Abstract
BackgroundThe human papillomavirus (HPV) life cycle is closely linked to keratinocyte differentiation. Oncogenic HPV infection has been shown to hamper the normal differentiation of keratinocytes; however, the underlying mechanisms responsible for this phenomenon are yet to be clarified. Here, we aimed to study the effects of HPV16 E6 and E7 oncogenes on the expression of involucrin (IVL), an established marker of keratinocyte differentiation, in human foreskin keratinocyte (HFK) cells.ResultsThe differentiation of HFK cells by serum and high calcium significantly increased both the mRNA and the protein levels of IVL. The E6 and E7 oncoproteins of HPV16 together caused strong down-regulation of IVL mRNA and protein both in proliferating and in differentiating HFK cells. To study the effects of HPV oncogenes on the IVL promoter, we made transient transfection assays and luciferase tests and found that HPV 16 E6 but not E7 repressed IVL promoter activity in proliferating HFK cells. The inhibitory effect of HPV 16 E6 on the human IVL promoter could be localised to the proximal regulatory region (PRR) of the gene.ConclusionsThese results suggest that the down-regulation of IVL promoter activity by HPV 16 E6 significantly contribute to the inhibition of endogenous IVL expression by the HPV 16 oncoproteins. In contrast, the down-regulation of endogenous IVL expression by HPV16 E7 is probably not caused by a direct and specific effect of E7 on the IVL promoter.
Highlights
The human papillomavirus (HPV) life cycle is closely linked to keratinocyte differentiation
Generation and characterization of human foreskin keratinocyte (HFK) cells expressing human papillomavirus 16 (HPV 16) oncogenes To study the effects of HPV oncogenes on the expression of cellular genes, human foreskin keratinocyte (HFK) cells were transduced by recombinant retroviruses carrying either the control vector (LXSN) or vectors encoding HPV16 E6 or E7 or both oncogenes
Transduction of HPV16 E6 resulted in a decreased level of p53 protein, while expression of HPV 16 E7 led to the stabilization and higher level (1.6-fold increase) of p53 protein [5,6]
Summary
The human papillomavirus (HPV) life cycle is closely linked to keratinocyte differentiation. The E6 and E7 oncoproteins of high-risk HPVs are responsible for the transforming activity of the virus [4]. The life cycle of human papillomaviruses is closely linked to keratinocyte differentiation. The cellular DNA replication machinery is reactivated by the E7 oncogene in differentiating keratinocytes to provide a cellular environment that is permissive for the replication of the viral genome [7,8]. This activity of HPV 16 E7 was shown to delay the induction of the keratinocyte differentiation markers involucrin and keratin 10 [9]
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