title: Induction of the members of Notch pathway in superficial basal cell carcinomas treated with imiquimod.
abstract: Basal cell carcinoma of the skin (BCC) is the most common skin tumor in Caucasians worldwide. Different therapeutic options are available to treat BCC, including topical immunotherapy. Imiquimod is topical Toll-like receptor 7 agonist that activates anti-tumor immune response and has been recently approved for the treatment of superficial BCC (sBCC). We sought to investigate the influence of imiquimod treatment on the members of the Notch signaling pathway, whose activity is known to be decreased in BCCs. Six patients with sBCC were evaluated for Notch1, Jagged1 and Delta1 expression before (pre-treatment) and after the beginning of the topical treatment (post-treatment) with imiquimod using real-time PCR and immunohistochemistry. We show selective transcriptional up-regulation of Notch pathway members (Notch1, Jagged1 and Delta1) in tumor cells of the sBCC post-treatment. Furthermore, we demonstrate minor increase of Notch1 protein expression on infiltrating cells as well as strong increase in Jagged1 protein expression in regressing sBCC tumors post-treatment. In this way, imiquimod may act as a stimulator of the Notch pathway in sBCC tumor cells by up-regulating protein expression of the Notch ligand, Jagged1. Via induction of Notch signaling imiquimod may exert tumor suppressor function, which together with its proinflammatory properties results in tumor regression.
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, Zurich, Switzerland.
authors.forename: Maja
authors.initials: M
authors.lastname: Wuest
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Mirjana
authors.initials: M
authors.lastname: Urosevic
mesh_terms: D000287:Administration, Topical; D000634:Aminoquinolines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D000077271:Imiquimod; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000187:drug effects / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; C064045:delta protein; D000077271:Imiquimod