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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

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