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-RasQ61L or K-RasG12D) 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.
Highlights
A number of genetic and epigenetic alterations involved in bladder tumourigenesis have been identified, including activating mutations in FGFR3 and Ras family genes, amplification of ERBB2, and loss of the TP53, RB1 and PTEN tumour suppressors.[2,3,4,5]
We have previously shown that activation of the Wnt signalling pathway in the bladder of mice alone fails to drive Urothelial cell carcinoma (UCC), it strongly cooperates with PTEN loss to drive tumourigenesis.[14]
We demonstrated a significant correlation between upregulation of b-catenin and activation of pERK1/2
Summary
A number of genetic and epigenetic alterations involved in bladder tumourigenesis have been identified, including activating mutations in FGFR3 and Ras family genes, amplification of ERBB2, and loss of the TP53, RB1 and PTEN tumour suppressors.[2,3,4,5]. Transgenic models have provided invaluable information regarding the molecular mechanisms behind H-Ras activation.[9] Previously published studies by the Wu lab demonstrate that mice carrying a transgene with a H-RasQ61L mutation have early-onset urothelial hyperplasia, with this hyperplasia progressing to low-grade non-invasive papillary tumours. The mice had evidence of significantly enlarged bladders and associated bladder outflow obstruction (hydronephrosis and hydroureter) These tumours were of a papillary non-invasive histology, with no evidence of muscle invasion or metastases. The fact that the bladder tumours in ‘low-copy’ mice developed localised, superficial papillary tumours with a much longer latency, suggests, in the absence of overexpression, H-Ras, activation requires a secondary event, either genetic or epigenetic, to fully induce bladder tumours.[10]. As yet there have been no studies investigating targeting K-Ras mutation to the murine bladder in an equivalent manner to H-Ras
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