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Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation
Sahlgrenska University Hospital, Gothenburg, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences.
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2012 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 134, no 1, 71-80 p.Article in journal (Refereed) Published
Abstract [en]

Psoriasin (S100A7), originally identified in psoriasis, is a calcium-binding protein belonging to the multigenic S100 family. In high-grade ductal carcinoma in situ, psoriasin was identified as one of the most abundant transcripts. We have previously shown that psoriasin was induced by reactive oxygen species (ROS). Moreover, the downregulation of psoriasin by short hairpin RNA (shRNA) led to the reduced expression of vascular endothelial growth factor (VEGF) and inhibited tumor growth in vivo. The aim of the present study was to investigate whether psoriasin could have direct effects on endothelial cells. In this study we demonstrated that psoriasin increased VEGF expression in mammary epithelial cells. The treatment of endothelial cells with recombinant psoriasin increased proliferation comparable to that of recombinant VEGF protein. No change in proliferation was seen when endothelial cells were infected with psoriasin-expressing adenoviruses, suggesting that the proliferative effect of psoriasin was mediated by a specific receptor. Treatment with sRAGE, targeting the receptor for advanced glycation end products (RAGE), thus inhibited endothelial cell proliferation and tube formation enhanced by recombinant psoriasin. We showed that VEGF expression was not induced by hydrogen peroxide, when psoriasin was silenced by shRNA, which led to the hypothesis that psoriasin induces ROS. Indeed, psoriasin was shown to induce ROS in both endothelial and epithelial cells. Moreover, sRAGE inhibited the psoriasin-dependent generation of ROS in endothelial cells. Finally, treatment with antioxidant Bcl-2 protein abolished the effect of psoriasin on endothelial cell proliferation. Our data suggest that psoriasin expression in mammary epithelial cells leads to increased endothelial cell proliferation in a paracrine manner through RAGE. Psoriasin may therefore play a role in breast cancer progression by promoting oxidative stress response and angiogenesis.

Place, publisher, year, edition, pages
2012. Vol. 134, no 1, 71-80 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-76132DOI: 10.1007/s10549-011-1920-5PubMedID: 22189627Scopus ID: 000306437500008OAI: oai:DiVA.org:liu-76132DiVA: diva2:512561
Note

funding agencies|Swedish Cancer Society||Swedish Psoriasis Association||Assar Gabrielsson Foundation||Welander Foundation||Tore Nilsson Foundation||

Available from: 2012-03-28 Created: 2012-03-28 Last updated: 2017-12-07
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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Vegfors, JennyCarlström, MariaPetersson, StinaEnerbäck, Charlotta

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Cell BiologyDermatology and VenerologyFaculty of Health SciencesDepartment of Dermatology and Venerology in Östergötland
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