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The Expression of Psoriasin (S100A7) and CD24 Is Linked and Related to the Differentiation of Mammary Epithelial Cells
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Sahlgrens University Hospital, Sweden .
Harvard University, USA .
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12Article in journal (Refereed) Published
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 hyperproliferative skin disorder psoriasis. The gene that encodes psoriasin and many other S100 genes are located within a gene cluster on chromosome region 1q21, known as the epidermal differentiation complex. This cluster contains genes for several differentiation markers that play important roles in the terminal differentiation of the epidermis. The purpose of the present study was to evaluate the role of psoriasin in the differentiation process of mammary epithelial cells. Normal mammary epithelial cells (MCF10A) cultured in confluence and suspension, conditions known to induce psoriasin expression, demonstrated a shift towards a more differentiated phenotype indicated by an increase in the expression of the luminal differentiation markers CD24 and MUC1 and the reduced expression of the breast stem cell marker CD44. The expression of psoriasin and MUC1 was most pronounced in the CD24(+)-enriched fraction of confluent MCF10A cells. The shift towards a more differentiated phenotype was abolished upon the downregulation of psoriasin using short hairpin RNA (shRNA) and small interfering RNA (siRNA). Using specific inhibitors, we showed that psoriasin and CD24 expression was regulated by reactive oxygen species (ROS) and the nuclear factor (NF)-kappa B signaling pathways. While immunohistochemical analyses of DCIS showed heterogeneity, the expression of psoriasin and CD24 showed a similar staining pattern. Our findings suggest that the expression of psoriasin is linked to the luminal differentiation marker CD24 in mammary epithelial cells. Psoriasin demonstrated an essential role in the shift towards a more differentiated CD24(+) phenotype, supporting the hypothesis that psoriasin plays a role in the differentiation of luminal mammary epithelial cells.

Place, publisher, year, edition, pages
Public Library of Science , 2012. Vol. 7, no 12
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-88366DOI: 10.1371/journal.pone.0053119ISI: 000312829100122OAI: oai:DiVA.org:liu-88366DiVA: diva2:602877
Note

Funding Agencies|Ingrid Asp Foundation||Swedish Cancer Society||Swedish Psoriasis Association||Welander Foundation||

Available from: 2013-02-04 Created: 2013-02-04 Last updated: 2017-12-06
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)
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Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2015-01-19Bibliographically approved

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Petersson, StinaEnerbäck, Charlotta

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Department of Clinical and Experimental MedicineFaculty of Health SciencesDepartment of Dermatology and Venerology in ÖstergötlandCell Biology
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