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The human adrenal gland proteome defined by transcriptomics and antibody-based profiling
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. (Fredrik Pontén)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. (Johan Botling)
KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden.
KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden.
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2017 (Engelska)Ingår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 158, nr 2, s. 239-251Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The adrenal gland is a composite endocrine organ with vital functions that include the synthesis and release of glucocorticoids and catecholamines. To define the molecular landscape that underlies the specific functions of the adrenal gland, we combined a genome-wide transcriptomics approach based on mRNA sequencing of human tissues with immunohistochemistry-based protein profiling on tissue microarrays. Approximately two-thirds of all putative protein coding genes were expressed in the adrenal gland and the analysis identified 253 genes with an elevated pattern of expression in the adrenal gland, with only 37 genes showing a markedly higher expression level (>5-fold) in the adrenal gland compared to 31 other normal human tissue types analyzed. The analyses allowed for an assessment of the relative expression levels for well-known proteins involved in adrenal gland function, but also identified previously poorly characterized proteins in the adrenal cortex, such as FERM domain containing 5 (FRMD5) and protein NOV homolog (NOV). In summary, we provide a global analysis of the adrenal gland transcriptome and proteome, with a comprehensive list of genes with elevated expression in the adrenal gland and spatial information with examples of protein expression patterns for corresponding proteins. These genes and proteins constitute important starting points for an improved understanding of the normal function and pathophysiology of the adrenal glands.

Ort, förlag, år, upplaga, sidor
2017. Vol. 158, nr 2, s. 239-251
Nationell ämneskategori
Endokrinologi och diabetes Klinisk laboratoriemedicin
Forskningsämne
Patologi
Identifikatorer
URN: urn:nbn:se:uu:diva-312934DOI: 10.1210/en.2016-1758ISI: 000397101700008PubMedID: 27901589OAI: oai:DiVA.org:uu-312934DiVA, id: diva2:1065382
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseTillgänglig från: 2017-01-16 Skapad: 2017-01-16 Senast uppdaterad: 2019-03-29Bibliografiskt granskad
Ingår i avhandling
1. Aspects of Gene Expression Profiling in Disease and Health
Öppna denna publikation i ny flik eller fönster >>Aspects of Gene Expression Profiling in Disease and Health
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The aim of this thesis is to in various ways explore protein expression in human normal tissue and in cancer and to apply that knowledge in biomarker discovery.

In Paper I the prognostic significance of RNA-binding motif protein 3 (RBM3) is explored in malignant melanoma. To further evaluate the prognostic significance of RBM3 expression was assessed in 226 incident cases of malignant melanoma from the prospective populationbased cohort study Malmö Diet and Cancer Study using tissue microarray technique (TMA). RBM3 was shown to be down regulated in metastatic melanoma and high nuclear expression in the primary tumor was an independent marker of prolonged over all survival. As a tool to facilitate clinical biomarker studies the Human Protein Atlas has created a tissue dictionary as an introduction to human histology and histopathology. In Paper II this work is introduced.

A cancer diagnosis can be a complex process with difficulties of establishing tumor type in localized disease or organ of origin in generalized disease. Immunohistochemically assisted diagnosis of cancer is common practice among pathologists where its application combined with known protein expression profiles of different cancer types, can strengthen or help dismiss a suspected diagnosis. In Paper III the diagnostic performance of 27 commonly used antibodies are tested in a predominantly metastatic, multicancer cohort using TMA technique. Overall these 27 diagnostic markers showed a low sensitivity and specificity for its intended use, highlighting the need for novel, more specific markers.

Breast, ovarian, endometrial and ovarian cancers affect predominantly women. Differential diagnostics between these cancer types can be challenging. In Paper IV an algorithm, based on six different IHC markers, to differentiate between these cancer types is presented. A new diagnostic marker for breast cancer, namely ZAG is also introduced.

In Paper V the transcriptomic landscape of the adrenal gland is explored by combining a transcriptomic approach with a immunohistochemistry based proteomic approach. In the adrenal gland we were able to detect 253 genes with an elevated pattern of expression in the adrenal gland, as compared to 31 other normal human tissue types analyzed. This combination of a transcriptomic and immunohistochemical approach provides a foundation for a deeper understanding of the adrenal glands function and physiology.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 43
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1294
Nyckelord
Cancer, biomarkers, differential diagnostics, immunohistochemistry, transcriptomics, protein profiling, adrenal gland.
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper
Forskningsämne
Patologi
Identifikatorer
urn:nbn:se:uu:diva-312939 (URN)978-91-554-9802-3 (ISBN)
Disputation
2017-03-10, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds v 20, Uppsala, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-02-17 Skapad: 2017-01-16 Senast uppdaterad: 2018-01-13

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Institutionen för immunologi, genetik och patologiScience for Life Laboratory, SciLifeLabKlinisk och experimentell patologi
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Endokrinologi och diabetesKlinisk laboratoriemedicin

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