In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis
- 12 May 2010
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (10), 4081-4091
- https://doi.org/10.1158/0008-5472.can-09-3335
Abstract
An important event in the development of cervical squamous cell carcinoma (SCC) is deregulated expression of high-risk human papillomavirus (HR-HPV) oncogenes, most commonly related to viral integration into host DNA. Mechanisms of development of the ∼15% of SCCs that contain extrachromosomal (episomal) HR-HPV are poorly understood due to limited longitudinal data. We therefore used the W12 model to study mechanisms of cervical carcinogenesis associated with episomal HPV16. In vitro progression of W12 normally occurs through selection of cells containing integrated HPV16. However, in one long-term culture, keratinocytes developed a selective growth advantage and invasive phenotype while retaining HPV16 episomes at increased copy number in the absence of transcriptionally active integrants. Longitudinal investigations revealed similarities between the episome- and integrant-associated routes of neoplastic progression. Most notable were dynamic changes in viral early gene expression in episome-retaining cells, consistent with continually changing selective pressures. An early increase in viral transcription preceded elevated episome copy number and was followed by a reduction to near baseline after the development of invasiveness. Episomal transcriptional deregulation did not require selection of a specific sequence variant of the HPV16 upstream regulatory region, although increased levels of acetylated histone H4 around the late promoter implicated a role for altered chromatin structure. Interestingly, invasive episome-retaining cells showed high levels of HPV16 E2/E6 proteins (despite decreased transcript levels) and reduced expression of IFN-stimulated genes, adaptations that support viral persistence and cell survival. Our findings suggest a unified working model for events important in cervical neoplastic progression regardless of HR-HPV physical state. Cancer Res; 70(10); 4081–91. ©2010 AACR.Other Versions
This publication has 57 references indexed in Scilit:
- Upstream Regulatory Region Alterations Found in Human Papillomavirus Type 16 (HPV-16) Isolates from Cervical Carcinomas Increase Transcription, ori Function, and HPV Immortalization Capacity in CultureJournal of Virology, 2009
- The E8 ∧ E2 Gene Product of Human Papillomavirus Type 16 Represses Early Transcription and Replication but Is Dispensable for Viral Plasmid Persistence in KeratinocytesJournal of Virology, 2008
- Regulation of human papillomavirus type 31 gene expression during the differentiation-dependent life cycle through histone modifications and transcription factor bindingVirology, 2008
- Type-Dependent Integration Frequency of Human Papillomavirus Genomes in Cervical LesionsCancer Research, 2008
- Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcriptsOncogene, 2007
- Effects of Histone Deacetylase Inhibitor (HDACi); Trichostatin-A (TSA) on the expression of housekeeping genesMolecular and Cellular Probes, 2006
- Clonal Selection for Transcriptionally Active Viral Oncogenes during Progression to CancerJournal of Virology, 2004
- Long-Term Effect of Interferon on Keratinocytes That Maintain Human Papillomavirus Type 31Journal of Virology, 2002
- Differentiation-Dependent Chromatin Rearrangement Coincides with Activation of Human Papillomavirus Type 31 Late Gene ExpressionJournal of Virology, 2001
- The Interaction between Human Papillomavirus Type 16 El and E2 Proteins is Blocked by An Antibody to the N‐Terminal Region of E2JBIC Journal of Biological Inorganic Chemistry, 1995