Abstract
The high rates of tumor recurrence and progression represent a major clinical problem in non-muscle invasive bladder cancer. Previous data showed that EZH2-dependent signaling mediates these processes, whereas the frequent alterations of PIK3CA gene (copy gains and mutations) are predictive of reduced recurrence. Here we show, using clinical samples and bladder cancer cell lines, a functional interaction between EZH2- and PIK3CA-dependent signaling pathways. PIK3CA alterations mediated, on the one hand, the increased expression of two miRNAs, miR-101 and miR-138, which posttranscriptionally downregulate EZH2 expression. On the other hand, PIK3CA alterations facilitate the activation of Akt which phosphorylates EZH2 on Ser21, precluding the trimethylation of histone H3 in K27. Remarkably the increased expression of miR101 or miR138 and the expression of Ser21-phosphorylated EZH2 are good prognostic factors regarding non-muscle invasive bladder cancer recurrence and progression. Collectively, this study provides molecular evidences indicating that the gene expression rewiring occurring in primary bladder tumors, associated with increased EZH2 expression and activity and mediating the increased recurrence and progression risk, are prevented by PIK3CA-dependent signaling. This molecular process may have deep implications in the management of bladder cancer patients and in the design of novel molecularly targeted therapeutic approaches.
Highlights
Bladder cancer (BC) is a complex disease caused by both genetic and environmental factors [1]
Using a highly sensitive PCR technique, we have previously demonstrated that PIK3CA gene alterations are extremely frequent in NMIBC being present in non-affected bladder tissue, and associate with low recurrence and progression [6]
We have previously shown in a series of 87 BC samples, using high sensitive PCR-based approaches, that the activating mutations (E545K/D, E542K and H1047R) or PIK3CA gene copy gains or amplifications may reach up to 50% of tumor samples, and they are present in non-tumoral tissue from BC patients, suggesting field cancerization processes [6]
Summary
Bladder cancer (BC) is a complex disease caused by both genetic and environmental factors [1]. Two major types of BC: non-muscle invasive (NMIBC), and muscle invasive tumors (MIBC) are characterized. This pathological classification defines the possible therapeutic options. The NMIBCs represent around 70% of BC and are treated by transurethral resections, in some cases followed by intravesical therapy. NMIBCs have a favorable prognosis, they show one of the highest rates of recurrence, which in some cases can progress into www.impactjournals.com/oncotarget muscle-invasive tumors. This makes necessary a regular surveillance by cystoscopy and urine cytology indefinitely (EAU guidelines) [2]. NMIBC represents one of the most costly malignancies to health care systems in developed countries [2]
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