In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis

摘要: An important event in the development of cervical squamous cell carcinoma (SCC) is deregulated expression high-risk human papillomavirus (HR-HPV) oncogenes, most commonly related to viral integration into host DNA. Mechanisms ∼15% SCCs that contain extrachromosomal (episomal) HR-HPV are poorly understood due limited longitudinal data. We therefore used W12 model study mechanisms carcinogenesis associated with episomal HPV16. In vitro progression normally occurs through selection cells containing integrated However, one long-term culture, keratinocytes developed a selective growth advantage and invasive phenotype while retaining HPV16 episomes at increased copy number absence transcriptionally active integrants. Longitudinal investigations revealed similarities between episome- integrant-associated routes neoplastic progression. Most notable were dynamic changes early gene episome-retaining cells, consistent continually changing pressures. increase transcription preceded elevated episome was followed by reduction near baseline after invasiveness. Episomal transcriptional deregulation did not require specific sequence variant upstream regulatory region, although levels acetylated histone H4 around late promoter implicated role for altered chromatin structure. Interestingly, showed high E2/E6 proteins (despite decreased transcript levels) reduced IFN-stimulated genes, adaptations support persistence survival. Our findings suggest unified working events regardless physical state. Cancer Res; 70(10); 4081–91. ©2010 AACR.