Microarray analysis identifies differentiation-associated genes regulated by human papillomavirus type 16 E6

Department of Microbiology and Holden Cancer Center, University of Iowa, 2202 MEBRF, 375 Newton Road, Iowa City, IA 52242, USA.
Virology (Impact Factor: 3.32). 10/2003; 314(1):196-205. DOI: 10.1016/S0042-6822(03)00390-8
Source: PubMed


In this study, we used oligonucleotide microarray analysis to determine which cellular genes are regulated by the human papillomavirus type 16 (HPV-16) E6 oncoprotein. We found that E6 causes the downregulation of a large number of cellular genes involved in keratinocyte differentiation, including genes such as small proline-rich proteins, transglutaminase, involucrin, elafin, and cytokeratins, which are normally involved in the production of the cornified cell envelope. In contrast, E6 upregulates several genes, such as vimentin, that are usually expressed in mesenchymal lineages. E6 also modulates levels of genes involved in inflammation, including Cox-1 and Nag-1. By using E6 mutants that differentially target p53 for degradation, we determined that E6 regulates cellular genes by both p53-dependent and independent mechanisms. The microarray data also indicate that HPV-16 E6 modulates certain effects of HPV-16 E7 on cellular gene expression. The identification of E6-regulated genes in this analysis provides a basis for further studies on their role in HPV infection and cellular transformation.

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    • "Inflammation has been linked to HPV-associated cancers but it is unknown whether and/or how HPVs may trigger inflammation and/or whether inflammation may be tumor promoting or antitumorigenic in the context of an HPV infection. E6 and E7 each contribute to epithelial-to-mesenchymal transition (EMT), a key step in activating invasion and metastasis (Duffy et al., 2003; Hellner et al., 2009). Moreover, E7 has been reported to induce angiogenesis (Chen et al., 2007), and E6 and E7 also deregulate cellular energetics. "
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    • "The HPV-16 E6/E7 transformed HTECs represent an early stage of HPV-associated transformation and should exhibit alterations that are specific for HPV transformation and not individualized alterations that have been selected for in specific cancer cell lines. Previous microarray expression studies from our lab and others have demonstrated that HPV-16 E6/E7 expression causes changes in expression of a large number of cellular genes, including many that code for cell-surface proteins (and hence would be good targets for aptamers) (Duffy et al., 2003; Pyeon et al., 2007; Wan et al., 2008). To identify aptamers that specifically bind to and internalize into HPV-16 transformed head and neck epithelial cells, we utilized cell-SELEX with a complex RNA aptamer library with a 30 nucleotide variable sequence and an estimated starting complexity of greater than 10 18 . "
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    • "Changes in the vasculature to facilitate immune extravasation and angiogenesis require tissue remodelling of the extracellular matrix, a process facilitated by matrix metalloproteinase (MMP) [13]. Several studies have correlated HPV E6 and E7 transcription with MMP transcription [45, 46] and genes in cervical epithelial cells involved in tissue differentiation and remodelling [47]. In addition, transfection studies have shown that E7 oncoprotein forms a complex with and downregulates leukocyte elastase inhibitor [48]. "
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