title: Cathepsin E, maspin, Plk1, and survivin are promising prognostic protein markers for progression in non-muscle invasive bladder cancer.
abstract: Bladder cancer is a common cancer with particularly high recurrence after transurethral resection. In this study, we investigated the prognostic value of the protein expression of cathepsin E, maspin, polo-like kinase 1 (Plk1), and survivin in patients with stage Ta and T1 urothelial carcinomas. Transcripts from the four genes encoding these proteins were previously included in gene expression signatures for outcome prediction for Ta/T1 bladder cancer. We used three different tissue microarrays with 693 non-muscle invasive urothelial carcinomas from Danish, Swedish, and Spanish patient cohorts with long-term follow-up. Protein expression was measured by immunohistochemistry, and antibody specificity was validated by Western blotting. In the Danish patient cohort, we found the expression of cathepsin E, maspin, Plk1, and survivin to be significantly associated with progression to stage T2 to T4 bladder cancer (for each marker: log-rank test; P < 0.001). Multivariate Cox regression analysis identified cathepsin E (P < 0.001), Plk1 (P = 0.021), maspin (P = 0.001), and survivin (P = 0.001) as independent prognostic markers. Furthermore, maspin, survivin, and cathepsin E expression significantly subgrouped patients already stratified by European Organization for Research and Treatment of Cancer risk scores. Finally, we successfully validated the results in tumors from 410 patients from both Sweden and Spain. We conclude that all four protein markers may have prognostic value in non-muscle invasive bladder cancer for guiding optimal treatment of patients. Additional prospective studies are needed for further validation of the clinical relevance of this marker panel.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Fristrup
authors.forename: Benedicte P
authors.initials: BP
authors.lastname: Ulhøi
authors.forename: Karin
authors.initials: K
authors.lastname: Birkenkamp-Demtröder
authors.forename: Francisco
authors.initials: F
authors.lastname: Mansilla
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Carbayo
authors.forename: Ulrika
authors.initials: U
authors.lastname: Segersten
authors.forename: Per-Uno
authors.initials: PU
authors.lastname: Malmström
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Joan
authors.initials: J
authors.lastname: Palou
authors.forename: Miguel
authors.initials: M
authors.lastname: Alvarez-Múgica
authors.forename: Karsten
authors.initials: K
authors.lastname: Zieger
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D020059:Cathepsin E / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015843:Serpins / Q000378:metabolism; D000077022:Survivin; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000473:pathology; D000097869:Polo-Like Kinase 1
chemical_list: D014408:Biomarkers, Tumor; D020059:Cathepsin E; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D015843:Serpins; D000077022:Survivin; D000097869:Polo-Like Kinase 1; C107489:BIRC5 protein, human; C085344:SERPIN-B5; C533925:CTSE protein, human