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Proteomic analysis of urinary biomarker candidates for nonmuscle invasive bladder cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. 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 Immunology, Genetics and Pathology, Genomics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
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2012 (English)In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 12, no 1, 135-144 p.Article in journal (Refereed) Published
Abstract [en]

Nonmuscle invasive tumors of the bladder often recur and thereby bladder cancer patients need regular re-examinations which are invasive, unpleasant, and expensive. A noninvasive and less expensive method, e.g. a urine dipstick test, for monitoring recurrence would thus be advantageous. In this study, the complementary techniques mass spectrometry (MS) and Western blotting (WB)/dot blot (DB) were used to screen the urine samples from bladder cancer patients. High resolving MS was used to analyze and quantify the urinary proteome and 29 proteins had a significantly higher abundance (p<0.05) in bladder cancer samples compared with control urine samples. The increased abundance found in urine from bladder cancer patients compared with controls was confirmed with Western blot for four selected proteins; fibrinogen β chain precursor, apolipoprotein E, α-1-antitrypsin, and leucine-rich α-2-glycoprotein 1. Dot blot analysis of an independent urine sample set pointed out fibrinogen β chain and α-1-antitrypsin as most interesting biomarkers having sensitivity and specificity values in the range of 66-85%. Exploring the Human Protein Atlas (HPA) also revealed that bladder cancer tumors are the likely source of these proteins. They have the potential of being useful in diagnosis, monitoring of recurrence and thus may improve the treatment of bladder tumors, especially nonmuscle invasive tumors.

Place, publisher, year, edition, pages
2012. Vol. 12, no 1, 135-144 p.
National Category
Urology and Nephrology Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-163407DOI: 10.1002/pmic.201000810ISI: 000298841000016PubMedID: 22065568OAI: oai:DiVA.org:uu-163407DiVA: diva2:463814
Available from: 2011-12-12 Created: 2011-12-12 Last updated: 2017-12-08Bibliographically approved
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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Lindén, MårtenLind, Sara BergströmSegersten, UlrikaWester, KennethMalmström, Per-UnoPettersson, Ulf

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