The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression via the AT-Hook Transcription Factor AKNA.

Joaquin Manzo-Merino,Rogelio Hernández-Pando,Vicente Madrid-Marina,Leonardo Castro-Muñoz,Crysele Calderón-Corona,Carla Contreras-Ochoa,Alicia Román-Gonzalez,Margarita Bahena-Román,Alfredo Lagunas-Martínez,Marcela Lizano,Kirvis Torres-Poveda

doi:10.3390/cancers10120521

Abstract

Persistent infection with high-risk Human Papillomavirus (HR-HPV) is the main requisite for cervical cancer development. Normally, HPV is limited to the site of infection and regulates a plethora of cellular elements to avoid the immune surveillance by inducing an anti-inflammatory state, allowing the progress through the viral cycle and the carcinogenic process. Recent findings suggest that the AT-hook transcriptional factor AKNA could play a role in the development of cervical cancer. AKNA is strongly related to the expression of co-stimulatory molecules such CD40/CD40L to achieve an anti-tumoral immune response. To date, there is no evidence demonstrating the effect of the HPV E6 oncoprotein on the AT-hook factor AKNA. In this work, minimal expression of AKNA in cervical carcinoma compared to normal tissue was found. We show the ability of E6 from high-risk HPVs 16 and 18 to interact with and down-regulate AKNA as well as its co-stimulatory molecule CD40 in a proteasome dependent manner. We also found that p53 interacts with AKNA and promotes AKNA expression. Our results indicate that the de-regulation of CD40 and AKNA is induced by the HPV E6 oncoprotein, and this event involves the action of p53 suggesting that the axis E6/p53A/AKNA might play an important role in the de-regulation of the immune system during the carcinogenic process induced by HR-HPV.

Highlights

The prevalence of different high-risk Human Papillomavirus (HR-HPV) genotypes and their attribution to the development of different types of cancer has been extensively described [1,2,3]. most HPV infections are asymptomatic and are cleared by the immune system, there are several factors that favor a small proportion of HPV infections to progress to cervical cancer includingHPV genotype, nutritional status and a failure in the immune system [4,5]; the particular contribution of each factor remains under investigation.Recent findings, suggest that the AT-hook transcriptional factor AKNA, could play a role in the development of CC [6]
We evaluated the production of AKNA in cervical biopsies from normal epithelium, cervicitis and infiltrating squamous cell carcinoma in 12 cases of hysterectomy
The results demonstrate a strong AKNA immunostaining in areas of normal cervical epithelium (Figure 1A,B) that progressively decrease in areas of cervicitis, being almost negative in areas of well and moderate differentiated squamous cell carcinoma (Figure 1C,D)

Summary

Introduction

HPV genotype, nutritional status and a failure in the immune system [4,5]; the particular contribution of each factor remains under investigation. Suggest that the AT-hook transcriptional factor AKNA, could play a role in the development of CC [6]. This gene is located on chromosome 9q32, a locus of genetic susceptibility to CC [7]. The akna gene encodes a transcription factor present in the germinal center of secondary lymphoid organs and immune system cells, such as B and T cells, natural killer and dendritic cells [8]. The N-terminal AT-hook domain of AKNA F1 isoform protein functionally tested in in vitro experiments has shown the ability to bind to the AT-rich promoter regions in both CD40 and CD40 ligand (CD40L), activating their expression to achieve an efficient immune response [8]

Methods

Results

Conclusion