Activation of the AKT pathway induces transitional cell carcinoma of the renal pelvis: identification in human tumors and confirmation in animal models Free

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Upper urinary tract transitional cell carcinomas (UUT-TCC) are relatively rare tumors. However, the underlying molecular mechanism(s) of tumorigenesis of this malignancy remain unclear. Through analysis of gene expression profiling data, we identified a gene expression signature indicative of AKT pathway activation in 9 of 13 (70%) UUT-TCCs. In contrast, the activated AKT gene expression signature was identified in only 14% (n=92) and 12% (n=25) of clear cell and papillary RCC, respectively. Therefore, we investigated the role of AKT activation in UUT-TCC in more detail. Sequence analysis of the PI3-kinase alpha subunit (PIK3CA) revealed that 13.6% (3/22) of human UUT-TCCs harbor activating mutations in the exon 9 of PIK3CA gene, with two cases of E545K and one case of E542K. In contrast, no mutation was found in the 87 cases of other types of renal neoplasms (including 15 chromophobe renal cell carcinomas, 10 renal oncocytomas, 15 papillary renal cell carcinomas, 32 clear cell renal cell carcinoms, 6 Wilms’s tumors, and 9 other tumors in the kidney). Moreover, to mimic AKT activation in UUT-TCC, mice were generated that carrieda conditional deletion of the Pten gene specificallyin the renal epithelium using the Ksp-Cre/lox system. We observed hyperplasia of the transitional epithelia in renal pelvis in mice that contained biallelic inactivation of Pten, with the incidence rate increasing from 36.4% in 6 months old mice to 65.2% in one year old mice. In addition, TCC of the renal pelvis occurred in the biallelic Pten knockout mice older than 7 months, with an incidence rate of 42.86% in the mice older than one year. Importantly, renal lymph node metastases of the TCC were also found in some animals. Laser capture microdisection followed by PCR confirmed the deletion of the Pten exons 4 and 5 in the animal tumor tissues. Immunohistochemistry analyses demonstrated increased phospho-mTOR levels in the animal tumors. Taken together, our results clearly show that activation of the AKT pathway plays an important role in the carcinogenesis of UUT-TCC.