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

ABSTRACT 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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    ABSTRACT: Approximately 12% of all human cancers are caused by oncoviruses. Human viral oncogenesis is complex, and only a small percentage of the infected individuals develop cancer, often many years to decades after the initial infection. This reflects the multistep nature of viral oncogenesis, host genetic variability, and the fact that viruses contribute to only a portion of the oncogenic events. In this review, the Hallmarks of Cancer framework of Hanahan and Weinberg (2000 and 2011) is used to dissect the viral, host, and environmental cofactors that contribute to the biology of multistep oncogenesis mediated by established human oncoviruses. The viruses discussed include Epstein-Barr virus (EBV), high-risk human papillomaviruses (HPVs), hepatitis B and C viruses (HBV and HCV, respectively), human T cell lymphotropic virus-1 (HTLV-1), and Kaposi's sarcoma herpesvirus (KSHV).
    Cell host & microbe 03/2014; 15(3):266-282. DOI:10.1016/j.chom.2014.02.011 · 12.33 Impact Factor
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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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    ABSTRACT: Human papillomavirus type 16 (HPV-16) associated oropharyngeal cancers are on a significant increase and better therapeutic strategies are needed. The HPV-16 oncogenes E6 and E7 are expressed in HPV-associated cancers and are able to transform human tonsillar epithelial cells (HTECs). We used cell-Systematic Evolution of Ligands by Exponential Enrichment (SELEX) to select for RNA aptamers that entered into HPV-16 E6/E7-HTECs. After 12 rounds of cell-SELEX, a pool of aptamers was obtained that had significantly greater internalization capacity (~5-fold) into E6/E7-HTECs as compared to primary HTECs or fibroblasts. Analysis of individual aptamers from the pool indicated variable internalization into E6/E7-HTECs (1-8-fold as compared to a negative control). Most of the individual aptamers internalized into E6/E7 and primary HTECs with similar efficiency, while one aptamer exhibited ~3-fold better internalization into E6/E7-HTECs. Aptamers that internalize into cells may be useful for delivering therapeutic agents to HPV-16 associated malignancies.
    Virology 11/2013; 446(1-2):325-33. DOI:10.1016/j.virol.2013.08.015 · 3.32 Impact Factor
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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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    ABSTRACT: Cervical cancer is one of the leading gynaecological malignancies worldwide. It is an infectious disease of the cervix, associated with human papillomavirus infection (HPV), infection with bacterial agents such as Chlamydia trachomatis and Neisseria gonorrhoea as well as human immunodeficiency virus (HIV). Furthermore, it is an AIDS-defining disease with an accelerated mortality in HIV-infected women with cervical cancer. With the introduction of robust vaccination strategies against HPV in the developed world, it is anticipated that the incidence of cervical cancer will decrease in the coming years. However, vaccination has limited benefit for women already infected with high-risk HPV, and alternative therapeutic intervention strategies are needed for these women. Many pathological disorders, including cervical cancer, are characterised by the exacerbated activation and maintenance of inflammatory pathways which are considered to be regulated by infectious agents. In cervical cancer, hyperactivation of these inflammatory pathways and regulation of immune infiltrate into tissues can potentially play a role not only in tumorigenesis but also in HIV infection. In this paper we will discuss the contribution of inflammatory pathways to cervical cancer progression and HIV infection and the role of HIV in cervical cancer progression.
    05/2012; 2012:548150. DOI:10.6064/2012/548150
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