scholarly journals Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses

2007 ◽  
Vol 205 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Maciej Lazarczyk ◽  
Christian Pons ◽  
José-Andrès Mendoza ◽  
Patricia Cassonnet ◽  
Yves Jacob ◽  
...  
Keyword(s):  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Intracellular Zinc ◽  
Host Restriction ◽  
Skin Cancers ◽  
E5 Protein ◽  
Hpv16 E5 ◽  
Cellular Zinc ◽  
Hybrid Screening ◽  
Zinc Distribution

Epidermodysplasia verruciformis (EV) is a genodermatosis associated with skin cancers that results from a selective susceptibility to related human papillomaviruses (EV HPV). Invalidating mutations in either of two genes (EVER1 and EVER2) with unknown functions cause most EV cases. We report that EVER1 and EVER2 proteins form a complex and interact with the zinc transporter 1 (ZnT-1), as shown by yeast two-hybrid screening, GST pull-down, and immunoprecipitation experiments. In keratinocytes, EVER and ZnT-1 proteins do not influence intracellular zinc concentration, but do affect intracellular zinc distribution. EVER2 was found to inhibit free zinc influx to nucleoli. Keratinocytes with a mutated EVER2 grew faster than wild-type keratinocytes. In transiently and stably transfected HaCaT cells, EVER and ZnT-1 down-regulated transcription factors stimulated by zinc (MTF-1) or cytokines (c-Jun and Elk), as detected with luciferase assays. To get some insight into the control of EV HPV infection, we searched for interaction between EVER and ZnT-1 and oncoproteins of cutaneous (HPV5) and genital (HPV16) genotypes. HPV16 E5 protein binds to EVER and ZnT-1 and blocks their negative regulation. The lack of a functional E5 protein encoded by EV HPV genome may account for host restriction of these viruses.

scholarly journals Human Papillomavirus 16 E5 Inhibits Interferon Signaling and Supports Episomal Viral Maintenance

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Matthew L. Scott ◽  
Brittany L. Woodby ◽  
Joseph Ulicny ◽  
Gaurav Raikhy ◽  
A. Wayne Orr ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Human Papillomaviruses ◽  
Host Immune System ◽  
Growth Factor Signaling ◽  
Human Papillomavirus 16 ◽  
Host Immune Responses ◽  
Protein Levels ◽  
E5 Protein ◽  
E5 Oncoprotein ◽  
Hpv16 E5

ABSTRACT Human papillomaviruses (HPVs) infect keratinocytes of stratified epithelia. Long-term persistence of infection is a critical risk factor for the development of HPV-induced malignancies. Through the actions of its oncogenes, HPV evades host immune responses to facilitate its productive life cycle. In this work, we discovered a previously unknown function of the HPV16 E5 oncoprotein in the suppression of interferon (IFN) responses. This suppression is focused on keratinocyte-specific IFN-κ and is mediated through E5-induced changes in growth factor signaling pathways, as identified through phosphoproteomics analysis. The loss of E5 in keratinocytes maintaining the complete HPV16 genome results in the derepression of IFNK transcription and subsequent JAK/STAT-dependent upregulation of several IFN-stimulated genes (ISGs) at both the mRNA and protein levels. We also established a link between the loss of E5 and the subsequent loss of genome maintenance and stability, resulting in increased genome integration. IMPORTANCE Persistent human papillomavirus infections can cause a variety of significant cancers. The ability of HPV to persist depends on evasion of the host immune system. In this study, we show that the HPV16 E5 protein can suppress an important aspect of the host immune response. In addition, we find that the E5 protein is important for helping the virus avoid integration into the host genome, which is a frequent step along the pathway to cancer development.

scholarly journals Different Methods in HPV Genotyping of Anogenital and Oropharyngeal Lesions: Comparison between VisionArray® Technology, Next Generation Sequencing, and Hybrid Capture Assay

2021 ◽  
Vol 2 (1) ◽  
pp. 29-41
Author(s):  
Giorgia Acquaviva ◽  
Michela Visani ◽  
Viviana Sanza ◽  
Antonio De Leo ◽  
Thais Maloberti ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Turnaround Time ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Next Generation ◽  
Hybrid Capture ◽  
Capture Assay ◽  
Anogenital Area ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

(1) Background: Human papillomaviruses (HPVs) are known to be related to the development of about 5% of all human cancers. The clinical relevance of HPV infection has been deeply investigated in carcinomas of the oropharyngeal area, uterine cervix, and anogenital area. To date, several different methods have been used for detecting HPV infection. The aim of the present study was to compare three different methods for the diagnosis of the presence of the HPV genome. (2) Methods: A total of 50 samples were analyzed. Twenty-five of them were tested using both next generation sequencing (NGS) and VisionArray® technology, the other 25 were tested using Hybrid Capture (HC) II assay and VisionArray® technology. (3) Results: A substantial agreement was obtained using NGS and VisionArray® (κ = 0.802), as well as between HC II and VisionArray® (κ = 0.606). In both analyses, the concordance increased if only high risk HPVs I(HR-HPVs) were considered as “positive”. (4) Conclusions: Our data highlighted the importance of technical choice in HPV characterization, which should be guided by the clinical aims, costs, starting material, and turnaround time for results.

scholarly journals HPV and Other Microbiota; Who’s Good and Who’s Bad: Effects of the Microbial Environment on the Development of Cervical Cancer—A Non-Systematic Review

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 714
Author(s):  
Matthias Läsche ◽  
Horst Urban ◽  
Julia Gallwas ◽  
Carsten Gründker
Keyword(s):  
Systematic Review ◽  
Cervical Cancer ◽  
High Risk ◽  
Cervical Carcinoma ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Inflammatory Reactions ◽  
Metabolic Signalling ◽  
Microbial Environment ◽  
High Risk Hpv

Cervical cancer is responsible for around 5% of all human cancers worldwide. It develops almost exclusively from an unsolved, persistent infection of the squamocolumnar transformation zone between the endo- and ecto-cervix with various high-risk (HR) human papillomaviruses (HPVs). The decisive turning point on the way to persistent HPV infection and malignant transformation is an immune system weakened by pathobionts and oxidative stress and an injury to the cervical mucosa, often caused by sexual activities. Through these injury and healing processes, HPV viruses, hijacking activated keratinocytes, move into the basal layers of the cervical epithelium and then continue their development towards the distal prickle cell layer (Stratum spinosum). The microbial microenvironment of the cervical tissue determines the tissue homeostasis and the integrity of the protective mucous layer through the maintenance of a healthy immune and metabolic signalling. Pathological microorganisms and the resulting dysbiosis disturb this signalling. Thus, pathological inflammatory reactions occur, which manifest the HPV infection. About 90% of all women contract an HPV infection in the course of their lives. In about 10% of cases, the virus persists and cervical intra-epithelial neoplasia (CIN) develops. Approximately 1% of women with a high-risk HPV infection incur a cervical carcinoma after 10 to 20 years. In this non-systematic review article, we summarise how the sexually and microbial mediated pathogenesis of the cervix proceeds through aberrant immune and metabolism signalling via CIN to cervical carcinoma. We show how both the virus and the cancer benefit from the same changes in the immune and metabolic environment.

scholarly journals Inhibition of Transfer to Secondary Receptors by Heparan Sulfate-Binding Drug or Antibody Induces Noninfectious Uptake of Human Papillomavirus

2007 ◽  
Vol 81 (20) ◽  
pp. 10970-10980 ◽  
Author(s):  
Hans-Christoph Selinka ◽  
Luise Florin ◽  
Hetal D. Patel ◽  
Kirsten Freitag ◽  
Michaela Schmidtke ◽  
...  
Keyword(s):  
Cell Surface ◽  
Neutralizing Antibodies ◽  
Structural Similarity ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Laminin 5 ◽  
Entry Pathway ◽  
Successful Infection ◽  
Major Mode ◽  
Endocytic Vesicles

ABSTRACT Infection with various human papillomaviruses (HPVs) induces cervical cancers. Cell surface heparan sulfates (HS) have been shown to serve as primary attachment receptors, and molecules with structural similarity to cell surface HS, like heparin, function as competitive inhibitors of HPV infection. Here we demonstrate that the N,N′-bisheteryl derivative of dispirotripiperazine, DSTP27, efficiently blocks papillomavirus infection by binding to HS moieties, with 50% inhibitory doses of up to 0.4 μg/ml. In contrast to short-term inhibitory effects of heparin, pretreatment of cells with DSTP27 significantly reduced HPV infection for more than 30 h. Using DSTP27 and heparinase, we furthermore demonstrate that HS moieties, rather than laminin 5, present in the extracellular matrix (ECM) secreted by keratinocytes are essential for infectious transfer of ECM-bound virions to cells. Prior binding to ECM components, especially HS, partially alleviated the requirement for cell surface HS. DSTP27 blocks infection by cell-bound virions by feeding into a noninfectious entry pathway. Under these conditions, virus colocalized with HS moieties in endocytic vesicles. Similarly, postattachment treatment of cells with heparinase, cytochalasin D, or neutralizing antibodies resulted in uptake of virions without infection, indicating that deviation into a noninfectious entry pathway is a major mode of postattachment neutralization. In untreated cells, initial colocalization of virions with HS on the cell surface and in endocytic vesicles was lost with time. Our data suggest that initial attachment of HPV to HS proteoglycans (HSPGs) must be followed by secondary interaction with additional HS side chains and transfer to a non-HSPG receptor for successful infection.

Human Papillomaviruses in Transplant-Associated Skin Cancers

2004 ◽  
Vol 30 (4, Part 2) ◽  
pp. 604-609 ◽  
Author(s):  
EGGERT STOCKFLETH ◽  
INGO NINDL ◽  
WOLFRAM STERRY ◽  
CLAAS ULRICH ◽  
TOBIAS SCHMOOK ◽  
...  
Keyword(s):  
Human Papillomaviruses ◽  
Skin Cancers

scholarly journals Lack of Conserved miRNA Deregulation in HPV-Induced Squamous Cell Carcinomas

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 764
Author(s):  
Jaroslav Nunvar ◽  
Lucie Pagacova ◽  
Zuzana Vojtechova ◽  
Nayara Trevisan Doimo de Azevedo ◽  
Jana Smahelova ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Mirna Expression ◽  
Hpv Infection ◽  
Squamous Cell Carcinomas ◽  
Human Papillomaviruses ◽  
Hpv Status ◽  
Mirna Expression Level ◽  
Cervical Tumors ◽  
Mirna Deregulation ◽  
Generation Sequencing

Squamous cell carcinomas (SCCs) in the anogenital and head and neck regions are associated with high-risk types of human papillomaviruses (HR-HPV). Deregulation of miRNA expression is an important contributor to carcinogenesis. This study aimed to pinpoint commonly and uniquely deregulated miRNAs in cervical, anal, vulvar, and tonsillar tumors of viral or non-viral etiology, searching for a common set of deregulated miRNAs linked to HPV-induced carcinogenesis. RNA was extracted from tumors and nonmalignant tissues from the same locations. The miRNA expression level was determined by next-generation sequencing. Differential expression of miRNAs was calculated, and the patterns of miRNA deregulation were compared between tumors. The total of deregulated miRNAs varied between tumors of different locations by two orders of magnitude, ranging from 1 to 282. The deregulated miRNA pool was largely tumor-specific. In tumors of the same location, a low proportion of miRNAs were exclusively deregulated and no deregulated miRNA was shared by all four types of HPV-positive tumors. The most significant overlap of deregulated miRNAs was found between tumors which differed in location and HPV status (HPV-positive cervical tumors vs. HPV-negative vulvar tumors). Our results imply that HPV infection does not elicit a conserved miRNA deregulation in SCCs.

Human Papillomaviruses in Transplant-Associated Skin Cancers

2004 ◽  
Vol 30 (4p2) ◽  
pp. 604-609 ◽  
Author(s):  
Eggert Stockfleth ◽  
Ingo Nindl ◽  
Wolfram Sterry ◽  
Claas Ulrich ◽  
Tobias Schmook ◽  
...  
Keyword(s):  
Human Papillomaviruses ◽  
Skin Cancers

scholarly journals Papillomavirus can be transmitted through the blood and produce infections in blood recipients: Evidence from two animal models

2019 ◽  
Author(s):  
Nancy M. Cladel ◽  
Pengfei Jiang ◽  
Jingwei J. Li ◽  
Xuwen Peng ◽  
Timothy K. Cooper ◽  
...  
Keyword(s):  
Animal Models ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Viral Dna ◽  
Internal Organs ◽  
Sexually Transmitted ◽  
Potential Source ◽  
Papillomavirus Infection ◽  
Blood Banks ◽  
Gain Access

AbstractHuman papillomavirus (HPV) infections are commonly thought to be strictly sexually transmitted. However, studies have demonstrated the presence of HPV in cancers of many non-sexual internal organs, raising the question as to how the viruses gain access to these sites. A possible connection between blood transfusion and HPV-associated disease has not received much attention. We show, in two animal models, that blood infected with papillomavirus yields infections at permissive sites. Furthermore, we demonstrate that blood from actively infected mice can transmit the infection to naïve animals. Finally, we report papillomavirus infections in the stomach tissues of animals infected via the blood. Stomach tissues are not known to be permissive for papillomavirus infection, although the literature suggests that HPVs may be associated with a subset of gastric cancers. These results indicate that the human blood supply, which is not screened for papillomaviruses, could be a potential source of HPV infection and subsequent cancers.SUMMARYHuman papillomaviruses cause 5% of human cancers. Currently, blood banks do not screen for these viruses. We demonstrate that blood transfused from papillomavirus-infected animals produces infections in recipients. Public health implications are significant if the same is true for humans.DefinitionsLocal papillomavirus infection:An infection initiated by the direct application of virus or viral DNA to the site of infectionIntravenous (IV) papillomavirus infection:An infection resulting from blood-borne delivery of virus or viral DNA to the site of infection.

scholarly journals ATP synthase modulation leads to an increase of spare respiratory capacity in HPV associated cancers

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Matthias Kirschberg ◽  
Sandra Heuser ◽  
Gian Paolo Marcuzzi ◽  
Martin Hufbauer ◽  
Jens Michael Seeger ◽  
...  
Keyword(s):  
Host Cell ◽  
Atp Synthase ◽  
Cell Metabolism ◽  
Human Papillomaviruses ◽  
Mitochondrial Activity ◽  
Positive Skin ◽  
Respiratory Capacity ◽  
Skin Cancers ◽  
Mitochondrial Atp Synthase ◽  
Cell Energy

Abstract Mucosal and skin cancers are associated with infections by human papillomaviruses (HPV). The manner how viral oncoproteins hijack the host cell metabolism to meet their own energy demands and how this may contribute to tumorigenesis is poorly understood. We now show that the HPV oncoprotein E7 of HPV8, HPV11 and HPV16 directly interact with the beta subunit of the mitochondrial ATP-synthase (ATP5B), which may therefore represent a conserved feature across different HPV genera. By measuring both glycolytic and mitochondrial activity we observed that the association of E7 with ATP5B was accompanied by reduction of glycolytic activity. Interestingly, there was a drastic increase in spare mitochondrial respiratory capacity in HPV8-E7 and an even more profound increase in HPV16-E7 expressing cells. In addition, we could show that ATP5B levels were unchanged in betaHPV positive skin cancers. However, comparing HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas (OPSCC) we noticed that, while ATP5B expression levels did not correlate with patient overall survival in HPV-negative OPSCC, there was a strong correlation within the HPV16-positive OPSCC patient group. These novel findings provide evidence that HPV targets the host cell energy metabolism important for viral life cycle and HPV-mediated tumorigenesis.

scholarly journals Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

2016 ◽  
Vol 310 (4) ◽  
pp. E258-E268 ◽  
Author(s):  
Catalina Troche ◽  
Tolunay Beker Aydemir ◽  
Robert J. Cousins
Keyword(s):  
Adipose Tissue ◽  
Cytokine Production ◽  
Zinc Transporter ◽  
Intracellular Zinc ◽  
Systemic Endotoxemia ◽  
Differentiation Marker ◽  
Plasma Leptin ◽  
Zinc Distribution ◽  
Lower Expression

Zinc is a signaling molecule in numerous metabolic pathways, the coordination of which occurs through activity of zinc transporters. The expression of zinc transporter Zip14 ( Slc39a14), a zinc importer of the solute carrier 39 family, is stimulated under proinflammatory conditions. Adipose tissue upregulates Zip14 during lipopolysaccharide-induced endotoxemia. A null mutation of Zip14 (KO) revealed that phenotypic changes in adipose include increased cytokine production, increased plasma leptin, hypertrophied adipocytes, and dampened insulin signaling. Adipose tissue from KO mice had increased levels of preadipocyte markers, lower expression of the differentiation marker (PPARγ), and activation of NF-κB and STAT3 pathways. Our overall hypothesis was that ZIP14 would play a role in adipocyte differentiation and inflammatory obesity. Global Zip14 KO causes systemic endotoxemia. The observed metabolic changes in adipose metabolism were reversed when oral antibiotics were administrated, indicating that circulating levels of endotoxin were in part responsible for the adipose phenotype. To evaluate a mechanism, 3T3-L1 cells were differentiated into adipocytes and treated with siRNA to knock down Zip14. These cells had an impaired ability to mobilize zinc, which caused dysregulation of inflammatory pathways (JAK2/STAT3 and NF-κB). The Zip14 deletion may limit the availability of intracellular zinc, yielding the unique phenotype of inflammation coupled with hypertrophy. Taken together, these results suggest that aberrant zinc distribution observed with Zip14 ablation impacts adipose cytokine production and metabolism, ultimately increasing fat deposition when exposed to endotoxin. To our knowledge, this is the first investigation into the mechanistic role of ZIP14 in adipose tissue regulation and metabolism.

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