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Ras mutation cooperates with β-catenin activation to drive bladder tumourigenesis.

Ahmad I, Patel R, Liu Y, Singh LB, Taketo MM, Wu XR, Leung HY, Sansom OJ - Cell Death Dis (2011)

Bottom Line: The Wnt signalling pathway is deregulated in approximately 25% of UCC, so we examined if this correlated with the activation of MAPK signalling in human UCC and found a significant correlation.Mechanistically this was associated with reduced levels of p21 with dependence on the MAPK signalling pathway.Taken together these data definitively show Ras pathway activation strongly cooperates with Wnt signalling to drive UCC in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Uro-oncology, The Beatson Institute for Cancer Research, Glasgow G61 1BD, Scotland.

ABSTRACT
Mutations in the Ras family of proteins (predominantly in H-Ras) occur in approximately 40% of urothelial cell carcinoma (UCC). However, relatively little is known about subsequent mutations/pathway alterations that allow tumour progression. Indeed, expressing mutant H-Ras within the mouse bladder does not lead to tumour formation, unless this is expressed at high levels. The Wnt signalling pathway is deregulated in approximately 25% of UCC, so we examined if this correlated with the activation of MAPK signalling in human UCC and found a significant correlation. To test the functional significance of this association we examined the impact of combining Ras mutation (H-Ras(Q61L) or K-Ras(G12D)) with an activating β-catenin mutation within the mouse bladder using Cre-LoxP technology. Although alone, neither Ras mutation nor β-catenin activation led to UCC (within 12 months), mice carrying both mutations rapidly developed UCC. Mechanistically this was associated with reduced levels of p21 with dependence on the MAPK signalling pathway. Moreover, tumours from these mice were sensitive to MEK inhibition. Importantly, in human UCC there was a negative correlation between levels of p-ERK and p21 suggesting that p21 accumulation may block tumour progression following Ras mutation. Taken together these data definitively show Ras pathway activation strongly cooperates with Wnt signalling to drive UCC in vivo.

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Related in: MedlinePlus

Correlation between β-catenin and pERK1/2 in human bladder UCC TMA. IHC of benign and UCC bladder samples revealing no β-catenin, pERK1/2 or p21 expression (a–c). In the UCC samples there was expression of nuclear β-catenin (d) corresponding upregulation of pERK1/2 (b), with scattered expression of p21 (c). Scatterplot demonstrating correlation between β-catenin and pERK1/2 (d). Each core size is 1.5 mm
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fig1: Correlation between β-catenin and pERK1/2 in human bladder UCC TMA. IHC of benign and UCC bladder samples revealing no β-catenin, pERK1/2 or p21 expression (a–c). In the UCC samples there was expression of nuclear β-catenin (d) corresponding upregulation of pERK1/2 (b), with scattered expression of p21 (c). Scatterplot demonstrating correlation between β-catenin and pERK1/2 (d). Each core size is 1.5 mm

Mentions: We have previously shown that in human UCC upregulation of the Wnt pathway (nuclear β-catenin) is associated with activation of the PI3K–pAKT pathway (loss of PTEN/upregulation of pAKTSer473). Given this strong correlation, we wanted to investigate which other oncogenic/tumour-suppressor pathways were associated with Wnt signal activation.14 Using the same tissue microarray of 80 human bladder cases: 60 UCC (transitional cell carcinomas), and 20 benign controls (Folio Biosciences, Columbus, OH, USA) we chose to investigate the MAPK pathway. Using the histoscore technique, we demonstrated a significant correlation between upregulation of β-catenin and activation of pERK1/2 (n=24/56, Pearson correlation coefficient=0.6769, P<0.0001 (two-tailed), Minitab v15, Minitab Inc., PA, USA) (Figure 1). Interestingly, these tumours appear to be a different subset to the ones expressing high levels of p-AKT as no correlation between levels of p-ERK and p-AKT was observed (Pearson correlation coefficient=0.083, P=0.45, Minitab v15).


Ras mutation cooperates with β-catenin activation to drive bladder tumourigenesis.

Ahmad I, Patel R, Liu Y, Singh LB, Taketo MM, Wu XR, Leung HY, Sansom OJ - Cell Death Dis (2011)

Correlation between β-catenin and pERK1/2 in human bladder UCC TMA. IHC of benign and UCC bladder samples revealing no β-catenin, pERK1/2 or p21 expression (a–c). In the UCC samples there was expression of nuclear β-catenin (d) corresponding upregulation of pERK1/2 (b), with scattered expression of p21 (c). Scatterplot demonstrating correlation between β-catenin and pERK1/2 (d). Each core size is 1.5 mm
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3101820&req=5

fig1: Correlation between β-catenin and pERK1/2 in human bladder UCC TMA. IHC of benign and UCC bladder samples revealing no β-catenin, pERK1/2 or p21 expression (a–c). In the UCC samples there was expression of nuclear β-catenin (d) corresponding upregulation of pERK1/2 (b), with scattered expression of p21 (c). Scatterplot demonstrating correlation between β-catenin and pERK1/2 (d). Each core size is 1.5 mm
Mentions: We have previously shown that in human UCC upregulation of the Wnt pathway (nuclear β-catenin) is associated with activation of the PI3K–pAKT pathway (loss of PTEN/upregulation of pAKTSer473). Given this strong correlation, we wanted to investigate which other oncogenic/tumour-suppressor pathways were associated with Wnt signal activation.14 Using the same tissue microarray of 80 human bladder cases: 60 UCC (transitional cell carcinomas), and 20 benign controls (Folio Biosciences, Columbus, OH, USA) we chose to investigate the MAPK pathway. Using the histoscore technique, we demonstrated a significant correlation between upregulation of β-catenin and activation of pERK1/2 (n=24/56, Pearson correlation coefficient=0.6769, P<0.0001 (two-tailed), Minitab v15, Minitab Inc., PA, USA) (Figure 1). Interestingly, these tumours appear to be a different subset to the ones expressing high levels of p-AKT as no correlation between levels of p-ERK and p-AKT was observed (Pearson correlation coefficient=0.083, P=0.45, Minitab v15).

Bottom Line: The Wnt signalling pathway is deregulated in approximately 25% of UCC, so we examined if this correlated with the activation of MAPK signalling in human UCC and found a significant correlation.Mechanistically this was associated with reduced levels of p21 with dependence on the MAPK signalling pathway.Taken together these data definitively show Ras pathway activation strongly cooperates with Wnt signalling to drive UCC in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Uro-oncology, The Beatson Institute for Cancer Research, Glasgow G61 1BD, Scotland.

ABSTRACT
Mutations in the Ras family of proteins (predominantly in H-Ras) occur in approximately 40% of urothelial cell carcinoma (UCC). However, relatively little is known about subsequent mutations/pathway alterations that allow tumour progression. Indeed, expressing mutant H-Ras within the mouse bladder does not lead to tumour formation, unless this is expressed at high levels. The Wnt signalling pathway is deregulated in approximately 25% of UCC, so we examined if this correlated with the activation of MAPK signalling in human UCC and found a significant correlation. To test the functional significance of this association we examined the impact of combining Ras mutation (H-Ras(Q61L) or K-Ras(G12D)) with an activating β-catenin mutation within the mouse bladder using Cre-LoxP technology. Although alone, neither Ras mutation nor β-catenin activation led to UCC (within 12 months), mice carrying both mutations rapidly developed UCC. Mechanistically this was associated with reduced levels of p21 with dependence on the MAPK signalling pathway. Moreover, tumours from these mice were sensitive to MEK inhibition. Importantly, in human UCC there was a negative correlation between levels of p-ERK and p21 suggesting that p21 accumulation may block tumour progression following Ras mutation. Taken together these data definitively show Ras pathway activation strongly cooperates with Wnt signalling to drive UCC in vivo.

Show MeSH
Related in: MedlinePlus