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

Bley IA, Zwick A, Hans MC, Thieser K, Wagner V, Ludwig N, Khalmurzaev O, Matveev VB, Loertzer P, Pryalukhin A, Hartmann A, Geppert CI, Loertzer H, Wunderlich H, Naumann CM, Kalthoff H, Junker K, Smola S, Lohse S (2022)

Publication Type: Journal article, Review article

Publication year: 2022

Journal

Translational Oncology Neoplasia Press

Book Volume: 15

Article Number: 101267

Journal Issue: 1

DOI: 10.1016/j.tranon.2021.101267

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.

Authors with CRIS profile

Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Carol-Immanuel Geppert Institute of Pathology

Involved external institutions

Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Universität des Saarlandes (UdS) DE Germany (DE) N.N. Blokhin Russian Cancer Research Center / Российский онкологический научный центр им. Н. Н. Блохина RU Russian Federation (RU) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Westpfalz-Klinikum DE Germany (DE) St. Georg Klinikum Eisenach gemeinnützige GmbH DE Germany (DE)

How to cite

APA:

Bley, I.A., Zwick, A., Hans, M.C., Thieser, K., Wagner, V., Ludwig, N.,... Lohse, S. (2022). IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells. Translational Oncology, 15(1). https://dx.doi.org/10.1016/j.tranon.2021.101267

MLA:

Bley, Isabelle Ariane, et al. "IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells." Translational Oncology 15.1 (2022).

BibTeX: Download