by log-rank test.

Mentions: The fact that activated STAT3 induces its own transcription34 led us to measure IL-6 and STAT3 mRNA levels in primary human tumours and to correlate them with clinical outcome. Using the Taylor gene expression profiling data set (GSE21032)35, we dichotomized samples based on the z-scores of IL-6 or STAT3 expression. Specifically for IL-6 expression, samples that had z-scores<−2 were defined as low IL-6 and all others (z-scores>−2) were used as a comparator for prognostic significance. Conversely, samples that had STAT3 z-scores>2 were defined as STAT3 high and all other samples (z-scores<2) were used as comparators. Time to biochemical recurrence (BCR) was assessed as an indicator of individual prognosis. BCR was defined by an increase to >0.2 ng ml−1 PSA in serum. Of note, patients with low IL-6 expression levels showed a significantly higher risk of BCR compared with patients with high IL-6 expression (Fig. 7a). In line, patients with high Stat3 mRNA levels demonstrate good prognosis. This may reflect a higher level of senescence competence compared with patients with lower Stat3 mRNA levels (Fig. 7b).


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/or p14ARF expression predicts early BCR in patients with PCa.(a,b) Kaplan–Meier analysis including number at risk of patients stratified into high or low lL6- and STAT3 mRNA expression predicting biochemical recurrence (BCR) of the Taylor data set35. (c) Distribution of STAT3 and p14ARF protein expression with low (≤7) or high (8–10) GSC in tumour specimens from men diagnosed with PCa. (d) Fisher's exact test of data shown in c and correlation of STAT3 to p14ARF expression. (e) Kaplan–Meier analysis of BCR-free survival ratio based on STAT3 protein expression in a panel of 204 PCa patients. (f) Kaplan–Meier analysis of BCR-free survival ratio based on p14ARF protein expression in a panel of 204 PCa patients. (g) Co-expression analyses of BCR-free survival of STAT3 and p14ARF. (h) Univariate and multivariate analyses of GSC, STAT3 or p14ARF protein levels. Data from a,b,e,f and g were analysed by log-rank test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4525303&req=5

f7: Loss of STAT3 and/or p14ARF expression predicts early BCR in patients with PCa.(a,b) Kaplan–Meier analysis including number at risk of patients stratified into high or low lL6- and STAT3 mRNA expression predicting biochemical recurrence (BCR) of the Taylor data set35. (c) Distribution of STAT3 and p14ARF protein expression with low (≤7) or high (8–10) GSC in tumour specimens from men diagnosed with PCa. (d) Fisher's exact test of data shown in c and correlation of STAT3 to p14ARF expression. (e) Kaplan–Meier analysis of BCR-free survival ratio based on STAT3 protein expression in a panel of 204 PCa patients. (f) Kaplan–Meier analysis of BCR-free survival ratio based on p14ARF protein expression in a panel of 204 PCa patients. (g) Co-expression analyses of BCR-free survival of STAT3 and p14ARF. (h) Univariate and multivariate analyses of GSC, STAT3 or p14ARF protein levels. Data from a,b,e,f and g were analysed by log-rank test.
Mentions: The fact that activated STAT3 induces its own transcription34 led us to measure IL-6 and STAT3 mRNA levels in primary human tumours and to correlate them with clinical outcome. Using the Taylor gene expression profiling data set (GSE21032)35, we dichotomized samples based on the z-scores of IL-6 or STAT3 expression. Specifically for IL-6 expression, samples that had z-scores<−2 were defined as low IL-6 and all others (z-scores>−2) were used as a comparator for prognostic significance. Conversely, samples that had STAT3 z-scores>2 were defined as STAT3 high and all other samples (z-scores<2) were used as comparators. Time to biochemical recurrence (BCR) was assessed as an indicator of individual prognosis. BCR was defined by an increase to >0.2 ng ml−1 PSA in serum. Of note, patients with low IL-6 expression levels showed a significantly higher risk of BCR compared with patients with high IL-6 expression (Fig. 7a). In line, patients with high Stat3 mRNA levels demonstrate good prognosis. This may reflect a higher level of senescence competence compared with patients with lower Stat3 mRNA levels (Fig. 7b).

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