Dataset Information

Expression of HPV16 E5 down-modulates the TGFbeta signaling pathway.

ABSTRACT:

Background

Infection 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.

Findings

The 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.

Conclusions

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.

SUBMITTER: French D

PROVIDER: S-EPMC3661392 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Publications

Expression of HPV16 E5 down-modulates the TGFbeta signaling pathway.

French Deborah D Belleudi Francesca F Mauro Maria Vittoria MV Mazzetta Francesca F Raffa Salvatore S Fabiano Vincenza V Frega Antonio A Torrisi Maria Rosaria MR

Molecular cancer 20130507

<h4>Background</h4>Infection 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 fact ...[more]

PMID: 23651589

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Project description:Background: Anti-epidermal-growth-factor-receptor (EGFR) therapies in combination with radiotherapy are being studied on de-escalation clinical trials for HPV-related oropharyngeal cancer (OPC) patients. The HPV16-E5 oncoprotein increases recycling of activated EGFR to the cell surface, enhancing factor signal transduction. Our aim was to evaluate viral HPV16-E5 oncogene expression as well as EGFR and phosphorylated-EGFR (pEGFR), protein levels as biomarkers for clinical outcome in a retrospective cohort of OPC patients. Methods: Formalin-fixed-paraffin-embedded OPCs were collected from 1990 to 2013. OPC samples containing HPV-DNA were subject to viral E6 * I mRNA detection and p16INK4a immunohistochemistry (IHC). HPV16-positive cases were evaluated for HPV16-E5 (RT-PCR) and EGFR/pEGFR (IHC). A stratified and matched random sample of HPV-negative samples was used as control and evaluated for EGFR/pEGFR. Overall survival (OS) and disease free survival (DFS) estimates were assessed for locally advanced OPC patients (stage III, IVa,b 7th edition). Results: Among 788 OPC patient samples, 53 were double positive for HPV16-DNA/p16INK4a. HPV16-E5 expression was found in 41 of 53 samples (77.4%). EGFR expression was observed in 37.7 vs 70.8% of HPV16-positive vs HPV-negative samples, respectively; (adjusted OR = 0.15) 5% CI = 0.04-0.56]). Expression of pEGFR followed an inverse pattern with 39.6 and 24.9% detection in HPV16-positive and HPV-negative samples; (adjusted OR = 1.58 [95% CI = 0.48-5.17]). Within HPV16-positive cases, no association between HPV16-E5/EGFR nor pEGFR was observed. With a median follow-up of 39.36 months (min = 0.03 - max = 272.07), the combination of HPV status and EGFR or pEGFR expression were predictors of better OS (p < 0.001, for both) and DFS (p < 0.001 for EGFR and p = 0.003 for pEGFR). Conclusions: HPV16-E5 is highly expressed on HPV16-positive OPCs. Interestingly, HPV16-positive cases expressed significantly more pEGFR while HPV-negative cases expressed more EGFR. The combinations of HPV status and EGFR or pEGFR may be useful biomarkers for evaluating prognosis outcome in OPC patients.

Dataset Information

Expression of HPV16 E5 down-modulates the TGFbeta signaling pathway.

Background

Findings

Conclusions

Publications

Expression of HPV16 E5 down-modulates the TGFbeta signaling pathway.

Similar Datasets

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