Influence of chromosomal integration on glucocorticoid-regulated transcription of growth-stimulating papillomavirus genes E6 and E7 in cervical carcinoma cells.

Abstract

In most cervical carcinoma cells the E6 and E7 genes of specific human papillomaviruses are transcribed from viral sequences integrated into host cell chromosomes. Glucocorticoids activate the promoter elements of various human papillomaviruses in transient-expression assays. We have analyzed the effect of dexamethasone on the transcription rate of human papillomavirus 18 E6 and E7 genes integrated at different chromosomal sites in four cervical cancer cell lines. Dexamethasone led to an increase in the transcription rate of the integrated E6-E7 sequences in C4-1 and C4-2 cells but led to a decrease in SW 756 cells and did not affect the transcription rate in HeLa cells. However, when the viral promoter elements derived from HeLa or SW 756 cells, in which dexamethasone does not activate transcription of the integrated E6-E7 sequences, were tested in transient-expression assays within the same cell lines, dexamethasone consistently activated the viral promoter. It thus appears that dominant regulatory mechanisms presumably depending on the chromosomal integration site are able to override the response of the viral promoter to steroid hormones. The growth rate of all dexamethasonetreated cell lines correlated consistently with the expression of the papillomavirus E6 and E7 genes, supporting their role in the maintenance of the proliferative phenotype of cervical carcinoma cells. Since human papillomaviruses are integrated into the host cell genome at variable, presumably randomly selected chromosomal loci, regulatory mechanisms that influence viral gene expression, and hence cell growth, may differ among cancers of independent clonal origin.

High-risk human papillomavirus clearance in pregnant women: trends for lower clearance during pregnancy with a catch-up postpartum

“…It has been suggested that pregnant women tend to have fewer sexual partners than non-pregnant women of the same age (De Roda Husman et al, 1995a) and therefore have a decreased risk to acquire a new HPV infection (Peng et al, 1990;Tenti et al, 1997). Pregnancy-related explanations for this change in HPV prevalence have been given in terms of possible selective activation of viruses by hormonal (von Knebel Doeberitz et al, 1991;Michelin et al, 1997) and immunological factors (Sethi et al, 1998). Sethi et al (1998) showed that serologic response to HPV type 16 was higher in non-pregnant than in pregnant women suggesting that pregnancy reduces humoral immune response against HPV.…”

Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

“…In particular the fact, that integration frequently disrupts the viral regulatory gene E2 from its own promoter is taken as an argument for a constitutive strong expression of the viral oncogenes (Baker et al, 1987;Romanczuk and Howley, 1992). Moreover, experimental data suggest that cis-acting elements within the flanking cellular sequences can positively modulate viral gene expression (von Knebel Doeberitz et al, 1991). There is also some evidence that integratederived viral-cellular fusion transcripts exhibit higher RNA stability because of the loss of AU-rich elements (AREs) present in viral 3 0 -UTR (untranslated region) sequences .…”

Systematic Review of Genomic Integration Sites of Human Papillomavirus Genomes in Epithelial Dysplasia and Invasive Cancer of the Female Lower Genital Tract

“…The relative expression levels of the viral oncogenes and their corresponding gene products appear to be directly influenced by the sequence context of individual integration sites. In addition, cis-acting regulatory sequences were shown to exert a strong influence on the expression level and regulation of the integrated viral oncogenes (14). Additional work demonstrated that in specific cervical cancer cell lines only one or few integrated genomes are transcribed, whereas many others within the same cells are transcriptionally silenced (15).…”