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doi:10.22028/D291-37810
Titel: | DKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells |
VerfasserIn: | Bley, Isabelle Ariane Zwick, Anabel Hans, Muriel Charlotte Thieser, Katrin Wagner, Viktoria Ludwig, Nicole Khalmurzaev, Oybek Matveev, Vsevolod Borisovich Loertzer, Philine Pryalukhin, Alexey Hartmann, Arndt Geppert, Carol-Immanuel Loertzer, Hagen Wunderlich, Heiko Naumann, Carsten Maik Kalthoff, Holger Junker, Kerstin Smola, Sigrun Lohse, Stefan |
Sprache: | Englisch |
Titel: | Translational Oncology |
Bandnummer: | 15 |
Heft: | 1 |
Verlag/Plattform: | Elsevier |
Erscheinungsjahr: | 2022 |
Freie Schlagwörter: | β-catenin Dickkopf1 HPV Penile cancer Wnt pathway Stemness |
DDC-Sachgruppe: | 610 Medizin, Gesundheit |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | Penile squamous cell cancer (PSCC) is the most frequent penile malignant disease. Infections with human papillomaviruses (HPV) are a major etiologic driver of PSCC. However, the molecular details of the underlying carcinogenesis are understudied because of rare clinical specimens and missing cell lines. Here, we investigated if the expression of high-risk HPV16 oncogenes causes an augmentation of the Wnt pathway using unique HPV-positive penile cancer (PeCa) cell lines in monolayer and organotypic 3D raft cultures as well as tissue micro arrays containing clinical tissue specimens. The HPV oncoproteins enhanced the expression of Leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) and the HPV-positive PeCa cells expressed a signature of Wnt target and stemness-associated genes. However, the notable lack of nuclear β-catenin in vitro and in situ raised the question if the enhanced expression of Wnt pathway factors is tantamount to an active Wnt signaling. Subsequent TOP-flash reporter assays revealed Wnt signaling as absent and not inducible by respective Wnt ligands in PeCa cell lines. The HPV-positive PeCa cells and especially HPV-positive PeCa specimens of the tumor core expressed the Wnt antagonist and negative feedback-regulator Dickkopf1 (DKK1). Subsequent neutralization experiments using PeCa cell line-conditioned media demonstrated that DKK1 is capable to impair ligand-induced Wnt signaling. While gene expression analyses suggested an augmented and active canonical Wnt pathway, the respective signaling was inhibited due to the endogenous expression of the antagonist DKK1. Subsequent TMA stainings indicated Dkk1 as linked with HPV-positivity and metastatic disease progression in PeCa suggesting potential as a prognostic marker. |
DOI der Erstveröffentlichung: | 10.1016/j.tranon.2021.101267 |
URL der Erstveröffentlichung: | https://www.sciencedirect.com/science/article/pii/S1936523321002588 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-378102 hdl:20.500.11880/34194 http://dx.doi.org/10.22028/D291-37810 |
ISSN: | 1936-5233 |
Datum des Eintrags: | 3-Nov-2022 |
Bezeichnung des in Beziehung stehenden Objekts: | Supplementary materials |
In Beziehung stehendes Objekt: | https://ars.els-cdn.com/content/image/1-s2.0-S1936523321002588-mmc1.docx |
Fakultät: | M - Medizinische Fakultät |
Fachrichtung: | M - Infektionsmedizin M - Urologie und Kinderurologie |
Professur: | M - Prof. Dr. Sigrun Smola M - Prof. Dr. Michael Stöckle M - Keiner Professur zugeordnet |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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1-s2.0-S1936523321002588-main.pdf | 24,3 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons