Dissertation committee:
Αθανάσιος Παπατσώρης, Αναπληρωτής Καθηγητής, Ιατρική, ΕΚΠΑ
Χαράλαμπος Δεληβελιώτης, Καθηγητής, Ιατρική, ΕΚΠΑ
Ανδρέας Σκολαρίκος, Αναπληρωτής Καθηγητής, Ιατρική, ΕΚΠΑ
Μιχάλης Χρυσοφός, Αναπληρωτής Καθηγητής, Ιατρική, ΕΚΠΑ
Ιωάννης Βαρκαράκης, Επίκουρος Καθηγητής, Ιατρική, ΕΚΠΑ
Ηρακλής Μητσογιάννης, Επίκουρος Καθηγητής, Ιατρική, ΕΚΠΑ
Αθανάσιος Δελλής, Επίκουρος Καθηγητής, Ιατρική, ΕΚΠΑ
Summary:
The purpose of this PhD thesis was to examine the involvement of specific components of the PI3K/AKT pathway in urinary bladder cancer.Samples from sixty-five tumors and thirteen normal bladder tissues were collected. Genomic DNA isolation from snap-frozen and paraffin-embedded laser-microdissected tissues was followed by Sanger sequencing, whereas total RNA was purified for use in RT-PCR analyses. Immunohistochemistry was carried out on sections of paraffin-embedded biopsy material.
Three pathogenic mutations (two missense and one frameshift) were identified in exon 20 of PIK3CA {c.3140A>G (p.His1047Arg), c.[3172A>T(;)3174C>T] (p.lle1058Phe), c.3203dupA (p.Asn1068Lysfs*5)} after laser capture microdissection, whereas PTEN mRNA expression was found to be downregulated in bladder cancer tissues compared to normal bladder urothelium. Upregulation of cytoplasmic and nuclear p-AKT expression was detected in low grade tumors, whereas in muscle invasive tumors, p-AKT was shown to be downregulated and confined to the cytoplasm. PTEN expression was weak and mainly cytoplasmic in superficial tumors, but stronger and nuclear in the muscle invasive tumors.
In conclusion,PI3K/AKT pathway activationis involved in bladder cancer initiation and progression. In this context, PIK3CA, p-AKT and nuclear PTEN could be used along with other biomarkers for prognostic purposes and for the selection of appropriate therapy in the clinical management of bladder cancer
Keywords:
Bladder cancer, PI3K/AKT pathway, PIK3CA mutation, Nuclear PTEN, p-AKT expression
