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Tumour expression of bladder cancer-associated urinary proteins
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, Urology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2013 (English)In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 112, no 3, 407-415 p.Article in journal (Refereed) Published
Abstract [en]

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?:

  • The current basis for diagnosis and prognosis in urinary bladder cancer is based on the pathologists' assessment of a biopsy of the tumour. Urinary biomarkers are preferable as they can be non-invasively sampled. Urinary cytology is the only test with widespread use but is hampered by poor reproducibility and low sensitivity.
  • By studying the protein expression in bladder tumour tissue samples of proteins previously found in elevated levels in the urine of patients with bladder cancer, we have been able to show that these proteins originate from the tumour. The immunoreactivity of three of the investigated proteins increased with higher stage. Also a serine peptidase inhibitor was found to be predictive of progression from non-muscle-invasive to muscle-invasive tumours.

OBJECTIVES:

  • To analyse the expression of five bladder cancer-associated urinary proteins and investigate if expression is related to the malignant phenotype of the tumour.
  • To explore the possible prognostic value of these proteins.

PATIENTS AND METHODS:

  • Urine samples, 16 from patients with bladder cancer and 26 from controls, were used in Western Blotting experiments.
  • Tissue microarrays with bladder tissue from 344 patients diagnosed with bladder cancer between 1984 and 2005 was used in immunohistochemistry experiments.
  • The proteins apolipoprotein E (APOE), fibrinogen β chain precursor (FGB), leucine-rich α2-glycoprotein (LRG1), polymerase (RNA) I polypeptide E (POLR1E), α1-antitrypsin (SERPINA1) and topoisomerase 2A (TOP2A) were probed with antibodies validated by the Human Protein Atlas.

RESULTS:

  • Increased expressions of APOE, FGB and POLR1E were correlated with increased tumour stage (P < 0.001).
  • Expression of SERPINA1 in Ta and T1 tumours was found to increase the risk of tumour progression (hazard ratio 2.57, 95% confidence interval 1.13-5.87; P = 0.025)

CONCLUSIONS:

  • All proteins previously detected in urine from patients with bladder cancer were also expressed in bladder cancer tissue.
  • The expression of APOE, FGB and POLR1E increased with stage and they are potential diagnostic markers.
  • SERPINA1 was identified as a prognostic marker candidate.
Place, publisher, year, edition, pages
2013. Vol. 112, no 3, 407-415 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-197160DOI: 10.1111/j.1464-410X.2012.11653.xISI: 000321429800024PubMedID: 23470167OAI: oai:DiVA.org:uu-197160DiVA: diva2:611777
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2013-03-18 Created: 2013-03-18 Last updated: 2017-12-06Bibliographically 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, MårtenSegersten, UlrikaRuneson, MarcusWester, KennethPettersson, UlfBergström Lind, SaraMalmström, Per-Uno

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