DKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells

作者：Isabelle Ariane Bley, Anabel Zwick, Muriel Charlotte Hans, Katrin Thieser, Viktoria Wagner, Nicole Ludwig, Oybek A. Khalmurzaev, Vsevolod Borisovich Matveev, Philine Loertzer, Alexey E. Pryalukhin, Arndt Hartmann, Carol‐Immanuel Geppert, Hagen Loertzer, Heiko Wunderlich, Carsten Maik Naumann, Holger Kalthoff, Kerstin Junker, Sigrun Smola, Stefan Lohse · 发表于：Translational Oncology · 年份：2021 · DOI：10.1016/j.tranon.2021.101267 · 被引用次数：25 · 研究领域：Genital Health and Disease、Wnt/β-catenin signaling in development and cancer、Cancer-related gene regulation

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...