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

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The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression Via the AT-Hook Transcription Factor AKNA cancers Article The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression via the AT-Hook Transcription Factor AKNA Joaquin Manzo-Merino 1,2,3,* , Alfredo Lagunas-Martínez 3, Carla O. Contreras-Ochoa 3, Marcela Lizano 2,4 , Leonardo J. Castro-Muñoz 2 , Crysele Calderón-Corona 3, Kirvis Torres-Poveda 3,5, Alicia Román-Gonzalez 3, Rogelio Hernández-Pando 6, Margarita Bahena-Román 3 and Vicente Madrid-Marina 3,* 1 CONACyT-Instituto Nacional de Cancerología, Mexico City 14080, Mexico 2 Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico; [email protected] (M.L.); [email protected] (L.J.C.-M.) 3 Chronic Infections and Cancer Division, Centro de Investigación Sobre Enfermedades Infecciosas (CISEI), Instituto Nacional de Salud Pública, Secretaría de Salud, Avenida Universidad 655, Col. Santa María Ahuacatitlan, Cuernavaca, Morelos 62100, Mexico; [email protected] (A.L.-M.); [email protected] (C.O.C.-O.); [email protected] (C.C.-C.); [email protected] (K.T.-P.); [email protected] (A.R.-G.); [email protected] (M.B.-R.) 4 Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico 5 CONACyT-Instituto Nacional de Salud Pública (INSP), Cuernavaca, Morelos 62100, Mexico 6 Section of Experimental Pathology, Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico; [email protected] * Correspondence: [email protected] (J.M.-M.); [email protected] (V.M.-M.); Tel.: +52-55-56280400 (ext. 31025) (J.M.-M.); +52-777-3293056 (V.M.-M.) Received: 19 September 2018; Accepted: 13 December 2018; Published: 17 December 2018 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. Keywords: HR-HPV; AKNA; E6 oncoprotein; CD40; p53; proteasome Cancers 2018, 10, 521; doi:10.3390/cancers10120521 www.mdpi.com/journal/cancers Cancers 2018, 10, 521 2 of 19 1. Introduction 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 [1–3]. Although 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 including HPV genotype, nutritional status and a failure in the immune system [4,5]; nevertheless, 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]. 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]. CD40 is a transmembrane surface receptor expressed in antigen-presenting cells and other non-hematopoietic cell types including endothelial cells, fibroblasts, smooth muscle cells, and epithelial cells [9–14]. The ligand for CD40 is the type II membrane protein CD40L, the CD40–CD40L interaction has a role in both cellular and humoral immune responses [15]. Dendritic cells mature and become active after CD40 ligation, producing high levels of pro-inflammatory cytokines and chemokines [16,17]. Despite all acquired data in the past years, the complete regulatory mechanism for HR-HPV persistent infection remains unknown. Therefore, we hypothesize that CD40 expression, is regulated by the HR-HPV E6 oncoprotein through the transcriptional factor AKNA. In this work, we show the ability of E6 from HR-HPV to bind to AKNA F1 isoform in a series of in vitro and in vivo binding assays. We also demonstrate a minimal expression of this factor and its co-stimulatory molecule CD40 in the HPV-positive cell lines, in comparison with the HPV-negative cell line HaCaT. Furthermore, ablation of E6 expression have a dramatic effect on the recovery of AKNA and CD40 levels, suggesting that AKNA expression is somehow regulated by HR-HPV E6 oncoproteins. These results indicate that the deregulation of AKNA might be a common event in the carcinogenic process induced by the HR-HPVs. 2. Results 2.1. AKNA Expression Is Ablated in Normal HPV Infected and Neoplastic Cervical Epithelium A recent study demonstrated that the transcription factor AKNA is associated to an increased risk for developing cervical cancer [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 (Figure1A,B) that progressively decrease in areas of cervicitis, being almost negative in areas of well and moderate differentiated squamous cell carcinoma (Figure1C,D). Also, we analyzed 6 cases of cervical epithelium with morphological changes induced by HPV infection (koilocytes) where AKNA staining was completely negative in the koilocytes (Figure1B, arrows). Additionally, we quantified the AKNA staining in the analyzed cases finding significantly lower protein levels in cancer cases compared to normal epithelium (Figure1E); although the cancer cases showed a wide range of AKNA signal indicating the tumor heterogeneity, the difference was clear when comparing with normal tissue. Thus, normal cervical epithelium shows strong AKNA production while in areas of dysplasia and local or invasive squamous cell carcinoma, there is a substantial decrease of AKNA production. Cancers 2018, 10, x 3 of 19 Cancersan immunofluorescence2018, 10, 521 approach and by western blot. AKNA immunostaining was detected at3 ofa 19 higher level in the HPV-negative cell lines compared with those HPV-positive (Figure 2A). A B ) 2 ** E) m 5000 ) 2 m 4000 ! 3000 2000 C D * * 1000 0 Total Total Intensity AKNA (Pixel/ Normal Cancer TotalIntensity A K N A (Pixel/ FigureFigure 1. 1.Representative Representative micrographs micrographs ofof conventionalconventional histology histology and and immunohistochemistry immunohistochemistry to todetect detect AKNAAKNA in in normal normal and and neoplastic neoplastic cervical cervical epithelium.epithelium. ( AA)) Normal Normal histological histological appearance appearance of ofuterine uterine cervix,cervix, showing showing squamous squamous stratified stratified epithelium epithelium supported supported by connective by connective tissue. (tissue.B) Normal (B) epitheliumNormal showingepithelium strong showing AKNA strong immunostaining. AKNA immunostaining. Arrows indicate Arrows koilocytes indicate where koilocytes AKNA stainingwhere AKNA is absent. (C)staining Intense is cervicitis absent. (C with) Intense small cervicitis fragment with of epitheliumsmall fragment (asterisk) of epithelium and large (asterisk) nodules and of large neoplastic nodules cells inof subjacent neoplastic connective cells in tissuesubjacent that correspondconnective totissue infiltrating that correspond areas of mild to differentiatedinfiltrating areas squamous of mild cell carcinomadifferentiated (arrows). squamous (D) Conserved cell carcinoma epithelium (arrows). (asterisk) (D) Conserved and neoplastic epithelium nodules (asterisk) (arrows) and neoplastic show slight AKNAnodules immunostaining (arrows) show slight (panels AKNAA and immunostainingB 200× magnification, (panels A panels and B C200×and magnification,D 100× magnification). panels C (E)and Digital D 100× pathology magnification). study confirmed (E) Digital AKNA pathology reduced study levels confirmed in cancer AKNA cases (reducedn = 6) compared levels in tocancer normal epitheliacases (n ( n= =6) 6)compared (** p < 0.01). to normal epithelia (n = 6) (** p < 0.01). 2.2. AKNA is
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