title: S100A8/A9 stimulates keratinocyte proliferation in the development of squamous cell carcinoma of the skin via the receptor for advanced glycation-end products.
abstract: Squamous cell carcinoma (SCC) is the most common neoplasm in organ transplant recipients (OTR) on long-term immunosuppression and occurs 60- to 100-fold more frequently than in the general population. Here, we present the receptor for advanced glycation end products (RAGE) and S100A8/A9 as important factors driving normal and tumor keratinocyte proliferation. RAGE and S100A8/A9 were transcriptionally upregulated in SCC compared to normal epidermis, as well as in OTR compared to immunocompetent patients (IC) with SCC. The proliferation of normal and SCC keratinocytes was induced by exposure to exogenous S100A8/A9 which in turn was abolished by blocking of RAGE. The migratory activities of normal and SCC keratinocytes were also increased upon exposure to S100A8/A9. We demonstrated that exogenous S100A8/A9 induces phosphorylation of p38 and SAPK/JNK followed by activation of ERK1/2. We hypothesize that RAGE and S100A8/A9 contribute to the development of human SCC by modulating keratinocyte growth and migration. These processes do not seem to be impaired by profound drug-mediated immunosuppression in OTR.
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Guergana
authors: G
authors: Iotzova-Weiss
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Piotr J
authors: PJ
authors: Dziunycz
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Sandra N
authors: SN
authors: Freiberger
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Severin
authors: S
authors: Läuchli
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Jürg
authors: J
authors: Hafner
authors: Institute of Immunology, University Clinic Münster, Münster, Germany.
authors: Thomas
authors: T
authors: Vogl
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Lars E
authors: LE
authors: French
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Günther F L
authors: GF
authors: Hofbauer
mesh_terms: D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D010766:Phosphorylation; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: C000593871:AGER protein, human; D040501:Calgranulin A; D040502:Calgranulin B; D000067759:Receptor for Advanced Glycation End Products