PI3K/AKT pathway activation in bladder carcinogenesis

Abstract

The PI3K/AKT pathway is considered to play a major role in bladder carcinogenesis, but its relationships with other molecular alterations observed in bladder cancer remain unknown. We investigated PI3K/AKT pathway activation in a series of human bladder urothelial carcinomas (UC) according to PTEN expression, PTEN deletions and FGFR3, PIK3CA, KRAS, HRAS, NRAS and TP53 gene mutations. The series included 6 normal bladder urothelial samples and 129 UC (Ta n 5 25, T1 n 5 34, T2-T3-T4 n 5 70). Expression of phospho-AKT (pAKT), phospho-S6-Ribosomal Protein (pS6) (one downstream effector of PI3K/AKT pathway) and PTEN was evaluated by reverse phase protein Array. Expression of miR-21, miR-19a and miR-222, known to regulate PTEN expression, was also evaluated. pAKT expression levels were higher in tumors than in normal urothelium (p < 0.01), regardless of stage and showed a weak and positive correlation with pS6 (Spearman coefficient R S 5 0.26; p 5 0.002). No association was observed between pAKT or pS6 expression and the gene mutations studied. PTEN expression was decreased in PTEN-deleted tumors, and in T1 (p 5 0.0089) and T2-T3-T4 (p < 0.001) tumors compared to Ta tumors; it was also negatively correlated with miR-19a (R S 5 20.50; p 5 0.0088) and miR-222 (R S 5 20.48; p 5 0.0132), but not miR-21 (R S 5 20.27; p 5 0.18) expression. pAKT and PTEN expressions were not negatively correlated, and, on the opposite, a positive and moderate correlation was observed in Ta (R S 5 0.54; p 5 0.0056) and T1 (R S 5 0.56; p 5 0.0006) tumors. Our study suggests that PI3K/AKT pathway activation occurs in the entire spectrum of bladder UC regardless of stage or known most frequent molecular alterations, and independently of low PTEN expression.Urothelial carcinoma of the bladder (UC) is the sixth most common cancer among both sexes in Western countries, with about 200,000 new cases diagnosed each year. 1 It most often affects men (sex ratio: 3/1) and its incidence increases with age, peaking between the sixth and seventh decades. 2 Tobacco smoking is the most important risk factor. 2 The two major groups of UC are nonmuscle-and muscle-invasive UCs. 3 Nonmuscle-invasive UCs comprise carcinoma in situ (CIS), and Ta and T1 tumors. Tumors classified as Ta are papillary, noninvasive, mostly low grade, frequently recur (50-70%) and may rarely and unpredictably progress to stage T1 (lamina propria invaded) and then to muscle-invasive (stages T2, T3 or T4) tumors (5-10%). 3,4 CIS (stage Tis) is a flat lesion, always of high grade, that evolves to invasive carcinoma in about 50% of cases, and is considered to be the main precursor of muscle-invasive UC. 2,3 Locally advanced and/or metastatic UC is associated with a poor prognosis and no truly effective systemic therapies are available. 2,3 These two carcinogenesis pathways, 5 the low-grade Ta and CIS pathways, are supported by molecular studies. 5,6 Fibroblast growth factor receptor 3 (FGFR3), which encodes a tyrosine kinase-linked cell surface receptor, is mutated in up to 80% of low-grade ...

A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis

“…Here, our main goal is to highlight mechanisms affected in bladder tumors to propose successive events that may lead to high-stage tumors in both Ta and CIS progression pathways. (26,27), and graded according to the 1973 WHO classification (28). All patients provided written informed consent, and ethics committees of all hospitals approved the study (Comit e de Protection des Personnes de l'hôpital Henri Mondor, Comit e de Protection des Personnes de Boulogne-Ambroise Par e, and Comit e de Protection des Personnes de Bicêtre).…”

“…Immediately after surgery, tissue samples were frozen in liquid nitrogen and stored at À80 C until nucleic acid extraction. DNA were extracted from frozen human bladder tissues as described in (26).…”

Aberrantly expressed microRNAs in bladder cancer and renal cell carcinoma

“…Additionally, upregulation of miR-19a in tissues and plasma samples from patients with BC has been reported, and this miRNA has been shown to act as an oncogene by targeting PTEN, which may have a significant role in human BC. 52,53 miRNA expression signatures of RCC We also reviewed six recently published miRNA expression signatures comparing RCC and normal kidney tissue using clinical specimens (Table 3). [18][19][20][21][22][23] Two signatures were constructed from deep sequencing and the other four signatures were constructed from microarrays.…”

Repression of engrailed 2 inhibits the proliferation and invasion of human bladder cancer in vitro and in vivo

“…The PI3K/AKT signaling pathway is a frequently dysregulated pathway in cancer (42,43) and possesses a major function in bladder carcinogenesis (44)(45)(46)(47)(48). PTEN is the antagonist of PI3K, which removes the 3' phosphate of PIP3 and attenuates downstream signaling of activated PI3K (49).…”