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

Abstract

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...

Human Papillomavirus and carcinogenesis: Novel mechanisms of cell communication involving extracellular vesicles

“…Experiments in animal models have further corroborated the in vitro data and provided clear evidence for the cooperation of the viral proteins with UV radiation in promoting SCC. Importantly, the in vivo models consisting in transgenic mice harbouring E6 and E7 of beta-types confirmed the hypothesis of the "hit-and-run" mechanism of HPV in the UV-mediated skin carcinogenesis [6][7][8][9][10]. The beta1 types, HPV5 and HPV8, are classified as 'possibly carcinogenic' in the IARC classification (International Agency for Research on Cancer) of carcinogenetic substances.…”

The Role of Beta HPV Types and HPV-Associated Inflammatory Processes in Cutaneous Squamous Cell Carcinoma

“…Beta HPV types are acquired soon after birth, especially through the direct contact of the child with his parents. The main risk factors for beta HPV infection are organ transplant, a positive history for sunburns and old age [28]. The first reports regarding the association of HPV infection with skin cancer date from 1920s when the first case of EV was described.…”

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

“…The "hit and run" hypothesis presents a challenge for epidemiologists that is further compounded by the fact that neither β-HPV infections nor NMSCs are rare. In fact, most people are sero-positive for at least one β-HPV and there are millions of NMSCs diagnosed each year [19][20][21]. The purposed link between β-HPV and NMSCs is best characterized in individuals with Epidermodysplasia verruciformis (EV), a genetic disease that is associated with an increased susceptibility to HPV infections, and in solid organ transplant recipients [22][23][24].…”