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

Article (PDF Available)inVirology 314(1):196-205 · October 2003with15 Reads
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.
    • "Several studies have correlated transcription of HPV E6 and E7 with transcription of MMP's [9,88,89], suggesting that HPV oncogenes can drive tissue remodelling. Indeed, microarray analysis supports these observations as HPV E6 and E7 oncoproteins have been 13 shown to regulate several genes involved in tissue differentiation and remodelling, including genes involved in angiogenesis [90], inflammation, apoptosis and tumour progression [9,91,92]. Many of the cellular and molecular changes associated with EMT in cervical cancer cells are regulated by HPV oncogenes [9,93,94]. "
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    • "Both in vitro and in vivo studies show that the functions of high-risk E6 and E7, of being necessary for the induction and maintenance of the transformed phenotype of cervical cancer cells by hijacking cellular pathways. The transforming properties of E6 and E7 proteins result, in part, from their ability to modulate many host proteins that regulate cell growth and differentiation (Burk, Chen, & Van Doorslaer, 2009; Duffy, Phillips, & Klingelhutz, 2003; Munger & Phelps, 1993). The E6 and E7 proteins of HPV16 and HPV18 are associated with cervical cancer. "
    [Show abstract] [Hide abstract] ABSTRACT: Cervical cancer is a malignant neoplasm of the cervix uteri that starts in the cervix and is the second most common type of cancer in women worldwide. Human papillomavirus (HPV) is the primary causal agent of cervical cancer. Among high-risk strains, HPV 16 is the most closely associated with cervical carcinoma. The two early proteins of HPV 16, E6 and E7, play a significant role in tumor formation. The proteins E6 and E7 are involved in cellular transformation. The transforming properties of E6 and E7 proteins result, in part, from their ability to modulate many host proteins that regulate cell growth and differentiation. The present study was carried out to identify novel putative drugs, which bind with both E6 and E7 proteins of HPV which causes the cervical cancer. The drug targets E6 and E7 were carefully chosen from literature and the 3D structure was modeled by ab initio method. The natural product library was constructed from various databases and literature to find the most suitable putative drug. All the ligands were docked using Molegro Virtual Docker and the lead molecules were investigated for ADME and toxicity.
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    • "In a previous study, we showed that HPV 16 E6 downregulates the activity of the human IVL pro- moter [21]. In this study, we went on to see the effects of HPV 16 oncogenes on the transcriptional activities of further differentiation-associated genes (DSC1, KRT4, S100A8 and SPRR1A), which were shown to have reduced expression by the HPV oncoproteins in this study and also in previous reports17181920. We found that the promoters of each of these genes were usually downregulated by the HPV oncogenes. "
    [Show abstract] [Hide abstract] ABSTRACT: The life cycle of human papillomaviruses (HPVs) is strictly linked to the differentiation of their natural host cells. The HPV E6 and E7 oncoproteins can delay the normal differentiation program of keratinocytes; however, the exact mechanisms responsible for this have not yet been identified. The goal of this study was to investigate the effects of HPV16 oncoproteins on the expression of genes involved in keratinocyte differentiation. Primary human keratinocytes transduced by LXSN (control) retroviruses or virus vectors expressing HPV16 E6, E7 or E6/E7 genes were subjected to gene expression profiling. The results of microarray analysis showed that HPV 16 E6 and E7 have the capacity to downregulate the expression of several genes involved in keratinocyte differentiation. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to confirm the microarray data. To investigate the effects of the HPV oncoproteins on the promoters of selected keratinocyte differentiation genes, luciferase reporter assays were performed. Our results suggest that the HPV 16 E6 and/or E7 oncogenes are able to downregulate the expression of several genes involved in keratinocyte differentiation (such as desmocollin 1, keratin 4, S100 calcium-binding protein A8 and small proline-rich protein 1A), at least partially by downregulating their promoter activity. This activity of the HPV oncoproteins may have a role in the productive virus life cycle, and also in virus-induced carcinogenesis.
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