title: PAX2 regulates ADAM10 expression and mediates anchorage-independent cell growth of melanoma cells.
abstract: PAX transcription factors play an important role during development and carcinogenesis. In this study, we investigated PAX2 protein levels in melanocytes and melanoma cells by Western Blot and immunofluorescence analysis and characterized the role of PAX2 in the pathogenesis of melanoma. In vitro we found weak PAX2 protein expression in keratinocytes and melanocytes. Compared to melanocytes increased PAX2 protein levels were detectable in melanoma cell lines. Interestingly, in tissue sections of melanoma patients nuclear PAX2 expression strongly correlated with nuclear atypia and the degree of prominent nucleoli, indicating an association of PAX2 with a more atypical cellular phenotype. In addition, with chromatin immunoprecipitation assay, PAX2 overexpression and PAX2 siRNA we present compelling evidence that PAX2 can regulate ADAM10 expression, a metalloproteinase known to play important roles in melanoma metastasis. In human tissue samples we found co-expression of PAX2 and ADAM10 in melanocytes of benign nevi and in melanoma cells of patients with malignant melanoma. Importantly, the downregulation of PAX2 by specific siRNA inhibited the anchorage independent cell growth and decreased the migratory and invasive capacity of melanoma cells. Furthermore, the downregulation of PAX2 abrogated the chemoresistance of melanoma cells against cisplatin, indicating that PAX2 expression mediates cell survival and plays important roles during melanoma progression.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Sophia Boyoung
authors.initials: SB
authors.lastname: Lee
authors.forename: Kai
authors.initials: K
authors.lastname: Doberstein
authors.forename: Peter
authors.initials: P
authors.lastname: Baumgarten
authors.forename: Anja
authors.initials: A
authors.lastname: Wieland
authors.forename: Christopher
authors.initials: C
authors.lastname: Ungerer
authors.forename: Claudia
authors.initials: C
authors.lastname: Bürger
authors.forename: Katja
authors.initials: K
authors.lastname: Hardt
authors.forename: Wolf-Henning
authors.initials: WH
authors.lastname: Boehncke
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Daniela
authors.initials: D
authors.lastname: Mihic-Probst
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Paul
authors.initials: P
authors.lastname: Gutwein
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009506:Nevus / Q000378:metabolism / Q000473:pathology; D051762:PAX2 Transcription Factor / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D008565:Membrane Proteins; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; D034741:RNA, Small Interfering; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D002945:Cisplatin