Transcriptional regulation of genes involved in keratinocyte differentiation by human papillomavirus 16 oncoproteins

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. Electronic supplementary materialThe online version of this article

The human papillomavirus E7 oncoprotein as a regulator of transcription

“…Through its regulation of the E2F/pocket protein system, E7 can regulate a large set of promoters (Nees, Geoghegan et al 2000; Johung, Goodwin et al 2007; Gyongyosi, Szalmas et al 2014; Zhou, Zhang et al 2016). Here are two examples for the purposes of illustration.…”

“…E7 binds (via the C terminus) to AP-1 proteins including c-Jun, JunB, JunD and c-Fos and activates c-Jun (Antinore, Birrer et al 1996). On the other hand, E7 can also inhibit the activity of AP-1, perhaps contributing to suppression of differentiation-related genes by E7 (Gyongyosi, Szalmas et al 2014). …”

“…Moreover, the genes regulated by each protein when expressed alone may be different from those regulated by the two working together. Over the years, many genome-wide studies have investigated the host gene expression patterns in cells containing E7, either alone or in combination with E6, in a variety of model systems (Chang and Laimins 2000; Nees, Geoghegan et al 2000; Nees, Geoghegan et al 2001; Garner-Hamrick, Fostel et al 2004; Johung, Goodwin et al 2007; Lu, Wright et al 2007; Cortes-Malagon, Bonilla-Delgado et al 2013; Gyongyosi, Szalmas et al 2014; Zhou, Zhang et al 2016). Cell cycle-related genes have consistently been found to be activated by E7, including not only genes activated at G1, but also G2/M phase genes (Nees, Geoghegan et al 2000; Garner-Hamrick, Fostel et al 2004; Johung, Goodwin et al 2007; Zhou, Zhang et al 2016).…”

“…Cell cycle-related genes have consistently been found to be activated by E7, including not only genes activated at G1, but also G2/M phase genes (Nees, Geoghegan et al 2000; Garner-Hamrick, Fostel et al 2004; Johung, Goodwin et al 2007; Zhou, Zhang et al 2016). In addition, differentiation-related genes (Nees, Geoghegan et al 2000; Johung, Goodwin et al 2007; Gyongyosi, Szalmas et al 2014), innate immune response genes (Chang and Laimins 2000; Nees, Geoghegan et al 2001; Cortes-Malagon, Bonilla-Delgado et al 2013; Zhou, Zhang et al 2016), DNA damage and stress response genes (Zhou, Zhang et al 2016), and growth factors (Nees, Geoghegan et al 2000) have appeared repeatedly. In studies that take differentiation into account, E7 has been found to have a more profound effect in differentiating cells than in undifferentiated cells (Nees, Geoghegan et al 2001; Vazquez-Ortiz, Garcia et al 2007).…”

Long Noncoding RNAs in HPV-Induced Oncogenesis

“…91 On the other hand, SncmtRNA-1 correlation with cell proliferation suggests a function for this transcript in cell cycle progression. 87,88 Besides that, a diversity of works have performed gene expression microarray 92,93 to compare transcriptome alteration upon HPV infection and/or activity, providing candidate's list of HPV-modulated lncRNAs. By analyzing these works, it is noticeable that some lncRNAs are differentially expressed according to HPV status, an indication that they may contribute to oncogenesis.…”