Cytokeratin 17 expression is commonly observed in keratinocytic skin tumours and controls tissue homeostasis impacting human papillomavirus protein expression.

Background: The structured expression of several keratins in the skin is associated with differentiation status of the epidermal layers, whereas other keratins are upregulated only during wound healing, in skin disorders and in cancers. One of these stress keratins, K17, is correlated with poor prognosis in various cancer types and its loss has been shown to decelerate tumour growth. K17 expression can also be detected in cutaneous squamous cell carcinomas, where ultraviolet irradiation and infection with cutaneous human papillomaviruses are important cofactors.

Viruses and phospholipids: Friends and foes during infection.

Viruses have evolved complex and dynamic interactions with their host cells to enable viral replication. In recent years, insights have been gained into the increasingly important role of the host cell lipidome in the life cycle of several viruses. In particular, viruses target phospholipid signaling, synthesis, and metabolism to remodel their host cells into an optimal environment for their replication cycle.

MAML1-induced HPV E6 oncoprotein stability is required for cellular proliferation and migration of cervical tumor-derived cells.

While a small proportion of high-risk (HR) alpha (α) human papillomaviruses (HPVs) is associated with numerous human malignancies, of which cervical cancer is the most prevalent, beta (β) HPVs predominantly act as co-factors in skin carcinogenesis. A characteristic feature of both α- and β-E6 oncoproteins is the presence of the LXXLL binding motif, which α-E6s utilize to form a complex with E6AP and which enables β-E6s to interact with MAML1. Here we show that multiple α-E6 oncoproteins bind to MAML1 via the LXXLL binding motif and that this results in increased protein stability.

Poly(I:C) Treatment Prevents Skin Tumor Formation in the Preclinical HPV8 Transgenic Mouse Model.

Actinic keratoses and cutaneous squamous cell carcinomas are associated with infections with human papillomavirus of genus beta (betaHPV) in immunosuppressed patients. To date, targeted therapy against betaHPV-associated skin cancer does not exist because of the large number of betaHPV without defined high-risk types. In this study, we hypothesized that the activation of innate antiviral immunity in the skin, asymptomatically infected with betaHPV, induces an antitumor response by in situ autovaccination and prevents the formation of betaHPV-associated skin cancer.

Human Beta Papillomavirus Type 8 E1 and E2 Proteins Suppress the Activation of the RIG-I-Like Receptor MDA5.

Persistent infections of the skin with the human papillomavirus of genus beta (β-HPV) in immunocompetent individuals are asymptomatic, but in immunosuppressed patients, β-HPV infections exhibit much higher viral loads on the skin and are associated with an increased risk of skin cancer. Unlike with HPV16, a high-risk α-HPV, the impact of β-HPV early genes on the innate immune sensing of viral nucleic acids has not been studied. Here, we used primary skin keratinocytes and U2OS cells expressing HPV8 or distinct HPV8 early genes and well-defined ligands of the nucleic-acid-sensing receptors , , , and to analyze a potential functional interaction.

HPV8 Reverses the Transcriptional Output in Lrig1 Positive Cells to Drive Skin Tumorigenesis.

K14-HPV8-CER transgenic mice express the complete early genome region of human papillomavirus type 8 (HPV8) and develop skin tumours attributed to the expansion of the Lrig1+ stem cell population. The correlation between HPV8-induced changes in transcriptional output in the stem cell compartment remains poorly understood. To further understand the oncogenic pathways underlying skin tumour formation we examined the gene expression network in skin tumours of K14-HPV8-CER mice and compared the differentially expressed genes (DEG) with those of the Lrig1-EGFP-ires-CreERT2 mice.

Impact of Human Papillomavirus on Wnt/Beta-Catenin Signaling in Morphological Inconspicuous Cervicovaginal Cells.

Introduction: The aim of this study was to identify early changes in the Wnt/beta-catenin signaling pathway in high-risk human papillomavirus (HPV) infected cervicovaginal cells and to correlate these changes with cell proliferation, apoptosis, and autophagic processes.

Methods: We evaluated 91 cervicovaginal smears of women with (n = 41) and without (n = 50) HPV-DNA. Smears were stained against beta-catenin, c-myc, secreted frizzled-related protein 4 (sFRP4), cleaved caspase-3, and the autophagy markers Beclin-1 and light chain 3B.

Inactivation of Polyomavirus SV40 as Surrogate for Human Papillomaviruses by Chemical Disinfectants.

Human papillomaviruses (HPV) are non-enveloped DNA viruses infecting cutaneous and mucosal squamous epithelia. Sexually transmitted HPV-types that are carcinogenic to humans such as HPV16 can induce cervical and other anogenital cancers. Virus transmission through fomites such as inadequately disinfected gynecological equipment is a further potential transmission route.

Safe and effective pool testing for SARS-CoV-2 detection.

Objectives: The global spread of SARS-CoV-2 is a serious public health issue. Large-scale surveillance screenings are crucial but can exceed test capacities. We (A) optimized test conditions and (B) implemented pool testing of respiratory swabs into SARS-CoV-2 diagnostics.

Comprehensive Analysis of VEGFR2 Expression in HPV-Positive and -Negative OPSCC Reveals Differing VEGFR2 Expression Patterns.

VEGF signaling regulated by the vascular endothelial growth factor receptor 2 (VEGFR2) plays a decisive role in tumor angiogenesis, initiation and progression in several tumors including HNSCC. However, the impact of HPV-status on the expression of VEGFR2 in OPSCC has not yet been investigated, although HPV oncoproteins E6 and E7 induce VEGF-expression. In a series of 56 OPSCC with known HPV-status, VEGFR2 expression patterns were analyzed both in blood vessels from tumor-free and tumor-containing regions and within tumor cells by immunohistochemistry using densitometry.

Novel Insights Into Cellular Changes in HPV8-E7 Positive Keratinocytes: A Transcriptomic and Proteomic Analysis.

Human papillomavirus type 8 (HPV8) is associated with the development of non-melanoma skin cancer. In the past we already delved into the mechanisms involved in keratinocyte invasion, showing that the viral E7 oncoprotein is a key player that drives invasion of basal keratinocytes controlled by the extracellular protein fibronectin. To unravel further downstream effects in E7 expressing keratinocytes we now aimed at characterizing gene and protein/phosphoprotein alterations to narrow down on key cellular targets of HPV8-E7.

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

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.

No Evidence for Role of Cutavirus in Malignant Melanoma.

Cutavirus was previously found in cutaneous melanoma. We detected cutavirus DNA in only 2/185 melanoma biopsies and in 0/52 melanoma metastases from patients in Germany. Viral DNA was localized in the upper epidermal layers.

HPV8 activates cellular gene expression mainly through Sp1/3 binding sites.

The human papillomavirus type 8 (HPV8) is associated with skin cancer development. The goal of this study was to investigate the effects of HPV8 oncoproteins on cellular gene expression and the identification of key regulators. We performed affymetrix microarray analyses to identify differentially expressed genes and common sequence motifs and identified Sp1/3 binding sites as being crucial.

BetaHPV E6 and E7 colocalize with NuMa in dividing keratinocytes.

Human papillomaviruses (HPVs) of genus betapapillomavirus (betaHPV) are implicated in skin carcinogenesis, but their exact role in keratinocyte transformation is poorly understood. We show an interaction of HPV5 and HPV8 oncoproteins E6 and E7 with the nuclear mitotic apparatus protein 1 (NuMA). Binding of E6 or E7 to NuMA induces little aneuploidy, cell cycle alterations, or aberrant centrosomes.

The Protein Tyrosine Phosphatase H1 PTPH1 Supports Proliferation of Keratinocytes and is a Target of the Human Papillomavirus Type 8 E6 Oncogene.

Human papillomaviruses (HPV) replicate their DNA in the suprabasal layer of the infected mucosa or skin. In order to create a suitable environment for vegetative viral DNA replication HPV delay differentiation and sustain keratinocyte proliferation that can lead to hyperplasia. The mechanism underlying cell growth stimulation is not well characterized.

Human papillomavirus type 8 oncoproteins E6 and E7 cooperate in downregulation of the cellular checkpoint kinase-1.

Human papillomavirus 8 (HPV8) is associated with the development of squamous cell carcinoma (SCC) of the skin. HPV-infected keratinocytes are able to override normal checkpoint control mechanisms and sustain cell cycle activity, allowing for synthesis of cellular proteins necessary for viral genome amplification. To study how HPV8 may disrupt cell cycle control, we analyzed the impact of HPV8 early gene expression on one of the key regulators of cell cycle and DNA damage response, checkpoint kinase-1 (CHK1).

Epigenetic Regulation of iASPP-p63 Feedback Loop in Cutaneous Squamous Cell Carcinoma.

Keratinocyte skin cancer, comprising cutaneous squamous (cSCC) and basal cell carcinoma, is the most common malignancy in the United Kingdom. P53 is frequently mutated in cSCC. iASPP is a key inhibitor of p53 and NF-κB signaling pathways and has been documented as highly expressed in several types of human cancer.

Phospholipidation of nuclear proteins by the human papillomavirus E6 oncoprotein: implication in carcinogenesis.

Phospholipids regulate numerous cellular functions and their deregulation is known to be associated with cancer development. Here, we show for the first time that expression of the E6 oncoprotein of human papillomavirus type 8 (HPV8) leads to a profound increase in nuclear phosphatidylinositol-4,5-bisphosphate (PI(4,5)P) lipid levels in monolayer cultures, that led to an aberrant phospholipidation of cellular proteins. Elevated PI(4,5)P levels in organotypic skin cultures, skin tumors of K14-HPV8-E6 transgenic mice as well as HPV8 positive skin carcinomas highly suggest a decisive role of PI(4,5)P in HPV associated squamous-cell-carcinoma development.

HPV16 increases the number of migratory cancer stem cells and modulates their miRNA expression profile in oropharyngeal cancer.

Human papillomavirus type 16 (HPV16) is a major risk for development of oropharyngeal squamous-cell-carcinoma (OPSCC). Although HPV OPSCC metastasize faster than HPV tumors, they have a better prognosis. The molecular and cellular alterations underlying this pathobiology of HPV OPSCC remain elusive.

HPV8-E6 Interferes with Syntenin-2 Expression through Deregulation of Differentiation, Methylation and Phosphatidylinositide-Kinase Dependent Mechanisms.

The E6 oncoproteins of high-risk human papillomaviruses (HPV) of genus alpha contain a short peptide sequence at the carboxy-terminus, the PDZ binding domain, with which they interact with the corresponding PDZ domain of cellular proteins. Interestingly, E6 proteins from papillomaviruses of genus beta (betaPV) do not encode a comparable PDZ binding domain. Irrespective of this fact, we previously showed that the E6 protein of HPV8 (betaPV type) could circumvent this deficit by targeting the PDZ protein Syntenin-2 through transcriptional repression (Lazic et al.

Molecular Mechanisms of Human Papillomavirus Induced Skin Carcinogenesis.

Infection of the cutaneous skin with human papillomaviruses (HPV) of genus betapapillomavirus (βHPV) is associated with the development of premalignant actinic keratoses and squamous cell carcinoma. Due to the higher viral loads of βHPVs in actinic keratoses than in cancerous lesions, it is currently discussed that these viruses play a carcinogenic role in cancer initiation. In vitro assays performed to characterize the cell transforming activities of high-risk HPV types of genus alphapapillomavirus have markedly contributed to the present knowledge on their oncogenic functions.