Molecular Mechanisms of Human Papillomavirus Induced Skin Carcinogenesis

Hufbauer, Martin; Akgül, Baki

doi:10.3390/v9070187

Cited by 63 publications

(56 citation statements)

References 72 publications

(83 reference statements)

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“…While normal epithelial cells exit the cell cycle upon differentiation or UV-induced DNA damage, HPV-infected cells are able to circumvent the governing checkpoint mechanisms and force cells to remain in the cell cycle, allowing for synthesis of cellular proteins necessary for viral genome amplification. 8,9 The betaHPV DNA loads in actinic keratoses exceed those in SCC, which suggests a particular involvement of betaHPV in the early stages of cutaneous oncogenesis. 4,5 The oncogenic potential of HPV of the genus betapapillomavirus (betaHPV) in skin carcinogenesis was originally identified in patients suffering from the rare inherited disease epidermodysplasia verruciformis (EV), who have an increased susceptibility to betaHPV infections.…”

Section: Introductionmentioning

confidence: 99%

“…Especially, immunosuppressed organ-transplant-recipients also have a higher susceptibility to betaHPV infections of the skin as well as an increased risk of developing SCC compared to healthy individuals. 8,9 The betaHPV DNA loads in actinic keratoses exceed those in SCC, which suggests a particular involvement of betaHPV in the early stages of cutaneous oncogenesis. 10 To unravel the molecular mechanisms underlying HPV8mediated skin tumor development, we previously expressed the complete early genome region (CER, inducing simultaneous expression of E6, E7, E1, E1^E4, E2) in primary human adult keratinocytes.…”

Section: Introductionmentioning

confidence: 99%

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

Akgül

Kirschberg

Storey

et al. 2019

Intl Journal of Cancer

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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). We found that expression of E1, E1̂E4, E2, E6 or E7 individually did not affect CHK1; however, keratinocytes expressing the complete early genome region (CER) of HPV8 showed a profound loss of CHK1 protein levels, that proved to be mediated by E6E7 co‐expression. Neither CHK1 promoter regulation nor the ubiquitin‐proteasome pathway are involved in HPV8‐mediated CHK1 repression. However, CHK1 protein repression in organotypic skin cultures was paralleled by downregulation of the autophagy marker LC3B. Treatment of HPV8‐CER expressing cells with the autophagy inhibitor Bafilomycin A1 rescued CHK1 expression and led to LC3B accumulation. Taken together, our data implicate that CHK1 autophagic degradation is enhanced by HPV8, which may contribute to the oncogenic potential of the virus.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Akgül

Kirschberg

Storey

et al. 2019

Intl Journal of Cancer

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“…Alterations of integrin network are linked to skin carcinogenesis. Accordingly, studies in monolayer and organotypic cultures showed that beta HPV8 is able to alter the integrin network, promoting invasion of human keratinocytes into the dermis (77)(78)(79).…”

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confidence: 99%

An Emerging Issue in Oncogenic Virology: the Role of Beta Human Papillomavirus Types in the Development of Cutaneous Squamous Cell Carcinoma

Rollison

Viarisio

Amorrortu

et al. 2019

J Virol

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Evidence suggests that beta human papillomaviruses (HPVs), together with ultraviolet radiation, contribute to the development of cutaneous squamous cell carcinoma. Beta HPVs appear to be not the main drivers of carcinogenesis but rather facilitators of the accumulation of ultraviolet-induced DNA mutations. Beta HPVs are promoters of skin carcinogenesis, although they are dispensable for the maintenance of the malignant phenotype. Therefore, beta HPV represents a target for skin cancer prevention, especially in high-risk populations. KEYWORDS UV radiation, human papillomavirus, skin cancer T he human papillomavirus (HPV) family comprises approximately 200 types that are able to infect the mucosal and cutaneous epithelia (1). They are subdivided into genera and species in the HPV phylogenetic tree according to the DNA sequence of the late gene L1 (2). The genus Alphapapillomavirus includes the mucosal high-risk (HR) HPV types that have been clearly associated with the development of cervical and anal cancers and a subset of other genital tract cancers, such as vulvar, vaginal, and penile carcinomas, as well as a subset of head and neck cancers (3). More than 40 years of research have elucidated many of the HR HPV mechanisms involved in cancer development. The products of two early genes, E6 and E7, are major oncoproteins able to deregulate many key cellular events and greatly facilitate the malignant transformation of the infected cells. Classic examples of processes targeted by HR HPV E6 and/or E7 oncoproteins are the cell cycle, DNA repair, apoptosis, senescence, and the immune response (4). In the context of the viral life cycle, these activities of E6 and E7 are essential to guarantee viral DNA replication and progeny production. As a side effect, they facilitate the accumulation of chromosomal abnormalities, leading to cancer development. Despite the accumulation of this DNA damage, constant expression of the viral oncogenes is required for the maintenance of the transformed phenotype. Indeed, experiments in in vitro models have shown that silencing of E6 and E7 expression in cervical cancer-derived cell lines, such as CaSki or HeLa, severely affects cell viability (5-8). Because of the biological properties of the HR HPV E6 and E7 in directly targeting several cellular proteins/pathways, HPV-positive cancer cells do not usually accumulate many mutations compared with cancers associated with other environmental factors. For instance, HPV-negative oropharyngeal cancers have more DNA mutations, which are often linked to tobacco use and/or alcohol consumption, compared with HPV-positive oropharyngeal cancers (9).Similar to the HR HPV types, cutaneous beta HPV types have also been implicated in carcinogenesis, although the model of carcinogenesis is quite different. Epidemiological and biological studies support the model of synergistic cooperation between Citation Rollison DE, Viarisio D, Amorrortu RP, Gheit T, Tommasino M. 2019. An emerging issue in oncogenic virology: the role of beta human papillomavirus types...

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“…Cutaneous HPV types of different genera are common on healthy skin (Antonsson et al, 2000). However, they are also found in several skin lesions such as benign skin warts (de Villiers et al, 2004; International Agency on Research on Cancer (IARC), 2012), and some types have been discussed to be involved in skin carcinogenesis (Hufbauer and Akgül, 2017).…”

Section: Introductionmentioning

confidence: 99%

Mucosal and cutaneous Human Papillomavirus seroprevalence among adults in the prevaccine era in Germany — Results from a nationwide population-based survey

Loenenbach

Poethko‐Müller

Pawlita

et al. 2019

International Journal of Infectious Diseases

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nationally representative study including men and women aged 18-79 years, were tested for antibodies to 19 mucosal and cutaneous HPV types. Multivariable regression models were developed to identify associations between demographic and behavioral characteristics and HPV seropositivity. Results: Of the 6517 serum samples tested, almost a quarter was seropositive for at least one of the nine HPV vaccine types with no clear age-pattern. HPV-6 and HPV-59 were the most common mucosal types, while HPV-1 and HPV-4 were the most common cutaneous HPV types. Factors independently associated with HPV-16 seroprevalence were seropositive to other sexually transmitted infections and lifetime number of sex partners, as well as urbanity (only among females). Conclusions: Prevalence of naturally acquired antibodies to HPV types which can be prevented by vaccination is high in both sexes and all age groups. These data can serve as baseline estimates to evaluate the population-level impact of the current vaccination strategy. sexually transmitted infections; STI+, seropositivity for at least one of the following sexually transmitted infections: Mycoplasma genitalium (Mg), Herpes simplex 2 (HS2), Chlamydia trachomatis (Ct).

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Molecular Mechanisms of Human Papillomavirus Induced Skin Carcinogenesis

Cited by 63 publications

References 72 publications

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

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

An Emerging Issue in Oncogenic Virology: the Role of Beta Human Papillomavirus Types in the Development of Cutaneous Squamous Cell Carcinoma

Mucosal and cutaneous Human Papillomavirus seroprevalence among adults in the prevaccine era in Germany — Results from a nationwide population-based survey

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