title: Skin tumor formation in human papillomavirus 8 transgenic mice is associated with a deregulation of oncogenic miRNAs and their tumor suppressive targets.
abstract: BACKGROUND
  Dysregulation of microRNA (miRNA) expression is regularly found in various types of cancer and contributes to tumorigenic processes. However, little is known about miRNA expression in non-melanoma skin cancer in which a pathogenic role of beta human papillomaviruses (HPV) is discussed. A carcinogenic potential of beta HPV8 could be demonstrated in a transgenic mouse model, expressing all early genes of HPV8 (HPV8-CER). A single UVA/B-dose induced oncogene expression and led to papilloma growth within three weeks.
  
  
  OBJECTIVE
  Expression of miRNAs and their targets during HPV8-mediated tumor formation in mice.
  
  
  METHODS
  Skin of untreated or UV-irradiated wild-type and HPV8-CER mice was analyzed for miRNA expression and localization by qPCR and in situ hybridization. MiRNA target protein expression was analyzed by immunohistochemical staining.
  
  
  RESULTS
  Early steps in skin tumor formation in HPV8-CER mice were associated with an upregulation of the oncogenic miRNA-17-5p, -21 and -106a and a downregulation of the tumor-suppressive miRNA-155 and -206, which could be demonstrated by qPCR and in situ hybridization. The respective targets of miRNA-21 and -106a, the tumor suppressors PTEN, PDCD4 and Rb with their pivotal role in cell cycle regulation, apoptosis and proliferation were found to be downregulated.
  
  
  CONCLUSIONS
  This is the first report demonstrating that a cutaneous HPV type deregulates the expression of miRNAs. These deregulations are closely related to the UV-induced upregulation of HPV8 oncogene levels, which suggest a direct or indirect HPV8-specific effect on miRNA expression. These data presume that HPV8 interferes with the miRNA mediated gene regulation to induce tumorigenesis.
authors.affiliation: Institute of Virology, University of Cologne, Fürst-Pückler-Str. 56, 50935 Cologne, Germany. Martin@Hufbauer.de
authors.forename: Martin
authors.initials: M
authors.lastname: Hufbauer
authors.forename: Daliborka
authors.initials: D
authors.lastname: Lazić
authors.forename: Markus
authors.initials: M
authors.lastname: Reinartz
authors.forename: Baki
authors.initials: B
authors.lastname: Akgül
authors.forename: Herbert
authors.initials: H
authors.lastname: Pfister
authors.forename: Sönke Jan
authors.initials: SJ
authors.lastname: Weissenborn
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D016147:Genes, Tumor Suppressor; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000821:virology*
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; C543896:Mirn106 microRNA, mouse