Viral oncogenesis and its role in nonmelanoma skin cancer

Arron, Sarah T.; Jennings, L.; Nindl, Ingo; Rösl, Frank; Bavinck, Jan Nico Bouwes; Seckın, Denız; Trakatelli, M.; Murphy, Gillian

doi:10.1111/j.1365-2133.2011.10322.x

Cited by 61 publications

(30 citation statements)

References 169 publications

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“…In normal cells, UVR upregulates cellular defense processes leading to p53 activation, cell cycle arrest, apoptosis, or DNA repair. Several βPV types (eg, HPV5, HPV8, HPV38, and HPV49) deregulate these crucial cellular regulatory pathways by targeting multiple transcription factors and/or transcriptional regulators, resulting in infected cells that are highly susceptible to chromosomal instability and malignant transformation by UVR 9, 15, 43. Synergy between βPV and UVR has also been documented in animal models.…”

Section: Discussionmentioning

confidence: 99%

Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study

Bavinck

Feltkamp

Green

et al. 2018

American Journal of Transplantation

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Organ transplant recipients (OTRs) have a 100‐fold increased risk of cutaneous squamous cell carcinoma (cSCC). We prospectively evaluated the association between β genus human papillomaviruses (βPV) and keratinocyte carcinoma in OTRs. Two OTR cohorts without cSCC were assembled: cohort 1 was transplanted in 2003‐2006 (n = 274) and cohort 2 was transplanted in 1986‐2002 (n = 352). Participants were followed until death or cessation of follow‐up in 2016. βPV infection was assessed in eyebrow hair by using polymerase chain reaction–based methods. βPV IgG seroresponses were determined with multiplex serology. A competing risk model with delayed entry was used to estimate cumulative incidence of histologically proven cSCC and the effect of βPV by using a multivariable Cox regression model. Results are reported as adjusted hazard ratios (HRs). OTRs with 5 or more different βPV types in eyebrow hair had 1.7 times the risk of cSCC vs OTRs with 0 to 4 different types (HR 1.7, 95% confidence interval 1.1‐2.6). A similar risk was seen with high βPV loads (HR 1.8, 95% confidence interval 1.2‐2.8). No significant associations were seen between serum antibodies and cSCC or between βPV and basal cell carcinoma. The diversity and load of βPV types in eyebrow hair are associated with cSCC risk in OTRs, providing evidence that βPV is associated with cSCC carcinogenesis and may present a target for future preventive strategies.

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Section: Discussionmentioning

confidence: 99%

Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study

Bavinck

Feltkamp

Green

et al. 2018

American Journal of Transplantation

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“…The role of HPV in cutaneous SCC, as well as BCC, is less clear, although recent studies have found more significant associations 11,13,24–28 . Immunosuppressed populations have higher rates of HPV infection, and in the absence of large prospective studies, it is difficult to identify whether the immunosuppression or the viral infection is the etiologic factor 11,13,26,28 . Further clouding the picture is the stronger association between the two in those with a greater sensitivity to UVR 29 .…”

Section: Skin Cancer and Oncogenic Virusesmentioning

confidence: 99%

“…The association between multiple cancers and HPV is well established 13,22,23 . The role of HPV in cutaneous SCC, as well as BCC, is less clear, although recent studies have found more significant associations 11,13,24–28 .…”

Section: Skin Cancer and Oncogenic Virusesmentioning

confidence: 99%

“…The strongest associations between HPV and NMSC, and SCC in particular have been <4.0 29 , with most others reporting point estimates to be <2.0 11,13,25,28 . The large number of HPV serotypes and differences in measuring infection have made it difficult to draw firm conclusions regarding a causal association 11,13,27,30 . As OTRs are increasingly vaccinated against HPV, it remains to be seen whether there will be a decrease in NMSC rates in this population 31 .…”

Section: Skin Cancer and Oncogenic Virusesmentioning

confidence: 99%

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Skin cancer in organ transplant recipients: More than the immune system

Wheless

Jacks

Potter

et al. 2014

Journal of the American Academy of Dermatology

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Organ transplant recipients (OTRs) are at increased risk of developing non-melanoma skin cancers (NMSC). This has long been thought to be due to immunosuppression and viral infection. However, skin cancer risk among individuals with AIDS or iatrogenic immunodeficiency does not approach the levels seen in OTRs, suggesting other factors play a critical role in oncogenesis. In clinical trials of OTRs, switching from calcineurin inhibitors to mammalian Target of Rapamycin (mTOR) inhibitors consistently led to a significant reduction in the risk of developing new skin cancers. New evidence suggests calcineurin inhibitors interfere with p53 signaling and nucleotide excision repair. These two pathways are associated with NMSC, and squamous cell carcinoma (SCC) in particular. This finding may help explain the predominance of SCC over basal cell carcinoma in this population. mTOR inhibitors do not appear to impact these pathways. Immunosuppression, viral infection, and impaired DNA repair and p53 signaling all interact in OTRs to create a phenotype of extreme risk for NMSC.

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“…Beta HPV types are suspected to play a role, together with UV radiation, in the development of nonmelanoma skin cancer, the most common cancer among Caucasians (9,13,14). In vitro and in vivo mouse models have revealed that E6 and E7 from certain beta HPV types have the ability, like those from the high-risk alpha HPV types, to deregulate molecular pathways related to cell survival, proliferation, and apoptosis The UVB-irradiated (ϩ) and nonirradiated (Ϫ) hTERT PHKs were processed for the oligonucleotide pulldown assay.…”

Section: Discussionmentioning

confidence: 99%

UV Radiation Activates Toll-Like Receptor 9 Expression in Primary Human Keratinocytes, an Event Inhibited by Human Papillomavirus 38 E6 and E7 Oncoproteins

Pacini

Ceraolo

Venuti

et al. 2017

J Virol

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Several lines of evidence indicate that cutaneous human papillomavirus (HPV) types belonging to the beta genus of the HPV phylogenetic tree synergize with UV radiation in the development of skin cancer. Accordingly, the E6 and E7 oncoproteins from some beta HPV types are able to deregulate pathways related to immune response and cellular transformation. Toll-like receptor 9 (TLR9), in addition to playing a role in innate immunity, has been shown to be involved in the cellular stress response. Using primary human keratinocytes as experimental models, we have shown that UV irradiation (and other cellular stresses) activates TLR9 expression. This event is closely linked to p53 activation. Silencing the expression of p53 or deleting its encoding gene affected the activation of TLR9 expression after UV irradiation. Using various strategies, we have also shown that the transcription factors p53 and c-Jun are recruited onto a specific region of the TLR9 promoter after UV irradiation. Importantly, the E6 and E7 oncoproteins from beta HPV38, by inducing the accumulation of the p53 antagonist ΔNp73␣, prevent the UV-mediated recruitment of these transcription factors onto the TLR9 promoter, with subsequent impairment of TLR9 gene expression. This study provides new insight into the mechanism that mediates TLR9 upregulation in response to cellular stresses. In addition, we show that HPV38 E6 and E7 are able to interfere with this mechanism, providing another explanation for the possible cooperation of beta HPV types with UV radiation in skin carcinogenesis.IMPORTANCE Beta HPV types have been suggested to act as cofactors in UVinduced skin carcinogenesis by altering several cellular mechanisms activated by UV radiation. We show that the expression of TLR9, a sensor of damage-associated molecular patterns produced during cellular stress, is activated by UV radiation in primary human keratinocytes (PHKs). Two transcription factors known to be activated by UV radiation, p53 and c-Jun, play key roles in UV-activated TLR9 expression. The E6 and E7 oncoproteins from beta HPV38 strongly inhibit UV-activated TLR9 expression by preventing the recruitment of p53 and c-Jun to the TLR9 promoter. Our findings provide additional support for the role that beta HPV types play in skin carcinogenesis by preventing activation of specific pathways upon exposure of PHKs to UV radiation.KEYWORDS UV radiation, Toll-like receptor 9, HPV38, primary keratinocytes, p53

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Viral oncogenesis and its role in nonmelanoma skin cancer

Cited by 61 publications

References 169 publications

Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study

Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study

Skin cancer in organ transplant recipients: More than the immune system

UV Radiation Activates Toll-Like Receptor 9 Expression in Primary Human Keratinocytes, an Event Inhibited by Human Papillomavirus 38 E6 and E7 Oncoproteins

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