Several studies have suggested the involvement of cutaneous human papillomaviruses (HPVs) in the development of nonmelanoma skin cancers. Here we have characterized the in vitro properties of E7 proteins of three cutaneous HPV types, 10, 20, and 38, which are frequently detected in skin specimens. We show that HPV38 E7 is able to inactivate the tumor suppressor pRb and induces loss of G 1 /S transition control, a key event in carcinogenesis. In contrast, HPV10 and HPV20 E7 proteins do not display these in vitro transforming activities. We also show that the two early proteins E6 and E7 of HPV38 are sufficient to corrupt the cell cycle and senescence programs in primary cells, inducing active and long-lasting proliferation of primary human keratinocytes, the natural host cells. Our study shows that E6 and E7 of this cutaneous HPV type have transforming activity in primary human cells, suggesting a role for HPV38 infection in skin carcinogenesis. In further support of such a role, we detected HPV38 DNA in approximately 50% of nonmelanoma skin cancers, but only in 10% of healthy skin specimens (P < 0.001).Nonmelanoma skin cancer is the most frequently occurring malignancy in the Caucasian population (34,38,47). Although these cancers have a good prognosis and are not normally associated with mortality, an increasing incidence of other invasive cancers and cancer mortality following nonmelanoma skin cancers has been reported (17,24,28,29). Several lines of evidence suggest the involvement of an infective agent in the etiology of this condition. Patients suffering from a rare genetic immune suppression termed epidermodysplasia verruciformis and individuals under long-lasting immunosuppression are prone to develop these cancers (21,22,30,37). Epidermodysplasia verruciformis patients are highly susceptible to human papillomavirus (HPV) infections by a specific subgroup of cutaneous HPVs, the so-called epidermodysplasia verruciformis types (e.g., HPV5 and HPV8), that lead to extensive verrucosis of confluent flat warts (22,30,37). In approximately 30% of cases, the HPV lesions develop into multifocal squamous cell carcinomas.Supporting the infectious role of cutaneous HPV types in the tumorigenesis of nonmelanoma skin cancers is the fact that other members of the papillomavirus family are clearly oncogenic (55). Indeed, clinical, epidemiological, and molecular data have demonstrated that mucosal high-risk HPV types (e.g., high-risk HPV16 and HPV18) are the etiological agents of anogenital cancers as well as a subgroup of head and neck cancers (55). The early region of these HPV types encodes two oncoproteins, E6 and E7, which associate with and neutralize the cellular tumor suppressors p53 and retinoblastoma (pRb), respectively (32,36).Independent studies suggest that cutaneous HPV types may also be involved in the development of squamous cell carcinoma and basal cell carcinomas in the general population (6,7,14,43). These indications are based only on studies assessing viral DNA presence in skin tumors by PCR, which ha...

Objective-In Canada, opportunistic screening programs have successfully reduced mortality from cervical cancer; however, minority or disadvantaged groups, as well as women in northern and rural areas, are inadequately recruited by this approach. Hence, we set out to examine the structural barriers that prevent First Nations women's participation in cervical cancer screening.Methods-Using a participatory action research approach and semistructured interview guides, we conducted in-depth interviews with 18 experienced health care professionals, 12 of whom were also community members. These individuals included nurses, nurse practitioners, community health representatives, social workers and physicians who provide care to women in our First CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptNations partner communities. In the current report, we explored perceived barriers to cervical cancer screening through the lens of service providers.Results-Structural barriers to cervical cancer screening for First Nations women included shortage of appropriate health care providers, lack of a recall-based screening system, geographic and transportation barriers; health literacy and socioeconomic inequalities, generational effects, and the colonial legacy.Conclusion-Existing, opportunistic cervical cancer screening programs do not perform well for First Nations women who experience significant screening-related health inequalities that are largely influenced by structural barriers. Sustainable screening interventions in First Nations communities require approaches that resolve these structural barriers, explore new ways of screening, and provide education for both women and health care providers. Many of the structural barriers are rooted in colonial history. Given the negative impact of the consequences of colonization on indigenous women worldwide, many of our findings strongly resonate with marginalized populations in other countries.

For the p53 Special IssueFunctional loss of the tumor suppressor p53 by alterations in its TP53 gene is a frequent event in cancers of different anatomical regions. Cervical cancer is strongly linked to infection by high-risk human papillomavirus (HPV) types. The viral oncoprotein E6 has the ability to associate with and neutralize the function of p53. E6 interacts with a 100-kDa cellular protein, termed E6 associated protein (E6AP; also called ubiquitin-protein ligase E3A or UBE3A), which functions as an ubiquitin protein ligase. The dimeric complex then binds p53 and E6AP catalyzes multi-ubiquitination and degradation of p53. The ability to promote p53 degradation is an exclusive property of E6 from the high-risk HPV types. Indeed, the low-risk E6 proteins lack this activity, although they can bind p53. Consistent with the E6 function of the high-risk HPV types, the majority of cervical cancer cells have a wild-type p53 gene, but the protein levels are strongly decreased. Several independent studies have shown that in a small percentage of cervical tumors the p53 gene is mutated. However, this event appears to be unrelated to the presence or absence of HPV infection and the nature of the tumor. Hum Mutat 21:307-312,

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