HPV16 Down-Regulates the Insulin-Like Growth Factor Binding Protein 2 to Promote Epithelial Invasion in Organotypic Cultures |
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| Authors: | Adam Pickard Simon S. McDade Marie McFarland W. Glenn McCluggage Cosette M. Wheeler Dennis J. McCance |
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| Affiliation: | 1 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, United Kingdom, ; 2 Belfast Health and Social Care Trust, Belfast, United Kingdom, ; 3 Department of Pathology, School of Medicine, University of New Mexico, Albuquerque, New Mexico, United States of America, ; University of Wisconsin-Madison, UNITED STATES, |
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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. |
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