HPV16 Down-Regulates the Insulin-Like Growth Factor Binding Protein 2 to Promote Epithelial Invasion in Organotypic Cultures

Adam Pickard*, Simon S. McDade, Marie McFarland, W. Glenn McCluggage, Cosette M. Wheeler, Dennis J. McCance

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

Cervical cancer is a multi-stage disease caused by human papillomaviruses (HPV) infection of cervical epithelial cells, but the mechanisms regulating disease progression are not clearly defined. Using 3-dimensional organotypic cultures, we demonstrate that HPV16 E6 and E7 proteins alter the secretome of primary human keratinocytes resulting in local epithelial invasion. Mechanistically, absence of the IGF-binding protein 2 (IGFBP2) caused increases in IGFI/II signalling and through crosstalk with KGF/FGFR2b/AKT, cell invasion. Repression of IGFBP2 is mediated by histone deacetylation at the IGFBP2 promoter and was reversed by treatment with histone deacetylase (HDAC) inhibitors. Our in vitro findings were confirmed in 50 invasive cancers and 79 cervical intra-epithelial neoplastic lesions caused by HPV16 infection, where IGFBP2 levels were reduced with increasing disease severity. In summary, the loss of IGFBP2 is associated with progression of premalignant disease, and sensitises cells to pro-invasive IGF signalling, and together with stromal derived factors promotes epithelial invasion.

Original languageEnglish
Article number1004988
Number of pages23
JournalPLoS Pathogens
Volume11
Issue number6
DOIs
Publication statusPublished - Jun 2015

Keywords

  • HUMAN-PAPILLOMAVIRUS TYPE-16
  • UTERINE CERVICAL-CANCER
  • GENE-EXPRESSION
  • BREAST-CANCER
  • HUMAN KERATINOCYTES
  • NATURAL-HISTORY
  • RETINOBLASTOMA PROTEIN
  • PROSTATE-CANCER
  • E7 ONCOPROTEIN
  • MESSENGER-RNA

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