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- Vegfors, Jenny, 1984-
(författare)
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Psoriasin For Better or for Worse in Sickness and in Health : The Role of Psoriasin in Angiogenesis and Differentation of Epithelial Cells
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Vegfors, Jenny, et al.
(författare)
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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
- 2014
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 3. |
- Vegfors, Jenny, et al.
(författare)
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Psoriasin (S100A7) is regulated by protein kinase C (PKC) and contributes to keratinocyte differentiation by regulating the expression of epidermal differentiation markers
- 2014
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Psoriasis is a chronic inflammatory skin disease that is characterized by hyperproliferation and a disturbed maturation of the epidermal cells. The differentiation process of keratinocytes in active psoriatic lesions differs from that of normal epidermis, denoted by an altered expression of differentiation markers. Psoriasin, a protein which is highly expressed in psoriasis, is located within the epidermal differentiation complex (EDC), a gene cluster that contains several genes that are important in the terminal differentiation of the human epidermis. The potential role of psoriasin in keratinocyte differentiation remain however unclear. The aim of this present study was to investigate the possible involvement of psoriasin in keratinocyte differentiation. We demonstrated, by immunohistochemical staining, a gradient of psoriasin expression in the psoriatic epidermis, from an undefined or weak expression in the basal layer to an intense expression in the suprabasal differentiated layers. The expression of psoriasin was up-regulated in cultured keratinocytes in response to stimuli known to induce differentiation, such as an elevation of extracellular calcium or 12-Otetradecanoylphorbol-13-acetate (TPA). Down-regulation of psoriasin expression, by siRNA, resulted in decreased expression of the differentiation markers involucrin, desmoglein 1, transglutaminase 1 and CD24. Inhibition of protein kinase C (PKC) counteracted the calciuminduced expression of psoriasin and involucrin. In summary, our data demonstrate that psoriasin is regulated by the PKC signaling pathway and contributes to keratinocyte differentiation by the regulation of differentiation markers.
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