Abstract
BackgroundInfection with high-risk human papillomavirus (HR-HPV) genotypes, mainly HPV16 and HPV18, is a major risk factor for cervical cancer and responsible for its progression. While the transforming role of the HPV E6 and E7 proteins is more characterized, the molecular mechanisms of the oncogenic activity of the E5 product are still only partially understood, but appear to involve deregulation of growth factor receptor expression. Since the signaling of the transforming growth factor beta (TGFbeta) is known to play crucial roles in the epithelial carcinogenesis, aim of this study was to investigate if HPV16 E5 would modulate the TGF-BRII expression and TGFbeta/Smad signaling.FindingsThe HPV16 E5 mRNA expression pattern was variable in low-grade squamous intraepithelial lesions (LSIL), while homogeneously reduced in high-grade lesions (HSIL). Parallel analysis of TGFBRII mRNA showed that the receptor transcript levels were also variable in LSILs and inversely related to those of the viral protein. In vitro quantitation of the TGFBRII mRNA and protein in human keratinocytes expressing 16E5 in a dose-dependent and time-dependent manner showed a progressive down-modulation of the receptor. Phosphorylation of Smad2 and nuclear translocation of Smad4 were also decreased in E5-expressing cells stimulated with TGFbeta1.ConclusionsTaken together our results indicate that HPV16 E5 expression is able to attenuate the TGFbeta1/Smad signaling and propose that this loss of signal transduction, leading to destabilization of the epithelial homeostasis at very early stages of viral infection, may represent a crucial mechanism of promotion of the HPV-mediated cervical carcinogenesis.
Highlights
The infection with high-risk human papillomavirus (HRHPV) genotypes, the HPV16 and HPV18 viruses, is a major risk factor for cervical cancer and appears to be responsible for its progression [1,2,3]
Taken together our results indicate that HPV16 E5 expression is able to attenuate the TGFbeta1/Smad signaling and propose that this loss of signal transduction, leading to destabilization of the epithelial homeostasis at very early stages of viral infection, may represent a crucial mechanism of promotion of the HPV-mediated cervical carcinogenesis
Modulation of HPV16 E5 and TGFβRII in low-grade squamous intraepithelial lesions (LSIL) and HSILs In order to investigate the possible existence of a relationship between the E5 viral protein of HPV16 and the TGFβRII expression, we first quantified the 16E5 and TGFβRII mRNA levels in various samples of low grade (LSIL) and high grade (HSIL) squamous intra-epithelial lesions by real-time RT-PCR and normalized them respect to their levels in the HPV16-positive cervical epithelial cell line W12 [19] at the passage 6 (W12p6), in which ~100 to 200 copies per cell of the E5-expressing HPV episomes were retained [20]; our unpublished data
Summary
Taken together our results indicate that HPV16 E5 expression is able to attenuate the TGFbeta1/Smad signaling and propose that this loss of signal transduction, leading to destabilization of the epithelial homeostasis at very early stages of viral infection, may represent a crucial mechanism of promotion of the HPV-mediated cervical carcinogenesis
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