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Stathmin-1 is a promising prognostic factor and potential therapeutic target in urinary bladder cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Experimentell Urologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Aim: The oncoprotein 18/stathmin 1 (STMN1), involved in cell cycle progression and cell migration, has been reported to be expressed in several types of cancer, and is associated with clinical outcome in e.g. breast and liver cancer. The aims in this study were to investigate the clinical significance of STMN1 and to examine if STMN1 might be a possible therapeutic target in urinary bladder cancer.

Experimental design: Immunohistochemical analyses of STMN1 protein expression were performed in a wide-range tissue microarray (115 Ta-, 115 T1-, 112 T2-4-tumors) and in a metastatic primary tumor/matched metastasis-material (90 patients). In the T24 cell line, the effect of STMN1 on cell proliferation was evaluated by inhibiting the cellular expression of STMN using STMN1-siRNA.

Results: Patients with T1- or muscle-invasive disease exhibiting high expression of the STMN1 protein had a poorer overall survival (OS) and disease specific survival (DSS). In a multivariate analysis adjusting for stage, age and gender the results were for T2-T4 patients: OS (HR=1.77 95% CI 1.02-3.07; p=0.04) and DSS (HR=2.04 95% CI 1.13-3.68; p=0.02); for T1-4 patients: DSS (HR=1.83 95% CI 1.09-3.08; p=0.02). In the metastatic bladder cancer material, the majority of the patients with one metastasis (69%) and with several matched metastases (70%) were STMN1-positive in both the primary tumor and the matched metastases. Moreover, the ability of the urinary bladder cancer cell line to grow was significantly reduced after 72 hours (p<0.0001) when transfecting the cells with a siRNA targeting STMN1.

Conclusion: Our results suggest that STMN1 protein-expression has a potential both as a prognostic marker and a novel treatment target in urinary bladder cancer.

National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-197155OAI: oai:DiVA.org:uu-197155DiVA: diva2:611804
Available from: 2013-03-18 Created: 2013-03-18 Last updated: 2015-06-24
In thesis
1. Proteomic Analysis of Urinary Bladder Cancer: Aiming for Novel Biomarkers
Open this publication in new window or tab >>Proteomic Analysis of Urinary Bladder Cancer: Aiming for Novel Biomarkers
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Urinary bladder cancer is a heterogeneous disease appearing in different forms, e.g. non-muscle invasive and muscle invasive. For all variants, the expression of proteins is interesting to analyze for diagnostic, predictive, prognostic and drug targeting purposes, since it reflects the altered gene expression causing the cancer. Since urothelial cells of the bladder are in direct contact with urine it is likely that this body fluid contains cancer-related proteins. In Paper I, unbiased analysis of proteins in urine from urinary bladder cancer patients and controls, using label-free quantification by mass spectrometry, was applied and four interesting proteins APOE, FGB, LRG and SERPINA1 were selected and further analyzed with western and dot blot. In Paper II, two more proteins, POLR1E and TOP2A, were validated as relevant proteins in bladder cancer urine. In Paper III and IV, the proteins GAL1 and STMN1 were investigated for their prognostic and therapeutic target potential in bladder cancer. In Paper II, III and IV, the expression of seven of the proteins were analyzed on tissue microarrays representing tumour tissue from 360 patients with different tumour stages. For the proteins identified by the urine screening approach, their protein expressions were confirmed in bladder cancer tissue. The expression level in tissue of five of the proteins, APOE, FGB, POLR1E (Paper II), GAL1 (Paper III) and STMN1 (Paper IV), increased with tumour stage, showing diagnostic relevance and three of the proteins, SERPINA1 (Paper II), STMN1 (Paper IV) and GAL1 (Paper III) had prognostic potential in urinary bladder cancer. In addition, GAL1 and STMN1 were demonstrated to be highly expressed in metastatic disease and inhibition of STMN1 reduced cell growth (Paper III and IV), indicating that these proteins are promising drug targets in urinary bladder cancer. In conclusion, the approach of this thesis has generated several candidate protein biomarkers in urine and tissue, validated with independent methods, which have the potential to improve the care for bladder cancer patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 879
Keyword
urine, APOE, FGB, GAL1, LRG1, POLR1E, SERPINA1, STMN1, TOP2A, biomarker, diagnostic biomarker, prognostic biomarker, predictive biomarker, mass spectrometry, western blot, dot blot, immunohistochemistry, IHC, tissue microarray, TMA, urothelium, antibody, antibody-based, urinblåsecancer, biomarkör, diagnos, prognos, urin, proteomik, masspektrometri, immunohistokemi, antikroppar
National Category
Medical and Health Sciences
Research subject
Molecular Biology; Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-197132 (URN)978-91-554-8625-9 (ISBN)
Public defence
2013-05-03, The Rudbeck Hall, Dag Hammarskjölds väg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2013-04-11 Created: 2013-03-18 Last updated: 2013-08-30Bibliographically approved

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Hemdan, TammerLindén, MårtenMalmström, Per-UnoSegersten, Ulrika

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