title: 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 = 25, T1 n = 34, T2-T3-T4 n = 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 RS = 0.26; p = 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 = 0.0089) and T2-T3-T4 (p < 0.001) tumors compared to Ta tumors; it was also negatively correlated with miR-19a (RS = -0.50; p = 0.0088) and miR-222 (RS = -0.48; p = 0.0132), but not miR-21 (RS = -0.27; p = 0.18) expression. pAKT and PTEN expressions were not negatively correlated, and, on the opposite, a positive and moderate correlation was observed in Ta (RS = 0.54; p = 0.0056) and T1 (RS = 0.56; p = 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.
authors.affiliation: APHP, Groupe Hospitalier Henri Mondor, Département de Pathologie, 51 avenue du Mal-de-Lattre-de-Tassigny, 94010, Créteil, France; INSERM, U955, Institut Mondor de Recherche Biomédicale, 94010, Créteil, France; Université Paris-Est Créteil, 94010, Créteil, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.forename: Sandra
authors.initials: S
authors.lastname: Rebouissou
authors.forename: Leanne
authors.initials: L
authors.lastname: de Koning
authors.forename: Asma
authors.initials: A
authors.lastname: Masmoudi
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hérault
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
authors.forename: Pascale
authors.initials: P
authors.lastname: Maille
authors.forename: Pascale
authors.initials: P
authors.lastname: Soyeux
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sibony
authors.forename: Alexandre
authors.initials: A
authors.lastname: de la Taille
authors.forename: Dimitri
authors.initials: D
authors.lastname: Vordos
authors.forename: Thierry
authors.initials: T
authors.lastname: Lebret
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
authors.forename: Yves
authors.initials: Y
authors.lastname: Allory
mesh_terms: D000368:Aged; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D035683:MicroRNAs / Q000096:biosynthesis; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D038601:Ribosomal Protein S6 / Q000096:biosynthesis / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001743:Urinary Bladder / Q000201:enzymology / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000201:enzymology*; D019459:Urothelium / Q000201:enzymology / Q000473:pathology; D018631:ras Proteins / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D051498:Receptor, Fibroblast Growth Factor, Type 3; D038601:Ribosomal Protein S6; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins; C117307:KRAS protein, human; C549214:MIRN19A microRNA, human; C524940:MIRN21 microRNA, human; C525710:MIR222, human; C495901:TP53 protein, human; C484760:PIK3CA protein, human; C496365:FGFR3 protein, human; C494929:PTEN protein, human; C579846:NRAS protein, human; C501009:HRAS protein, human
keywords: PI3K/AKT pathway; PTEN; RPPA; bladder; carcinoma; phospho-S6 ribosomal protein