Intratype variants of the E2 protein from human papillomavirus type 18 induce different gene expression profiles associated with apoptosis and cell proliferation
- 17 Downloads
Persistent infections with high-risk human papillomaviruses (HR-HPVs) are linked to development of cervical cancer due to a deregulation of the productive viral cycle in the host cell, leading to cell transformation. The E2 viral protein is expressed early during an HPV infection and regulates viral replication and transcription. Other functions have been attributed to E2, such as the promotion of apoptosis that are independent of its role in the regulation of the expression of E6 and E7 viral oncogenes. Moreover, it has been shown that the HPV16 E2 protein has regulatory effects on cellular gene expression, suggesting that it participates in the modulation of different cellular processes. Intratype genomic variations within high-risk HPV types have an impact on the prognosis of HPV-related lesions. Nevertheless, the biological significance of HPV18 E2 intratype variations has not been analysed previously. The aim of this study was to determine whether HPV18 E2 intratype variations differentially modulate gene expression and whether cell-death-related genes are affected by variations in E2. We demonstrate that HPV18 E2 intratype Asian Amerindian (AsAi) and African (Af) variants differentially affect gene expression profiles. Although the E2-AsAi variant was found to modulate a larger number of cellular genes, both E2 variants affected similar cellular processes. Nevertheless, E2-AsAi and E2-Af variants showed differences in their ability to induce apoptosis, where E2-Af had a stronger effect. The differences in gene expression profiles in cells harbouring E2 intratype variants suggest a possible effect on diverse cellular signalling pathways, and this might suggest an approach for identifying biological processes regulated by HPV18 E2 intratype variants.
Dulbecco´s modified Eagle´s medium
Quantitative reverse transcription PCR
- ΔΔ Ct
Double delta Ct
Alma Mariana Fuentes González is a Ph.D. student from Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM) and received a scholarship from CONACyT (268404). We thank María Alexandra Rodríguez-Sastre and Patricia de la Torre from Instituto de Investigaciones Biomédicas, UNAM for technical assistance.
All of the authors listed made substantial contributions to the manuscript and qualify for authorship, and no authors have been omitted. Conception and design, ML; development of methodology and acquisition of data, AMFG, JOMB, JFR and JMM; analysis and interpretation of data, AMFG, JMM, JOMB, ML, APT, CPP; writing and revision of the manuscript, AMFG, JMM, ML, JOMB and ACP. All the authors read and approved the final manuscript.
This work was partially supported by CONACYT México grant CB-166808 and INCan Ref. 005/017/IBI.
Compliance with ethical standards
Conflict of interest
There are no commercial or financial conflicts of interest to declare.
- 4.Burk RD, Terai M, Gravitt PE et al (2003) Distribution of human papillomavirus types 16 and 18 Variants in squamous cell carcinomas and adenocarcinomas of the cervix. Cancer Res 63:7215–7220Google Scholar
- 8.Contreras-Paredes A, De la Cruz-Hernández E, Martínez-Ramírez I et al (2009) E6 variants of human papillomavirus 18 differentially modulate the protein kinase B/phosphatidylinositol 3-kinase (akt/PI3K) signaling pathway. Virology 383:78–85. https://doi.org/10.1016/j.virol.2008.09.040 CrossRefGoogle Scholar
- 11.Wu E-Q, Tang Y-Y (2014) Research progress in roles of high-risk human papillomavirus E2 protein. Chin J Virol 30:201–207Google Scholar
- 31.Bellanger S, Tan CL, Xue YZ et al (2011) Tumor suppressor or oncogene? A critical role of the human papillomavirus (HPV) E2 protein in cervical cancer progression. Am J Cancer Res 1:373–389Google Scholar
- 37.Zhang L, Yang B, Zhang A et al (2016) Association between human papillomavirus type 16 E6 and E7 variants with subsequent persistent infection and recurrence of cervical high-grade squamous intraepithelial lesion after conization. J Med Virol 88:1982–1988. https://doi.org/10.1002/jmv.24541 CrossRefGoogle Scholar
- 38.Zhang L, Liao H, Yang B et al (2015) Variants of human papillomavirus type 16 predispose toward persistent infection. Int J Clin Exp Pathol 8:8453–8459Google Scholar
- 39.Hochmann J, Sobrinho JS, Villa LL, Sichero L (2016) The Asian-American variant of human papillomavirus type 16 exhibits higher activation of MAPK and PI3K/AKT signaling pathways, transformation, migration and invasion of primary human keratinocytes. Virology 492:145–154. https://doi.org/10.1016/j.virol.2016.02.015 CrossRefGoogle Scholar
- 46.Crook T, Wrede D, Vousden KH (1991) p53 point mutation in HPV negative human cervical carcinoma cell lines. Oncogene 6:873–875Google Scholar
- 47.Kazemi S, Papadopoulou S, Li S et al (2004) Control of subunit of eukaryotic translation initiation factor 2 (eIF2) Phosphorylation by the human papillomavirus type 18 E6 oncoprotein: implications for eIF2-dependent gene expression and cell death. Mol Cell Biol 24:3415–3429. https://doi.org/10.1128/MCB.24.8.3415-3429.2004 CrossRefGoogle Scholar
- 58.Alsamman K, El-Masry OS (2018) Interferon regulatory factor 1 inactivation in human cancer. Biosci Rep 38:BSR20171672. https://doi.org/10.1042/bsr20171672