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Psoriasin (S100A7) contributes to stress-induced angiogenesis in psoriasis by the regulation of angiogenic factors in keratinocytes and promotion of angiogenic properties of dermal endothelial cells
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Dermatology and Venerology.
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

The S100 protein psoriasin, S100A7, is highly expressed in psoriasis. Vascular modifications occur early in the development of psoriasis and angiogenesis is one of the key features in the pathogenesis of the disease. This study aims to define the angiogenic properties of psoriasin in keratinocytes and to investigate the effects on dermal endothelial cells, thereby promoting angiogenesis in psoriasis. We showed that psoriasin expression, demonstrated by qPCR, is induced by hydrogen peroxide (H2O2) in keratinocytes and by cellular stress, such as hypoxia and cobalt chloride (CoCl2). Down-regulation of psoriasin, by siRNA, decreased the H2O2-induced expression of VEGF, heparin-binding EGF-like growth factor (HB-EGF) and matrix metalloproteinase (MMP)-1, and counteracted the reduction of the anti-angiogenic factor thrombospondin (THBS)-1. Extracellularly psoriasin was found to induce cell proliferation, migration and tube formation to a similar degree as VEGF and to induce the pro-angiogenic factors VEGF and IL-8 in dermal endothelial cells. Furthermore, we demonstrated that psoriasin-induced migration was mediated by the phosphoinositide-3-kinase (PI3K) and nuclear factor-kappa beta (NF-κB) signaling pathways. In conclusion, psoriasin is induced by cellular stress conditions and amplifies H2O2-induced expression of angiogenic factors relevant for psoriasis in keratinocytes. Moreover, psoriasin contributes to key features of the angiogenic process by inducing proliferation, migration and tube formation and increasing pro-angiogenic factors in dermal endothelial cell. Altogether, our data suggest that psoriasin is promoted by oxidative stress and mediate angiogenesis in psoriasis.

Place, publisher, year, edition, pages
2014.
National Category
Rheumatology and Autoimmunity Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-110028OAI: oai:DiVA.org:liu-110028DiVA: diva2:742286
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2015-04-09Bibliographically approved
In thesis
1. Psoriasin For Better or for Worse in Sickness and in Health: The Role of Psoriasin in Angiogenesis and Differentation of Epithelial Cells
Open this publication in new window or tab >>Psoriasin For Better or for Worse in Sickness and in Health: The Role of Psoriasin in Angiogenesis and Differentation of Epithelial Cells
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Psoriasin (S100A7), a member of the S100 family of calcium-binding proteins, is highly expressed in high-grade ductal carcinoma in situ (DCIS) and in the benign hyper-proliferative skin disorder psoriasis. Both breast cancer and psoriasis are diseases which are characterized by hyperproliferation and a disturbed differentiation of the epithelial cells as well as a pronounced angiogenesis. The potential role of psoriasin in angiogenesis and the epithelial differentiation remain unclear.

The aim of this thesis was to investigate the cellular effects of psoriasin in angiogenesis and the differentiation processes, with special emphasis on breast cancer and psoriasis.

We found that psoriasin expression was induced in mammary epithelial cells and keratinocytes by oxidative stress. Psoriasin expression was shown to induce vascular endothelial growth factor (VEGF) expression and several other pro-angiogenic factors in epithelial cells. Upon down-regulation of psoriasin, H2O2-induced expression of VEGF was decreased as well as the pro-angiogenic factors heparin-binding EGF-like growth factor (HBEGF) and matrix metalloproteinase (MMP)-1. Extracellular psoriasin contributed to the subsequent induction of proliferation, migration and tube formation of endothelial cells. The proliferative effect of psoriasin was shown to be mediated by the receptor for advanced glycation end products (RAGE). Furthermore, psoriasin induced reactive oxygen species (ROS) in both endothelial and epithelial cells through the action of RAGE, and contributed to the expression of the pro-angiogenic factors in endothelial cells.

The expression of psoriasin was up-regulated in mammary epithelial cells and keratinocytes in response to differentiation-inducing stimuli and was shown to be regulated by pathways involved in epithelial cell differentiation. Upon psoriasin down-regulation the shift towards a more differentiated CD24+-phenotype of mammary epithelial cells was abolished. Furthermore, the expression of the differentiation markers involucrin, desmoglein 1, transglutaminase 1 and CD24 was decreased in keratinocytes upon down-regulation of psoriasin expression. In vivo we demonstrated a gradient of psoriasin expression in the psoriatic epidermis, with intense expression in the suprabasal differentiated layers, and a similar staining pattern between psoriasin and the differentiation marker CD24 in DCIS tumors.

In conclusion, our findings describe psoriasin as a mediator in the angiogenic process and a contributor of epithelial cell differentiation. Consequently, psoriasin is possibly a contributor to the development and progression of breast cancer and psoriasis and a potential target in the treatment of these diseases.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 58 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1412
National Category
Dermatology and Venereal Diseases Basic Medicine
Identifiers
urn:nbn:se:liu:diva-110031 (URN)10.3384/diss.diva-110031 (DOI)978-91-7519-283-3 (ISBN)
Public defence
2014-09-26, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2015-01-19Bibliographically approved

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Vegfors, JennyBivik, CeciliaEkman, Anna-KarinEnerbäck, Charlotta

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Vegfors, JennyBivik, CeciliaEkman, Anna-KarinEnerbäck, Charlotta
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Division of Cell BiologyDivision of Inflammation MedicineFaculty of Health SciencesDepartment of Dermatology and Venerology
Rheumatology and AutoimmunityHealth Sciences

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