IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells

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 li...

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Autores principales:	Isabelle Ariane Bley, Anabel Zwick, Muriel Charlotte Hans, Katrin Thieser, Viktoria Wagner, Nicole Ludwig, Oybek Khalmurzaev, Vsevolod Borisovich Matveev, Philine Loertzer, Alexey Pryalukhin, Arndt Hartmann, Carol-Immanuel Geppert, Hagen Loertzer, Heiko Wunderlich, Carsten Maik Naumann, Holger Kalthoff, Kerstin Junker, Sigrun Smola, Stefan Lohse
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	β-catenin Dickkopf1 HPV Penile cancer Wnt pathway Stemness Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/87a28aa8aacd4a919e9d6017b6163a14
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spelling	oai:doaj.org-article:87a28aa8aacd4a919e9d6017b6163a142021-11-12T04:29:52ZIDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells1936-523310.1016/j.tranon.2021.101267https://doaj.org/article/87a28aa8aacd4a919e9d6017b6163a142022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1936523321002588https://doaj.org/toc/1936-5233Penile 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.Isabelle Ariane BleyAnabel ZwickMuriel Charlotte HansKatrin ThieserViktoria WagnerNicole LudwigOybek KhalmurzaevVsevolod Borisovich MatveevPhiline LoertzerAlexey PryalukhinArndt HartmannCarol-Immanuel GeppertHagen LoertzerHeiko WunderlichCarsten Maik NaumannHolger KalthoffKerstin JunkerSigrun SmolaStefan LohseElsevierarticleβ-cateninDickkopf1HPVPenile cancerWnt pathwayStemnessNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENTranslational Oncology, Vol 15, Iss 1, Pp 101267- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	β-catenin Dickkopf1 HPV Penile cancer Wnt pathway Stemness Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	β-catenin Dickkopf1 HPV Penile cancer Wnt pathway Stemness Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Isabelle Ariane Bley Anabel Zwick Muriel Charlotte Hans Katrin Thieser Viktoria Wagner Nicole Ludwig Oybek Khalmurzaev Vsevolod Borisovich Matveev Philine Loertzer Alexey Pryalukhin Arndt Hartmann Carol-Immanuel Geppert Hagen Loertzer Heiko Wunderlich Carsten Maik Naumann Holger Kalthoff Kerstin Junker Sigrun Smola Stefan Lohse IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells
description	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.
format	article
author	Isabelle Ariane Bley Anabel Zwick Muriel Charlotte Hans Katrin Thieser Viktoria Wagner Nicole Ludwig Oybek Khalmurzaev Vsevolod Borisovich Matveev Philine Loertzer Alexey Pryalukhin Arndt Hartmann Carol-Immanuel Geppert Hagen Loertzer Heiko Wunderlich Carsten Maik Naumann Holger Kalthoff Kerstin Junker Sigrun Smola Stefan Lohse
author_facet	Isabelle Ariane Bley Anabel Zwick Muriel Charlotte Hans Katrin Thieser Viktoria Wagner Nicole Ludwig Oybek Khalmurzaev Vsevolod Borisovich Matveev Philine Loertzer Alexey Pryalukhin Arndt Hartmann Carol-Immanuel Geppert Hagen Loertzer Heiko Wunderlich Carsten Maik Naumann Holger Kalthoff Kerstin Junker Sigrun Smola Stefan Lohse
author_sort	Isabelle Ariane Bley
title	IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells
title_short	IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells
title_full	IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells
title_fullStr	IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells
title_full_unstemmed	IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells
title_sort	idkk1 inhibits canonical wnt signaling in human papillomavirus-positive penile cancer cells
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/87a28aa8aacd4a919e9d6017b6163a14
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IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells

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