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A web-based tool for in silico biomarker discovery based on tissue-specific protein profiles in normal and cancer tissues
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2008 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 7, no 5, 825-844 p.Article in journal (Refereed) Published
Abstract [en]

Here we report the development of a publicly available Web-based analysis tool for exploring proteins expressed in a tissue- or cancer-specific manner. The search queries are based on the human tissue profiles in normal and cancer cells in the Human Protein Atlas portal and rely on the individual annotation performed by pathologists of images representing immunohistochemically stained tissue sections. Approximately 1.8 million images representing more than 3000 antibodies directed toward human proteins were used in the study. The search tool allows for the systematic exploration of the protein atlas to discover potential protein biomarkers. Such biomarkers include tissue-specific markers, cell type-specific markers, tumor type-specific markers, markers of malignancy, and prognostic or predictive markers of cancers. Here we show examples of database queries to generate sets of candidate biomarker proteins for several of these different categories. Expression profiles of candidate proteins can then subsequently be validated by examination of the underlying high resolution images. The present study shows examples of search strategies revealing several potential protein biomarkers, including proteins specifically expressed in normal cells and in cancer cells from specified tumor types. The lists of candidate proteins can be used as a starting point for further validation in larger patient cohorts using both immunological approaches and technologies utilizing more classical proteomics tools.

Place, publisher, year, edition, pages
2008. Vol. 7, no 5, 825-844 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-103798DOI: 10.1074/mcp.M700411-MCP200ISI: 000255830200001PubMedID: 17913849OAI: oai:DiVA.org:uu-103798DiVA: diva2:218724
Available from: 2009-05-20 Created: 2009-05-20 Last updated: 2015-10-29
In thesis
1. Tissue Microarrays for Analysis of Expression Patterns
Open this publication in new window or tab >>Tissue Microarrays for Analysis of Expression Patterns
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins are essential building blocks in every living cell, and since the complete human genome was sequenced in 2004, researchers have attempted to map the human proteome, which is the functional representation of the genome. One such initiative is the Human Protein Atlas programme (HPA), which generates monospecific antibodies towards all human proteins and uses these for high-throughput tissue profiling on tissue microarrays (TMAs). The results are publically available at the website www.proteinatlas.org.

In this thesis, TMAs were used for analysis of expression patterns in various research areas. Different search queries in the HPA were tested and evaluated, and a number of potential biomarkers were identified, e.g. proteins exclusively expressed in islets of Langerhans, but not in exocrine glandular cells or other abdominal organs close to pancreas. The identified candidates were further analyzed on TMAs with pancreatic tissues from normal and diabetic individuals, and colocalization studies with insulin and glucagon revealed that several of the investigated proteins (DGCR2, GBF1, GPR44 and SerpinB10) appeared to be beta cell specific. Moreover, a set of proteins differentially expressed in lung cancer stroma was further analyzed on a clinical lung cancer cohort in the TMA format, and one protein (CD99) was significantly associated with survival. In addition, TMAs with tissue samples from different species were generated, e.g. for mapping of influenza virus attachment in various human and avian tissues. The results showed that the gull influenza virus H16N3 attached to human respiratory tract and eye, suggesting possible transmission of the virus between gull and human. TMAs were also used for analysis of protein expression differences between humans and other primates, and two proteins (TCF3 and SATB2) proved to be significantly differentially expressed on the human lineage at both the protein level and the RNA level.  

In conclusion, this thesis exemplifies the potential of the TMA technology, which can be used for analysis of expression patterns in a large variety of research fields, such as biomarker discovery, influenza virus research or further understanding of human evolution.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 62 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 846
Tissue microarrays, Antibody-based proteomics, Immunohistochemistry, Biomarker discovery, Diabetes, Lung cancer, Influenza virus, Evolution
National Category
Endocrinology and Diabetes Infectious Medicine Cancer and Oncology Medical Genetics
Research subject
urn:nbn:se:uu:diva-186272 (URN)978-91-554-8551-1 (ISBN)
Public defence
2013-01-25, Rudbeck hall, Rudbeck laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Available from: 2012-12-21 Created: 2012-11-28 Last updated: 2013-02-11Bibliographically approved

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Lindskog, CeciliaKampf, CarolinePontén, Fredrik
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